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Herbal medicinal products affecting memory and cognitive disorders

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October 11, 2010 at 7:45 am

Effect of herbal medicinal products on neurotransmission and enhancing cognition

Herbal medicinal products have played a pivotal role in development of CNS-active drugs that affect neurotransmissions in the brain. The interest of CNS-active herbal medicinal products originated from opioid alkaloids, e.g. morphine from Papaver somniferum and the tropane alkaloid cocaine from Erythroxylon coca. Anticholinesterase agents such as physostigmine from Physostigma venosum have shown significant activity on the CNS. This chapter deals with various medicinal plants, and compounds derived from them, which affect neurotransmission related to behaviour and memory dysfunction.

Acorus calamus L. (sweet flag, calamus)

Acorus calamus L. (Araceae) is a semi-aquatic, perennial, aromatic herb with creeping rhizomes. In Ayurveda, herbal medicines with rasayana effects (plants having adaptogen-like properties) are believed to be restorative, to attain longevity, intelligence and freedom from age-related disorders. Acorus calamus is regarded in Ayurvedic medicine as promoting rasayana effects and has been used to treat memory loss. Acorus calamus is used in Ayurvedic medicine on a regular basis for the treatment of loss of memory and other mental disorders. Acorus calamus extract has also been used as a traditional Chinese prescription and its beneficial effects on memory disorder, on learning performance, lipid peroxide content and anti-ageing effect in senescence have been reported. The in-vitro acetylcholinesterase inhibitory effect of hydroalcoholic extract and essential oil of Acorus calamus rhizomes has been reported, based on Ellman’s method. The essential oil showed stronger inhibition than the hydroalcoholic extract. Methanol extracts of Acorus calamus showed significant acetylcholinesterase enzyme inhibition at the concentration 200 µg/mL. Mukherjee et al. (2007) reported the in-vitro acetylcholinesterase inhibitory effect of β-asarone and α-asarone from the Acorus calamus. β-Asarone is at least an order of magnitude more active than its trans isomer α-asarone, so the acetylcholinesterase-inhibitory activity of the oil can be ascribed to β-asarone. Since cognitive performance and memory are related to acetylcholine levels, the acetylcholinesterase-inhibitory effect of the plant may account for its traditional use.

Albizia lebbeck Benth. (lebbeck)

Albizia lebbeck Benth. (Mimosaceae), is a well-known Indian medicinal plant and it has been reported to possess nootropic activity. The saponin-rich n-butanol fraction separated from leaves of Albizia lebbeck has been shown to affect the normal and impaired memory function in rats. Semi-purified saponins at doses of 10, 25 and 50 mg/kg, when administered orally, enhanced the learning and memory of normal and amnesic rats induced by scopolamine. Administration of 10 and 25 mg/kg of the saponin-containing butanol fraction increased the step-down latencies in acquisition and retention period as measured by inflexion ratio on the second and ninth day at levels comparable with the standard nootropic agent piracetum (100 mg/kg) tested in both the passive avoidance ‘step-through test’ using a passive avoidance chamber and the elevated plus maze test.

The nootropic effect of the natural saponins was correlated with concentrations of various neuro-chemicals of the rat brain, since dopamine and GABA levels decreased, and serotonin and noradren-aline increased in the Albizia lebbeck-tteated mice. The memory-enhancing property of the saponin fraction from Albizia lebbeck is considered to be due to inhibition of GABA and enhancement of noradrenaline in the brain. Three active albizia saponins A, B, and C were isolated and identified.

Amaranthus paniculatus L. (amaranth)

Amaranthus paniculatus L. (Amaranthaceae) is said to overcome the problems of psychological stress and affordability and its effects have been tested in stress-induced memory dysfunction. Stress was induced by gamma radiation in mice and methanolic extract of Amaranthus paniculatus at a dose of 600 mg/kg and 800 mg/kg was administered orally for 15 days. It was observed that mice supplemented with the extract, and trained in Hebb William’s maze model D, took less time to reach the goal than those without any treatment. The mice treated with Amaranthus paniculatus were further exposed to gamma radiation by 60Co-beam therapy; the surviving mice took less time to reach their goals than those without plant extract. This finding is explained by presuming that mice supplemented with Amaranthus paniculatus have a lower concentration of free radicals formed by the radiation stress and so less damage occurs to the relevant parts of the brain, therefore leading to sustenance of the learning ability even after irradiation. The study has been correlated with the antioxidative property of nutrients and their effect on maintaining cholinergic neurone integrity, which is essential for maintaining the learning and memory process.

Azadirachta indica A. Juss. (neem)

Azadirachta indica (Meliaceae) is a well-known traditional herb in India and is reported to exert therapeutic effects relating to the CNS. Azardirachitin is a major constituents found in neem. The aqueous extract of leaves at the dose of 500 mg/kg for 7 days significantly improved the memory, which was impaired by cerebral hypoperfusion inducing ischaemic insult. The memory task of the ischaemic rats was tested after 2 weeks of hypoperfusion period in the Morris water maze. The aqueous extract from Azadirachta indica significantly prevented the delay in escape latencies and increased the acquisition memory of rats.

Bacopa monniera L. (brahmi)

Bacopa monnieri L. (Scrophulariaceae) has a long history of use in India as an anti-ageing and memory-enhancing ethnobotanical therapy. It has been mentioned in religious, social and medical treatises of India since the time of Atharvan Ved (800 BC); the first clear reference to its CNS effect is to be found in Charak Sambita, written in the first century AD. It is mentioned in the authentic Ayurvedic treatise, Susrutu Sambita, which describes brahmi as efficacious in the loss of intellect and memory.

The alcoholic extract of brahmi showed a beneficial effect on the acquisition, consolidation and retention of three newly acquired behavioural responses in albino rats. Alcoholic extract of brahmi (40 mg/kg) and its two important chemical constituents, bacosides A and B (10 mg/kg), were investigated for shock-motivated brightness discrimination reaction, active conditioned avoidance and conditioned taste aversion response. Preadministration for 3 days with bacosides A and B significantly improved the acquisition, consolidation and retention in all three behavioural paradigms. Beside this effect bacosides attenuated the retrograde amnesia produced by immobilisation-induced stress, and scopolamine.

In another experiment, standardised Bacopa monniera extract was concluded to be beneficial in animal models of Alzheimer’s disease and elevated levels of their central cholinergic markers such as choline acetyltransferase and acetylcholine. Chronic administration of Bacopa monniera given orally for 12 weeks improved the speed of early information processing, verbal learning rate and memory consolidation in humans. This finding supported previous preclinical animal studies and clinical studies in children and patients with anxiety neurosis. Bacopa monniera interferes with cholinergic transmission and also has some serotonergic modulation.

Celastrus paniculatus Willd. (staff tree)

Celastrus paniculatus (Celastraceae) seeds and seed oil have been used in Ayurvedic medicine for stimulating intellect and sharpening the memory. It has been reported to have beneficial effects in psychiatric patients. Administration of the seed oil, rich in sesquiterpenes, to rats also reversed a scopolamine-induced memory deficit assessed in navigational memory performance, but this effect was not associated with acetylcholinesterase activity. The seed oil (3 g/kg) significantly improved the retention ability of the drug-treated rat passive avoidance paradigm and decreased levels of noradrenaline, dopamine, serotonin and their metabolites. Beside this, the memory-enhancing effect of Celastrus paniculatus was correlated with the antioxidant-enhancing effect of the drug on brain tissue. These data indicate that Celastrus paniculatus oil causes an overall decrease in the turnover of the three central monoamines and implicates the involvement of these aminergic systems in the learning and memory process.

Centella asiatica L. (gotu kola)

Centella asiatica (Umbelliferae) is a reputed ancient Ayurvedic remedy to enhance memory and longevity. The pharmacological basis to explain the reputed anti-amnesic effects of Centella asiatica has been explored experimentally. Studies have shown that the alcoholic extract has a tranquillising effect in rats, which was attributed to α-triterpene and brahmoside. Centella asiatica ethanolic extract was also found to elicit a marked increase in neurite outgrowth in human SH-SY5Y cells in the presence of nerve growth factor. Asiatic acid in Centella ethanolic extract showed marked activity at 1 µg/mL. Neurite elongation by Asiatic acid was completely blocked by the extracellular-signal-regulated kinase (ERK) pathway inhibitor PD 098059 (10 urnol/L). Male Sprague-Dawley rats given Centella ethanolic extract in their drinking water (300-330 mg/kg daily) demonstrated more rapid functional recovery and increased axonal regeneration (larger-calibre axons and greater numbers of myelinated axons) compared with controls, indicating that the axons grew at a faster rate. Further studies showed that the extract of Centella asiatica leaf possessed cholinomimetic action in vivo and that it may also influence cholinergic activity, and thus cognitive function.

Cognitive-enhancing effects have been observed in rats following oral administration of an aqueous extract of Centella asiatica, this effect being associated with an antioxidant mechanism in the CNS. The essential oil from Centella asiatica leaf contains monoterpenes, e.g. α-pinene, β-pinene and γ-terpinene, which are reported to inhibit acetylcholinesterase. However, monoterpene acetylcholinesterase inhibitors are weak compared with the anticholinesterase alkaloid, physostigmine. In view of the relatively weak anticholinesterase activity of monoterpenes reported to date, it is unlikely that they would be therapeutically effective in cognitive disorders. Asiatic acid, a triterpene from Centella asiatica (L.) has been patented as a treatment for dementia and an enhancer of cognition by Hoechst (EP 0 383 171 A2).

Clitoria ternatea L.

The root of the Indian medicinal plant Clitoria ternatea (Fabaceae) has a reputation for promoting intellectual behaviour. Clitoria ternatea contains the triterpenes taraxerol and taraxerone as major phytoconstituents. Administration of Clitoria ternatea root extract to rats showed an increase in acetylcholine and choline acetyltransferase in rat brain and they were shown to increase the acetylcholinesterase activity in cortical regions. An aqueous extract of the root also increased acetylcholine levels in rat hippocampus, and it was hypothesised that this effect may be due to an increase in acetylcholine synthesis.

Coptis chinensis Franch.

Coptis chinensis (Ranunculaceae) has been used in traditional Chinese medicine for several conditions. Studies have shown that methanol extract fraction of Coptis chinensis improved scopolamine-induced learning and memory deficit in rats. The contained alkaloids berberine and palmatine have been shown to possess acetylcholinesterase inhibition in vitro.

Curcuma longa L. (turmeric)

Curcuma longa (Zingiberaceae) has also been used for culinary purposes. Turmeric has several components with immunomodulatory and antioxidant properties. Curcumin, an antioxidant present in turmeric, has been shown to protect the brain in vivo from ethanol-induced oxidative stress. It modulated glutathione-linked detoxification enzymes and reduced the lipid peroxidation in rat brain under oxidative stress. Some compounds from C. longa, including curcumin, demethoxycurcumin, bisdemethoxycurcumin and calebin-A (and some of its synthetic analogues), were shown to protect PCI 2 cells from β-amyloid insult in vitro, and this activity was suggested to be due to an antioxidant effect.

In another study using a rat intraventricular Aβ infusion model, curcumin at a dose of 25 mg/kg reduced the isoprostane index of oxidative damage, amyloid plaque burden and Aβ-induced spatial memory deficits in the Morris water maze in rats. Curcumin has been shown to lower the oxidised proteins and interleukin-1β in the transgenic mouse model of Alzheimer’s disease.

Ocimum sanctum L. (tulsi)

In Ayurveda, Ocimum sanctum (Lamiaceae) is described as rasayana. These Ayurvedic rasayanas have been reported in literature to improve physical and mental health, increase non-specific resistance of body, promote physiological functions and augment cognition. The aqueous extract of leaves of Ocimum sanctum at a dose of 500 mg/kg for 7 days significantly improved memory in rats, which was impaired by cerebral hypoperfusion-induced ischaemic insult. The memory task of the ischaemic rats was tested after 2 weeks of hypo-perfusion period in the Morris water maze and those treated with Ocimum sanctum extract had delayed escape latencies. This effect was correlated with their ability to reduce the lipid peroxidation, superoxide dismu-tase and increase in tissue sulphydryl groups and ascorbic acid contents of the hypoperfused brain tissue.

Panax ginseng C.A. Mey. (ginseng)

Interest in the use of Panax ginseng (Araliaceae) comes from its purported ‘adaptogen’ or ‘tonic’ activity, which is thought to increase the body’s capacity to tolerate external stresses, leading to increased physical or mental performance. Panax ginseng alone was tested in young (3 months) and old (26 months) rats, on a battery of negatively reinforced learning tests (two-way active avoidance; passive avoidance/step-down; passive avoidance/step-through), and on the Morris water maze. Ginseng (17, 50, 150 mg/kg), administered orally to young rats, increased the number of avoidance responses in the two-way passive avoidance test at all doses tested.

Although an extensive literature documenting adaptogenic effects in laboratory animal systems exists, results from human clinical studies are conflicting and variable. However, there is evidence that extracts of ginseng can have an immunostimulatory effect in humans, and this may contribute to the adaptogen or tonic effects of these plants. The major secondary products present in ginseng roots are an array of triterpene saponins, collectively called ginsenosides. The ginsenosides, of which there are at least 30, glycosylated derivatives of two major aglycones, panaxadiol and panaxatriol, are considered to be the most relevant for pharmacological activity. From laboratory studies, it has been suggested that the pharmacological target sites for these compounds involve the hypothalamus-pituitary-adrenal axis, owing to the observed effects on serum levels of adrenocorticotrophic hormone and corticosterone.

Salvia species (sage)

Several species of Salvia (Lamiaceae) have been reported to have potential activity in CNS.

Al-Yousuf et al. (2002) reported that Salvia aegyptiaca L. is used for treating various unrelated conditions that include nervous disorders, dizziness and trembling. This work examines some effects of the crude acetone and methanol extracts of the plant given at single oral doses of 0.25, 0.5, 1 or 2 g/kg, on the CNS in mice. It is concluded that the crude methanol and acetone extracts of Salvia aegyptiaca have CNS depressant properties, manifested as antinociception and sedation.

Perry et al. (2002) reported that Salvia lavandulaefolia Vahl. (Spanish sage) extracts and constituents have demonstrated anticholinesterase, antioxidant, anti-inflammatory, oestrogenic and CNS depressant (sedative) effects, all of which are currently relevant to the treatment of Alzheimer’s disease. The essential oil inhibits the enzyme acetylcholinesterase from human brain tissue and bovine erythrocyte and individual monoterpenoid constituents inhibit acetylcholinesterase with varying degrees of potency.

In a study in healthy volunteers, essential oil administration produced significant effects on cognition. In a pilot open-label study involving oral administration of the essential oil to patients with Alzheimer’s disease, a significant increase in diastolic and systolic blood pressure was observed in two patients; however, this may have been due primarily to pre-existing hypertension and there were no abnormalities in other vital signs or blood samples during the trial period.

Salvia elegans Vahl, popularly known as mirto, is a shrub that has been widely used in Mexican traditional medicine for the treatment of different CNS diseases, principally anxiety.

The antidepressant and anxiolytic-like effects of hydroalcoholic (60%) extract of Salvia elegans (leaves and flowers) have been reported in mice. The extract, administered orally, was able to increase the percentage of time spent and the percentage of arm entries in the open arms of the elevated plus maze, as well as to increase the time spent by mice in the illuminated side of the light-dark test, and to decrease the immobility time of mice subjected to the forced swimming test. The same extract was not able to modify the spontaneous locomotor activity measured in the open-field test. These results provide support for the potential antidepressant and anxiolytic activity of Salvia elegans. Wake et al. (2000) also reported that S. elegans displayed differential displacement at nicotinic and muscarinic acetylcholine receptors, with the highest [3H](N)-scopolamine displacement.

In a double-blind, placebo-controlled, crossover study, 30 healthy participants received a different treatment in counterbalanced order on each occasion (placebo, 300, 600 mg dried sage leaf). On each day mood was assessed before the dose and at 1 h and 4 h afterwards. Both doses of sage led to improved ratings of mood in the absence of the stressor (that is, in pre-DISS mood scores) post-dose, with the lower dose reducing anxiety and the higher dose increasing ‘alertness’, ‘calmness’ and ‘contentedness’ on the Bond-Lader mood scales. Task performance was improved for the higher dose at both post-dose sessions, but reduced for the lower dose at the later testing session.

Withania somnifera L. (ashwagandha)

Withania somnifera (Solanaceae) root is one of the most highly regarded herbs in Ayurvedic medicine. Withania somnifera, an Ayurvedic rasayana (memory-facilitating drug), was shown to attenuate amnesic effects in animal models of Alzheimer’s disease by reversal of cholinergic dysfunction induced by ibotenic acid. Ayurvedic formulations based on Withania somnifera induced a similar amnesia-reversal effect in rats. The steroidal derivatives sitoindosides IX and from Withania somnifera, augmented learning acquisition and memory in both young and old rats. The root extract of Withania somnifera reversed scopolamine-induced disruption of acquisition and attention and attenuated amnesia following electroconvulsive shock in mice. These effects are attributed to nootropic activity.

The mechanism of this memory-enhancing effect is attributed to enhanced acetylcholinesterase activity and reversed the ibotenic acid altered cholinergic marker such as acetylcholine and choline acetyl transferase. Therefore preferential action is on cholinergic neurotransmission in the cortical and basal forebrain areas involved in cognitive function. In another experiment Withania somnifera (50 mg/kg) which contains sitoindosides VII-IX and withaferin A as the major bioactive entities, the relative abundance of these compounds in the extract being responsible for 28-30% significant enhancement of leaning as tested in passive avoidance test in chronically stressed rats.

Disorders of central nervous system | Tags: , , , , , , , , , , , , ,

Neurochemistry of cognition and cognitive dysfunction

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October 8, 2010 at 7:39 am

The human brain is very complex and is based on specialised cells designed to transmit information, called neurones. Neurones are an integral part and basic functional unit of the brain, which contains almost one billion of these cells. The neurones consists of a cell body containing a nucleus and an electricity-conducting fibre called an axon, which also gives rise to many branches before ending at nerve terminals. Neurones send signals by transmitting electrical impulses along their axons. When the signals reach the end of the axons, they trigger the release neurotransmitters, which then bind to receptors in adjacent neurones. This point of vital contact is called the synapse. The synaptic response involves the closing and opening of ion channels, which pass through the cell membranes and enable the ions to flow through them. This phenomenon creates an electrical current that provides tiny voltage changes across the membrane which leads to altered synaptic connectivity.

This network is capable of controlling a vast array of activities, including heart rate, body movement, perception, sexual function, emotions, learning and memory. The organisation and neurotransmitter content of intrinsic cerebral cortical and hippocampal neurones, and those of extrinsic inputs to these regions, are described below with respect to neuronal systems known to be affected in Alzheimer-type dementia. For the intrinsic neurones, particular attention is focused on the neuropeptides such as cholecystokinin, vasoactive intestinal polypeptide, somatostatin and neuropeptide Y, which are apparently stable post mortem and provide biochemical markers that can be used to judge the integrity of neuropeptide-containing cells in dementia.

Neurochemistry of cognition and cognitive dysfunction: cholinergic hypothesis

The first neurochemical was identified 70 years ago as acetylcholine. The neurones that release acetyl-choline are called cholinergic neurones and control the heartbeat and voluntary muscles, causing them to contract. Acetylcholine also serves as a neurotrans-mitter in many regions of the brain and plays an important role in learning and memory function. Mammalian brain contains several groups of cholinergic projection neurones located within the basal forebrain and brainstem. Cholinergic axons exert their neurotransmitter effect through the mediation of nicotinic and muscarinic receptors. Cholinergic neurones and cholinergic neurotransmitter pathways are highly implicated in cognition and cognitive dysfunction. The cholinergic neurones are centred on the medial septum, around the vertical limb of the diagonal band of Broca, around the horizontal limb of the diagonal band of Broca, and are also found around the nucleus basalis of Meynert.

All cholinergic neurones of the human basal fore-brain and brain stem contain the cholinergic enzymes choline acetyltransferase and acetylcholinesterase. Much of the research on the participation of neurotransmitter systems in cognitive decline associated with ageing and Alzheimer’s disease has concentrated on the role of acetylcholine, because of its correlation with the degree of cognitive dysfunction, and learning and memory deficits produced in humans, even though the role of interaction between acetylcholine and other neurotransmitters such as noradrenaline, dopamine, serotonin, γ-aminobutyric acid (GABA) and several neuropeptides affecting cognition are also important. To improve cholinergic transmission, different strategies have been suggested including increased acetylcholine synthesis, the augmentation of pre-synaptic acetylcholine release, and stimulation of postsynaptic acetylcholine muscarinic and nicotinic receptors and reduction of acetylcholine synaptic degradation with cholinesterase inhibitors. Several aspects of the functional features of the cholinergic system are shown in Figure: Functional features of the cholinergic system.

Figure: Functional features of the cholinergic system

Assessment of neurodegeneration

Animal models used for the assessment

Drugs effective in neurodegenerative disease should have several aims: to improve the cognitive impairment, control the behavioural and neurological symptoms, delay the progression of the disease and to prevent the onset. To attain these targets, cell and animal models are needed in which pathogenetic hypothesis and potential effectiveness of new drugs are to be tested, exploiting links between the molecular and biochemical studies on the disease and the reality of human pathology. Animal models of Alzheimer’s disease can provide insight into the neurological and pathological mechanisms of cognitive and behavioural changes in patients. Monitoring of behavioural changes in animal models could both provide insight into the neurobiology of these behavioural changes and help validate the felicity of the model to Alzheimer’s disease. Animal models will play a critical role in further defining the events and processes underlying the final phenotypic expression.

Aged animals models

Aged animals (rats, mice and monkeys) have been investigated on a variety of learning and memory tasks. Aged rodents have been shown to have memory impairment on tasks such as the Morris water maze and passive avoidance tests. This behavioural impairment has provided a model that resembles the neuropsychiatric symptoms commonly observed in Alzheimer’s disease. The senescence-accelerated mouse (SAM) exhibits age-related deficits in learning and memory in the Morris water maze and radial arm maze and decreased acetylcholine synthesis in hippocampus pyramidal neurones. The effect of nerve growth factor (NGF) on cognition of aged rats has been assessed by intraven-tricular infusion of NGF, delayed alternation, Morris water maze, and sensory motor tasks. NGF has been most thoroughly assessed in this setting and has shown effects in rats, which have provided a model for the assessment of cholin-ergic neurones and the cholinoprotective effects of compounds potentially useful in the treatment of Alzheimer’s disease.

Brain lesion models

In concert with the recognition of the importance of the cholinergic deficit in Alzheimer’s disease, early models of the disease concentrated on surgical or chemical lesions of the basal forebrain. Transection of the fornix results in degeneration of cholinergic cells in the basal forebrain. These experiments involved primarily rats, monkeys and baboons, which demonstrated deficits in attention and memory, tested in various maze paradigms such as passive active avoidance, Morris water maze and the eightarm radial arm maze. Lesion studies have focused primarily on the behavioural changes of the animals, with only limited attention to the pathological to the neuropsychiatric symptoms commonly observed in Alzheimer’s disease. Ageing studies are all likely to contribute information important to our understanding of the disease, and none are likely to represent a completely isomorphic model that is fully predictive of the pathogenesis, course, and treatment of human Alzheimer’s disease.

Amyloid beta protein infusion induced model of Alzheimer’s disease

Artificially created amyloid (AS) deposits in normal rats, and transgenic mice overexpressing amyloid precursor protein (APP) are the models in which possible treatments are tested. They are aimed at preventing formation of AS deposits or its transformation in neuritic plaques. Synthetic amyloid beta protein (Aβ1-42) application in vitro, using neuroglial and astrocytes, has also been used to screen various neuroprotective drugs. The injection of synthetic Aβ peptides β12-28, β25-35, and β1-40 into the septum of adult rats induced a marked decrease in basal and potassium-evoked acetylcholine release in the hippocampus. These findings confirmed in vivo the neurotoxic effects of Aβ observed in primary neuronal cell cultures exposed to Aβ peptides.

The multiple mechanisms through which Ap peptides, involving oxidative stress, loss of cellular calcium homeostasis and mitochondrial dysfunction have been reviewed and, in both in-vitro and in-vivo experiments, it has been shown that Aβ neurotoxicity depends on its fibrillary aggregation forming a sheet. These preclinical experiments give support to the hypothesis of the pivotal pathogenetic role of AS deposit in Alzheimer’s disease, throw some light on the molecular mechanisms of AS toxicity, and offer an experimental model for testing potentially useful drugs. Undoubtedly, there are limitations in the validity of intracerebral Ap injections as a model of Alzheimer’s disease.

Amyloid precursor protein transgenic mouse model

The development of transgenic mice, mimicking the genetic mutations occurring in familial Alzheimer’s disease and showing some of the neurochemical and morphological alterations of the disease, is another example of the interactions between clinical and preclinical investigations into this disease. The clinical and genetic investigations have identified the early-onset, familial forms of the disease, and the genes in which autosomal dominant mutations take place. There is a clear recognition of autosomal dominant cases induced by mutations of APP (chromosome 21), presenilin 1 (chromosome 14), or presenilin 2 (chromosome 1), which allowed development of transgenic mouse models of Alzheimer’s disease. These transgenic animals exhibit some of the pathological hallmarks of the disease, including neuritic plaques, although they have not evidenced neurofibrillary tangles and have limited cell death. These models facilitate investigation of the relationship of amyloid deposition to other aspects of the pathology of Alzheimer’s disease, including inflammation, hormonal levels, trophic factor influences, calcium metabolism, amino acid toxicity and apoptosis. However, there has been limited behavioural testing of transgenic mice, but impairments of memory have been reported on the Morris water maze, spatial reference memory and Y-maze alternation tasks.

Apolipoprotein knockout models

Cognitive tasks analogous to the deficits observed in human Alzheimer’s disease need to be developed for application to transgenic, knockout and other models currently used to investigate pathogenesis. Tests of language are obviously not applicable but assessment of attention, memory, spatial orientation and executive function are feasible. A variety of transgenic and knockout apolipoprotein models are available to screen novel molecules for the treatment of the disease. The E-4 allele of apolipoprotein (ApoE-4) confers an increased risk for Alzheimer’s disease and a decreased age of onset. Review of the cognitive testing and behavioural measures of the various available animal models reveals the impoverished state of these assessments and the need to develop new evaluation technologies.

Brain inflammation models

Epidemiological and clinical studies, reporting the efficacy of non-steroidal anti-inflammatory drugs (NSAIDs) in reducing the incidence and progression of Alzheimer’s disease, provided strong support for the critical involvement of inflammatory processes in the pathogenesis of the disease. Brain inflammation is considered to be a pathogenetic link in many neurodegenerative diseases, including Alzheimer’s disease. The long-term lipopolysaccharide (LPS) infusion into the fourth ventricle was followed by astrocyte activation, an increase in microglia cells, an increase in the levels of interleukin (IL)-1β, tumour necrosis factor (TNF)-α, APP mRNA and the degeneration of hippocampal neurones.

In-vitro screening methods for acetylcholinesterase inhibition

Several methods have been reported for the screening of acetylcholinesterase inhibitory activity from herbal medicinal products (HMPs). Acetylcholinesterase inhibition was initially detected by the use of gut-bath pharmacological methods with isolated tissue preparations such as guinea pig ileum. These methods are costly in several respects, including time, animal tissue and amounts of compound needed, so they have been replaced by more sensitive chemical methods. Consideration of the relative merits of various methods that might be useful in studying the time course of acetylcholinesterase activity in very small tissue samples use a combined method reported by Koelle (1951) with a sulphydryl reagent studied by Ellman (1959). This Ellman method is extremely sensitive and is applicable to either small amounts of tissue or to low concentrations of enzyme.

Figure: The detection of acetylcholinesterase activity by Ellman’s method.

The principle of this colorimetric method is the measurement of the rate of production of thio-choline, as acetylthiocholine is hydrolysed by the acetylcholinesterase enzyme. Thiocholine reacts with Ellman reagent [5,5'-dithiobis-(2-nitro-benzoic acid) (DTNB)] to produce 2-nitrobenzoate-5-mercaptothiocholine and 5-thio-2-nitrobenzoate (Figure: The detection of acetylcholinesterase activity by Ellman’s method). This product has a yellow chromophore that can be detected at 405 nm. The reaction with the thiol has been shown to be sufficiently rapid so as not to be rate limiting in the measurement of the enzyme, and in the concentrations used does not inhibit the enzymatic hydrolysis. The absorbance obtained using a standard volume of a known concentration of the substrate with a fixed dose of acetylcholinesterase is compared with that in the presence of an added compound or extract, a significant reduction indicating an inhibitory role for the substance added.

This visible spectroscopy procedure requires several millilitres of reaction mixture and it was sometimes difficult to obtain enough material to show an effect. The development of the method for use on a smaller scale, using microtitre well plates and a microplate reader, has been introduced and has enabled determinations to be performed with a much higher throughput. Microtitre plate assay method requires smaller amounts of reagents and test substances.

The Ellman reaction has also been adapted for thin-layer chromatography (TLC) bioautography assay for acetylcholinesterase inhibitory activity. The TLC plate is developed in the usual way. After development, enzyme-inhibitory activities of the developed spots were detected by spraying the substrate, dye and enzyme based on Ellman’s method. After incubating the plates, white spots on a yellow background showed inhibition of acetylcholinesterase. A false-positive test is carried out, to confirm any acetylcholinesterase-inhibiting activity arising from inhibition of thiocholine hydrolysis caused by the enzyme. To detect false-positive reactions, the plate is sprayed with substrate, dye and enzyme without test compounds. After a few minutes incubation, a yellow background appeared, the occurrence of white spots indicating false-positive reactions.

A similar method for TLC detection has been introduced by Marston et al. (2002), which uses acetylnaphthol as the substrate and measures the amount of naphthol, the reaction product formed, by its chromogenic reaction with Fast Blue B salt.

High-performance liquid chromatography (HPLC) with online coupled ultraviolet, mass spectrometric and biochemical detection methods for the identification of acetylcholinesterase inhibitors has also been developed. This uses a reverse-phase column with the column eluate being split into two streams, one with an ultraviolet detector and the other connected to a biochemical detection system. This latter system consisted of the eluant being mixed with acetylcholinesterase and DTNB before the online introduction of acetylthiocholine. The intensity of the reaction product was measured at 405 nm by means of a spectrophotometer as an indication of the amount of thiocholine-DTNB product formed. A HPLC method for the detection of acetylcholinesterase inhibition on immobilised acetylcholinesterase column and high-performance liquid chromatography with online coupled ultraviolet, mass spectrometric and biochemical detection for acetylcholinesterase inhibitory activity has also been reported.

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Herbal medicinal products for tinnitus

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September 18, 2010 at 4:57 pm

The nature of tinnitus

Tinnitus is a chronic, auditory disorder characterised by a ‘ringing’ or ‘buzzing’ in the ears. The two main subtypes of tinnitus are ‘objective’ and ‘subjective’ tinnitus: whereas ‘objective’ tinnitus can be heard by someone else and is usually associated with a vascular problem in the ear, ‘subjective’ tinnitus is an auditory illusion. While objective tinnitus can be treated by surgery, there is no known cure for subjective tinnitus. Subjective tinnitus can be caused by damage to the inner ear as a result of physical trauma, excessive noise, vascular insufficiency, a viral or bacterial infection, Meniere’s disease or exposure to ototoxic chemicals (e.g. aspirin or cancer chemotherapeutic agents such as cisplatin). Tinnitus can occur on its own or in combination with vestibular symptoms (e.g. as in Meniere’s disease). Either way, it is a debilitating condition that can affect all aspects of life and sometimes even leads to suicide. Parnes (1997) estimated that approximately 1 % of the population has chronic tinnitus that causes distress and that 90% of patients with hearing loss experience some tinnitus. Almost 40% of people aged 60 or over have tinnitus and as many as 50% of all tinnitus sufferers also have depression.

The mechanisms that underlie the development of subjective tinnitus are unclear. However, animal studies suggest that exposure to intense sound, resulting in cochlear hair cell damage, causes hyper-activity in the brainstem cochlear nucleus, which receives auditory information directly from the inner ear. Similar changes in cochlear nucleus neurones have been reported following outer hair cell loss as a result of treatment with cisplatin. Other studies have confirmed that this type of hyper-activity can be found in higher auditory centres in the brain, including the superior olive, the inferior colliculus and even the auditory cortex, following noise- or chemically induced trauma to the cochlea.

Such neuronal hyperactivity is similar to the epileptiform discharge that occurs in the trigeminal nucleus during trigeminal neuralgia and in the dorsal horn of the spinal cord during phantom limb pain, and it has therefore been suggested that subjective tinnitus is a form of sensory epilepsy. Consistent with this hypothesis, antiepileptic drugs are sometimes used to treat tinnitus. However, they are not always effective and can have serious adverse side-effects. For this reason, many other drugs have been tested and the search for more effective treatments continues. Because of the shortcomings of the conventional medications used to treat tinnitus, herbal remedies have been investigated, particularly Ginkgo biloba extracts. This chapter evaluates their efficacy and safety in comparison with other drug treatments.

Conventional medications for tinnitus

A diverse range of drugs has been used to treat tinnitus, but no single therapy is accepted by all clinicians. Only some of these drug treatment options are based on an understanding of the mechanisms of tinnitus; many others have been discovered serendipitously. Unfortunately, there are many spurious claims for clinical effects.

Intratympanic gentamicin therapy has been used to treat tinnitus associated with Meniere’s disease. Diamond et al. (2003) concluded that a subjective improvement in tinnitus occurred in approximately 57% of patients. Similarly, Lange et al. (2004) reported a significant reduction in tinnitus in 50% of patients treated with intratympanic gentamicin 2-4 years earlier. By contrast, a 5-year follow-up study of patients who had received intratympanic gentamicin therapy showed no significant effect on any hearing measure, even though 74% still reported complete relief from vertigo.

Other kinds of intratympanic drug therapy have been investigated. Sakata et al. (2001) used intratympanic injection of 4% lidocaine in an attempt to depress cochlear hair cell function and relieve tinnitus. Lidocaine relieved tinnitus in 81% of patients; however, vertigo developed as a result of the infusion. Intratympanic administration of steroids has also been used. Cesarani et al. (2002) studied 50 patients who received transtympanic infusion of dexamethasone, 3 times per day for 3 months. Two weeks after the last administration, tinnitus had disappeared in 34% of patients, 40% experienced a significant decrease in its intensity, and 26% reported no effect. Shulman and Goldstein (2000) also reported relief from tinnitus in 7 of 10 patients after intratympanic steroid therapy. Intratympanic administration of acetylcholinesterase inhibitors and acetylcholine receptor agonists has also been investigated, with varying success.

Because benzodiazepines activate the benzodiazepine-binding site on the GABAA receptor, increasing hyperpolarisation, benzodiazepine treatment is an obvious strategy to reduce neuronal hyperactivity associated with tinnitus. Benzodiazepines such as alprazolam have proven useful, but it is often difficult to determine how much of the therapeutic effect is attributable specifically to the relief of tinnitus and how much is due to a general anxiolytic effect.

The benzodiazepine antiepileptic drug, clonazepam, as well as the antiepileptic drugs gabapentin and phenytoin, have also been used to treat tinnitus. A retrospective survey of 25 years of clinical use suggested that tinnitus was improved in approximately 32% of patients treated with clonazepam. However, adverse side-effects, such as drowsiness, depression, nightmares and reduced libido, were reported in 16.9% of patients although they decreased with continued therapy.

Shulman et al. (2002) have argued that for patients with tinnitus of central origin, benzodiazepines can provide long-term relief in 90% of cases. In an imaging study using single photon emission computed tomography, Shulman et al. (2000) found that patients with severe tinnitus exhibited a reduction in benzodiazepine-binding sites in the medial temporal cortex, suggesting a possible neural basis for the therapeutic effects of benzodiazepines. By contrast, drugs that act as agonists at the GABAB receptor, such as baclofen, have not proven effective and have been associated with severe adverse side-effects.

Antidepressants have also been used to treat tinnitus. If tinnitus causes depression in a particular patient, then the relief of the depression will usually result in some relief from the tinnitus as well. This finding demonstrates that tinnitus is not just a sensory problem but a phenomenon that involves the entire CNS, including emotional areas of the brain such as the limbic system. Folmer and Shi (2004) studied 30 patients who developed depression after the onset of their tinnitus and received selective serotonin reuptake inhibitor therapy as treatment. At 20.6 months, the patients showed a statistically significant reduction in their tinnitus severity scores, which correlated with a decrease in their depressive symptoms.

One of the more unusual treatments for tinnitus is the intravenous administration of local anaesthetics, which was discovered in 1937. Although lidocaine was shown to reduce tinnitus, its in-vivo instability and adverse side-effects (e.g. nausea, dizziness, potentially fatal cardiovascular effects) have limited its use. There has been some controversy about whether lidocaine actually achieved its effects as a result of blocking sodium channels or as a result of some other non-specific effect of the drug, since other agents with similar actions have not produced the same effect.

Recently, there have been a number of reports of the use of systemically administered lidocaine for the treatment of tinnitus. Marzo et al. (2004) reported that intravenous lidocaine successfully treated incapacitating tinnitus caused by inner-ear tertiary syphillis. Savastano (2004) reported that intradermal injection of lidocaine relieved tinnitus with no adverse side-effects. Otsuka et al. (2003) reported that intravenous lidocaine relieved tinnitus either partially or completely in 70.9% of cases studied over a 24-year period. However, it is not clear how or where lidocaine is acting to achieve these effects, although recent studies using intratympanic injection suggest that it may be working either as a vasodilator or sodium-channel blocker in the inner ear.

Various other vasodilators have been investigated for the treatment of tinnitus but recent studies have failed to confirm their efficacy. Because prostaglandins stimulate vasodilation, the synthetic prostaglandin El (PGE1) analogue, misoprostol, has been investigated and found to be effective in relieving tinnitus in about 33% of patients. Yilmaz et al. (2004) studied 28 patients receiving misoprostol and 12 patients receiving placebo: 64% of the patients receiving misoprostol reported a reduction in tinnitus loudness (33% for placebo), with 33% showing an improvement according to their subjective tinnitus score (17% for placebo).

Finally, diuretics have been used to treat tinnitus associated with Meniere’s disease, which is believed to be caused by hypertension of the endolymphatic fluid. The loop diuretic, frusemide, has been effective in treating Meniere’s-associated tinnitus. However, other attempts to regulate osmotic pressure, using mannitol and glycerol, have had little success.

Herbal remedies

The published peer-reviewed literature on herbal medicines to treat tinnitus is dominated by the use of Ginkgo biloba extracts. From extensive PubMed and other database searches, we could find virtually no other published papers in peer-reviewed journals on the effects of herbal medicines in tinnitus.

Ginkgo biloba extracts

Ginkgo biloba (Ginkgoaceae) is an ancient Chinese tree that has been cultivated for thousands of years. Purified extracts, marketed under the trade names Rokan, Tanakan, Tebonin and Ginkgold, are used throughout the world, although they are especially popular in Europe and in the USA. Ginkgo biloba extracts have been licensed in Germany for the treatment of cerebral vascular insufficiency. They are available as over-the-counter medications in western Europe and as herbal preparations in the USA, Australia and New Zealand.

EGb-761 is a standardised extract containing 24% flavonoids, 7% proanthocyanid ins and 6% terpenoids. The flavonoids are mainly flavonol-glycosides with antioxidant properties, while the terpenoid fraction contains ginkgolides, sesquiter-pene and bilobalide. Ginkgolide B in particular has potent platelet-activating factor receptor antagonist properties. Many of the CNS effects of EGb-761 have been attributed to the combination of its antiox-idant and platelet-activating factor receptor antagonist actions. However, it is also a vasodilator, which might be the only rationale for speculating that it would be useful in the management of tinnitus.

Hilton and Stuart (2004) critically evaluated the clinical evidence for the efficacy of Ginkgo biloba in treating tinnitus and concluded that there were insufficient reliable data on which to base a conclusion, as a result of the methodological flaws of the available studies. Very few studies have used double-blind, placebo-controlled designs. Interestingly, when these sorts of controls have been employed, the results have usually been negative. In an effort to focus on the best-designed clinical trials, Ernst and Stevinson (1999) performed a meta-analysis of only those clinical trials that employed standardised Ginkgo extracts that were compared with either placebo or another active medication, and where the primary complaint was tinnitus. Only five trials fulfilled these criteria.

Meyer (1986) studied 103 patients with tinnitus using a randomised, double-blind, placebo-controlled design. Patients received EGb 761 (Tanakan) daily for 1-3 months and their tinnitus severity was assessed using a three-point scale. The EGb 761 group experienced a decrease in tinnitus severity but Ernst and Stevinson (1999) point out that the paper, available in French only, lacked a clear description of the methods used.

In another study, Meyer (1986) studied 259 patients with tinnitus over 1 year. Patients receiving EGb 761 (Tanakan) daily for at least 1 month were compared with those receiving nicergoline or almitrine-raubasine. According to a specialist analysis, tinnitus appeared to show greater improvement in the EGb 761 group compared with the other two treatments. However, Ernst and Stevinson (1999) criticised this study for lack of random allocation of patients to the different treatment groups and lack of methodological detail in the published report; for example, it was not clear whether the patients and experimenters were blind to the treatment groups.

Holgers et al. (1994) recruited 80 patients into an open trial in which all of them received a Ginkgo biloba extract daily (Seredrin). This was followed by a double-blind, placebo-controlled phase of the trial using only the 20 patients who appeared to respond to the extract. However, according to patients’ subjective reports, there were no significant effects of the Ginkgo biloba extract at the end of the trial.

Morgenstern and Bierman (1997) performed a randomised, double-blind study of 99 patients with chronic tinnitus, who received a Ginkgo biloba extract (Tebonin) or placebo daily for 12 weeks. The loud-ness of the tinnitus was evaluated using audiometry. They reported a significant reduction in loudness (from 42 to 39 dB) in the ginkgo-treated group. Juretzek (1998) treated 60 patients with chronic tinnitus with daily injections of EGb 761 for 10 days, and then randomly allocated them to oral EGb 761 or placebo for 3 months. The second phase of the design was double blind and tinnitus was assessed using audiometry. Juretzek also reported a significant reduction in tinnitus in the EGb 761 group compared with placebo.

The first large, double-blind, placebo-controlled study of the effect of Ginkgo biloba extracts on tinnitus was reported by Drew and Davies (2001). They recruited 1121 people between 18 and 70 years and matched 978 according to sex, age and the duration of their tinnitus. For 12 weeks, participants received either the ginkgo extract LI 1370 (Lichtwer Pharma, Berlin, Germany) or placebo. Subjects assessed their tinnitus in terms of loudness and how much it disrupted their daily life, using rating scales. However, there was no significant difference in either measure compared with placebo. In the most recent randomised, placebo-controlled, double-blind clinical trial, Rejai et al. (2004) also found no therapeutic effect of Ginkgo biloba compared with placebo in 66 patients with tinnitus. The primary outcome measures were the tinnitus handicap inventory, the Glasgow health status inventory and the average hearing threshold at 0.5, 1, 2 and 4 kHz. In a meta-analysis of clinical trials by the same authors, they found that only 21.6% of patients with tinnitus reported benefit from Ginkgo biloba versus 18.4% of patients who reported benefit from a placebo.

Because Ginkgo biloba extracts have vasodilatory effects, when they are combined with drugs such as aspirin, they can increase bleeding. Nonetheless, most of the evidence for haemorrhagic responses following the use of Ginkgo biloba extracts is based on anecdotal and case reports. Kohler et al. (2004) compared bleeding time, coagulation parameters and platelet activity in response to 2 X 120 mg/day EGb 761, or placebo, for 7 days and found no significant difference in any of these measures.

To date, only one study has investigated the effects of EGb 761 on salicylate-induced tinnitus using a conditioned-behaviour paradigm in rats. Daily oral administration of 25, 50 and 100 mg/kg EGb 761 was found to reduce tinnitus behaviour compared with vehicle. It should be noted, however, that these are very high doses and it is unlikely that they could be used in humans without adverse side-effects (even 25 mg/kg/day for a 70 kg adult corresponds to 1750 mg/day, which is more than five times the average daily dose used in humans).

Clearly, the investigation of the effects of Ginkgo biloba extracts on tinnitus has suffered from a lack of systematic clinical trials employing double-blind and placebo-controlled designs. While some clinical trials have yielded positive results, these studies are few and have been limited either by design flaws, the small size of the significant effects, or else the results have not been published in peer-reviewed journals. By contrast, the two most systematic clinical trials, which are double-blind and placebo-controlled, and are published in peer-reviewed journals, have yielded negative results.

Other herbal medicines

Very little has been published on the use of other herbal medicines to treat tinnitus. Yang (1989) has reported a blind trial in which patients with tinnitus were given either ‘Western medicines’ (i.e. diazepam, nicotinic acid, bromides, vitamin B, ATP, carbamazepine or lidocaine) and traditional Chinese medicine (TCM) or the Western medicines alone. TCM consisted of Rhizoma Gastrodiae, Ramulus Uncariae cum Uncis, Poria cocos, Flos Chrysanthemi, Akebia Quinata, Radix Polygoni Multflori, Fructus Liquidambris, Radix Rehmanniae, Rhizoma Alismatis, Radix Scrophulariae, Fructus Lycii, Radix Glycyrrhizae, Semen Plantaginis and Semen Vaccariae. Relief from tinnitus was observed in 84.4% of those receiving Western medicine and traditional Chinese medicine and 55% of those receiving Western medicine only. Unfortunately, given the mixture of drug and herbal remedies the patients received, it is difficult to attribute an improvement in tinnitus to any particular agent, and in any case, there was no placebo control group.

It is important to recognise that in traditional Chinese medicine, tinnitus is believed to be caused by changes in the relationship between the ear and the internal organs, such as the kidney, the liver, the gall bladder, the spleen and the stomach. TCM aims to treat tinnitus by achieving a balance of the yin and yang, external and internal, hot and cold, weak and strong. From the viewpoint of traditional Chinese medicine, tinnitus is only one of the symptoms the patient presents with and the doctor needs to observe a series of symptoms using inspection, by listening and smelling, inquiring and palpation, to make the right diagnosis. For example, it is believed that normal kidney function will be reflected by normal hearing and a kidney dysfunction (Shen kui) will result in hearing loss or tinnitus. If the tinnitus is caused by kidney dysfunction, the patient tends also to experience vertigo and dizziness, a sore back, the tongue has a red look with no ‘fur’ or little fur and there is a weak pulse. There are many different types of tinnitus in traditional Chinese medicine and most recently, tinnitus has been divided into five types at the Third Chinese Zhong Xi Yi Je He Otolaryngology Society Annual Meeting in 2002: Wai Gan Fen Re Xing (related to respiratory infection), Gan Hou Sbang Rao Xing (related to abnormal liver function), Tan Re Yujie Xing (related to the ‘hot’ state in TCM), Shen jing Kui Xu Xing (related to kidney dysfunction) and Pi Qi Xu Ruo Xing (related to abnormal spleen function).

Japanese herbal medicines have also been used to treat tinnitus. Okamoto et al. (2005) used Yoku-kan-san (TJ-54) to successfully treat tinnitus associated with undifferentiated somatoform disorder, presenting with headache and insomnia. Unfortunately, this was only a case report and therefore no controls were employed.

Importance of animal models for testing herbal remedies

A major problem for the development of new drug treatments for tinnitus is the paucity of animal models of the disorder. It is difficult to determine whether an animal such as a rat or a mouse is actually experiencing tinnitus, and many studies of the neurophysiological and neurochemical mechanisms of tinnitus simply assume that an animal has tinnitus following cochlear lesions produced by intense sound, surgery or chemical toxicity. This is not a valid assumption given that similar conditions in humans do not necessarily produce tinnitus.

To overcome this problem, a number of researchers have developed animal models of tinnitus in which rats are trained to respond differentially in a conditioned avoidance task depending upon whether they hear certain frequencies of background noise. For example, rats trained to make a particular response in the presence of a 10-kHz background noise, will continue to make the trained response, in the absence of the background noise, if tinnitus has been induced by the administration of a drug such as salicylate. In humans, salicylates produce tinnitus of approximately 10 kHz, and rats treated with salicylates respond in behavioural tasks as if they hear a continuous background noise at around 10 kHz. Using this type of conditioned-behavioural model, it is possible to screen new drugs for their potential application to the treatment of tinnitus.

Unfortunately, at present, such animal models have not been used extensively for the investigation of the neural mechanisms of tinnitus or for potential drug treatments. In addition to more well-controlled clinical trials, it is vital that herbal medicines be tested in realistic animal models of tinnitus.

Conclusions

It is clear from the studies reviewed here that the published literature on herbal medicines and tinnitus is small and in most cases focused on Ginkgo biloba extracts, where some evidence for efficacy has been found. Nevertheless, even the research on Ginkgo biloba and tinnitus lacks a substantial number of systematic, well-controlled clinical trials, in which double-blind protocols have been used. Unfortunately, most of the trials that have been well designed have failed to demonstrate efficacy for Ginkgo biloba in the treatment of tinnitus.

The only reasonable conclusion that can be reached at present is that the available data indicate that conventional medications offer more therapeutic benefit for patients with tinnitus than herbal alternatives. Given that clinical trials are expensive to run and are usually not undertaken unless there is substantial preclinical evidence to suggest that they may establish the efficacy of a new drug, it is probably very important that researchers and clinicians, who are interested in potential herbal treatments for tinnitus, use conditioned-behavioural models of tinnitus in animals to screen herbal agents. This would provide a clear path for the development of herbal remedies to treat tinnitus before initiating clinical trials.

Disorders of central nervous system | Tags: , , , ,

Why do herbal extracts have an effect on the CNS?

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September 8, 2010 at 4:39 pm

CNS – central nervous system

One common theme within this brief review of CNS-active herbs is the multiplicity of potential mechanisms of action. Interestingly, while the literature on the in-vitro, in-vivo, animal and human behavioural effects of herbal extracts is enormous, and growing exponentially, the simple question of why bioactives from plants have CNS effects in mammals is largely overlooked. Herbal extracts owe their bioactive effects to a vast array of ‘secondary metabolites’ that are not directly involved, either in the plant’s metabolism or indeed in its immediate ability to survive. Instead, these chemical compounds have developed via evolutionary and ecological pressure to serve a variety of functions that enhance the plant’s longer-term survivability, e.g. the provision of colour, a host of localised protective roles (e.g. antioxidant, free-radical scavenging, ultraviolet absorption, antiproliferative, antiviral, etc.), roles in interplant relationships (e.g. allelopathic defence against competitors), interactions with a range of heterotrophs, including defence against fungi and bacteria, deterrence and attraction of insects and herbivores, and even symbiotic hormonal and central nervous system interactions with higher life forms, most notably insects.

It seems axiomatic that the physiological effects of consuming secondary metabolites within mammals can therefore be seen as being as a result of the similarity in biological processes across the eukaryotes, in this case the plant and animal kingdoms. The effects within humans may be merely a coincidental consequence of this similarity, but they may also take the form of a similar action as that exerted by the plant over other external organisms (e.g. insects), or alternatively a similar action to that which occurs within the plant itself. As an example of the former, acetylcholine is the major excitatory CNS neurotransmitter in insects, and a range of extracts that have beneficial properties within the acetylcholine neurotransmitter system at low doses in humans may owe these properties to compounds functioning as toxic, predation deterrents within plant-insect relationships.

With regard to secondary metabolites exerting similar effects in their source plant and mammals, examples may include similarities in the protective effects conferred on the end-consumer. These include not only CNS-relevant antioxidant effects but also the more general antifungal/viral, antiproliferative, anti-ultraviolet light, etc. effects of consuming many secondary metabolites in mammals. In this respect, and inextricably linked to several of these general protective effects, it is interesting to note that the ubiquitous signalling molecule, nitric oxide, acts in plants in a similar manner as it does in animals. In plants it plays a key role in several processes including protection during physical stress, disease and ageing. In mammals this distinction is also clearly seen in the three isoforms of nitric oxide synthase, the enzyme responsible for nitric oxide synthesis. Two of these produce nitric oxide at a comparatively slow rate and contribute to a host of homeostatic physiological processes important to health. The third isoform, inducible nitric oxide synthase, on the other hand, produces nitric oxide at a rapid rate during immune and inflammatory responses to stressors and, when overactivated or activated for prolonged periods, is implicated in a range of pathological conditions.

What is particularly intriguing is that the expression of potentially bioactive secondary metabolites during plant stress, for example, hypericin produced in the cells of Hypericum perforatum L., is related to nitric oxide production, and that the secondary metabolite components of a number of herbal medicines play a role in the regulation of nitric oxide homeostasis in mammalian tissue models. As an example, a number of authors have suggested that the ginsenoside constituents of Panax ginseng may owe their efficacy in various domains to their ability to enhance constitutive nitric oxide synthesis throughout the tissues of the body, including the brain. Similarly, the active components of Ginkgo biloba L. and a wide range of polyphenols from a number of sources have beneficial effects both in increasing constitutive nitric oxide synthase activity, thereby potentially improving, for instance, vascular tone and cerebral tissue perfusion, while also reducing the potentially damaging overproduction of inducible nitric oxide synthase.

Given that neuronal nitric oxide synthase is also present throughout the brain, that levels are related to mood disorders and that nitric oxide functions as a neurotransmitter in its own right, and is involved in synaptic plasticity and hippocampal long-term potentiation (LTP) and general memory processes, it becomes tempting to suggest that some of the CNS effects of herbal extracts are via the commonalities with regards to this signalling molecule.

Conclusions

From the hundreds of medicinal herbs that have demonstrated potential CNS-relevant properties in-vitro, and the 80 that have been assessed in animal models, the above describes only nine that have been subjected to more than cursory, methodologically adequate investigation in humans. For two of them (Bacopa monniera and Crocus sativus), the research base is currently weak but may improve with time. Only four have generated enough research to be subjected to the meta-analyses favoured by the medical establishment.

One commonality between them is that they all possess multiple, potentially bioactive constituents, and may exert a multiplicity of CNS-relevant physiological effects. There are good arguments to be made for offering a polypharmacological treatment for complex CNS conditions. However, the very complexity of these potential treatments will hinder their application in a wider medical setting.

Overall, a great deal of more focused research is required to reach a full understanding of the bioactive constituents of plants (including the issues of standardisation and replication of extracts), their effects in mammalian physiological systems and their efficacy.

Disorders of central nervous system | Tags: , , , ,

Cognitive performance

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September 6, 2010 at 4:21 pm

Bacopa monniera Wettst. (Water hyssop)

Bacopa monniera has been used in Ayurvedic medicine for some 3000 years. Its traditional and contemporary indications include anxiety and cognitive performance and the active constituents are thought to be triterpenoid saponins, of which the most prevalent are known as bacoside A and B.

Potential CNS-relevant mechanisms include an enhancement of protein kinase activity in the hippocampus, interactions with the cholinergic and monoaminergic neurotransmitter systems, and antioxidant properties.

Bacopa monniera extracts have been shown in animal models to protect cognitive function in the face of a number of challenges and exert anxiolytic effects in stress paradigms.

In humans the behavioural effects have received little methodical attention. However, several double-blind, placebo-controlled studies have assessed the cognitive and mood effects of Bacopa monniera extracts. In the first of these Stough et al. (2001a) investigated the effects of 5 and 12 weeks’ administration of 300 mg of a standardised (55% bacosides) extract in 46 healthy adult participants. By the 12-week endpoint, self-ratings of ‘anxiety state’, and cognitive tasks assessing speed of early information processing, verbal learning rate and memory consolidation were beneficially modulated in the group taking extract.

A second study using the same extract, involving 76 middle-aged participants, demonstrated a lack of any cognitive or mood effect following 3 months’ administration of 300 or 450 mg extract (depending on body weight). However, an assessment 6 weeks after the end of the trial showed that the group taking extract had outperformed placebo on a single task, a ‘delayed recall of word pairs’ task. The authors tentatively interpret this as a possible attenuation of ‘forgetting’, but allow for the effect being a statistical anomaly. Given the lack of a clear effect from these two studies, Bacopa monniera requires further research.

Ginkgo biloba L. (Gingko)

Ginkgo biloba extract contains a number of species-specific flavonoids and the terpenoids: bilobalide and ginkgolides A, B, C and J. Potential CNS-relevant mechanisms of action include:

• a potential antagonism of platelet activating factor

• enhanced nitric oxide bioavailability

• scavenging and inhibition of free radicals

• modulation of a number of neurotransmitter systems

• beneficial effects on blood viscosity and circulation

• both in-vitro and in-vivo protection against hypoxic challenges

• in-vivo neuro-protective properties

• increased cerebral perfusion in humans.

There is also some evidence of cognitive enhancement in both younger and older ‘cognitively intact’ populations administered 120 mg or 180 mg of gingko extract for 7 days or longer, although evidence in this respect is not unequivocal.

Several placebo-controlled, balanced crossover experiments, with relatively small sample sizes have also demonstrated improved cognitive performance in young adults following single doses of GBE. In the last of these studies, Kennedy et al. (2000) demonstrated linear, dose-dependent speeding of attention task performance for the two highest doses under investigation (240 mg, 360 mg gingko extract), and improved memory following the lowest dose (120 mg) in 20 participants. A later re-analysis of the data for the lowest dose not only confirmed this memory enhancement effect but also suggested modest but significant slowing on attention tasks following this typical daily dose.

A large number of studies have assessed the efficacy of chronic administration of Ginkgo biloba in the amelioration of the cognitive declines associated with ageing and dementia. In this respect a comprehensive Cochrane review meta-analysed the 33 extant studies involving cohorts with dementia or age-related cognitive impairment that met their inclusion criteria. The authors concluded that ‘Overall there is promising evidence of improvement in cognition and function associated with Ginkgo‘. However, in a recent update and re-analysis, Birks and Grimley-Evans (2007) added a further three studies and deleted two studies and, in terms of cognitive function, fractionated their analyses by the length of treatment and the instrument employed. While there was evidence of improvement either following some treatment durations or dependent on the cognitive assessment instrument utilised, their revised overall conclusion was that the evidence with regards overall efficacy in dementia or cognitive impairment is ‘inconsistent and unconvincing’.

Two potentially interesting randomised, controlled trials have also been published recently. Napryeyenko and Borzenko (2007) investigated the effects of ginkgo in 400 patients with mild-to-moderate dementia who also had concomitant neuropsychiatric symptoms (who would be expected to show more rapid decline than average) and demonstrated significant improvements in cognitive functioning and neuropsychiatric symptoms following 6 months’ treatment with the extract Egb 761. A single trial has also assessed the effects of two doses of Egb 761 in people with anxiety disorders. Results showed a significant dose-related improvement in Hamilton Rating Scale for Anxiety and a number of clinical measures. With regards safety, Birks and Evans (2007) conclude that Ginkgo biloba appears to be safe and comparable with placebo in terms of negative side-effects across studies.

Panax ginseng C.A. Mey. (Ginseng)

‘Ginseng’ is generally taken to refer to the dried root of several species in the plant genus Panax (Araliaceae family). The most widely used family member is Panax ginseng, which has a medicinal history stretching back more than 5000 years.

The major active constituents of the Panax genus are thought to be the species-specific saponins, also known as ginsenosides, of which over 30 have been identified.

Ginsenosides have a number of effects relevant to general health, including bolstering of the immune system, anti-inflammatory, antihepatotoxic and anti-carcinogenic effects. With regards to brain function, ginseng exerts a number of central and peripheral physiological effects that are potentially relevant. These include a host of neuro-protective properties, cardiovascular effects, modulation of the hypothalamic-pituitary-adrenal axis, neurotransmission, and glucoregulation. While ginsenosides are known to exert a plethora of effects at a cellular level, a number of authors have suggested that the modulation of nitric oxide synthesis contributes to many of their wider effects including those within the CNS.

Animal behaviour models suggest that ginsenosides have antistress and anxiolytic effects, moderate fatigue, improve memory in impaired rodents and improve learning and memory in several hippocampal/amygdala-dependent behavioural tasks in intact rodents. Potential mechanisms of the latter include the ability to foster neurogenesis and modulate long-term potentiation in the hippocampus.

In humans there is no clear evidence from controlled studies of ergogenic or antifatigue effects. Similarly, while a number of studies have demonstrated improvements in subjective ‘wellbeing’ or ‘quality of life’ attributable to ginseng monotherapy, a number of other studies have failed to find this effect. However, it should be noted that the lack of clear efficacy in these domains may reflect methodological shortcomings.

A number of randomised, double-blind, placebo-controlled, balanced-crossover studies investigating single doses of Panax ginseng have identified positive cognitive effects in healthy young adults. The most consistent finding is of improved secondary memory performance following standardised ginseng extract G115 alone, and in combination with both Ginkgo biloba and guarana (Paullinia cupana). Improvements have also been noted in the speed of performing attention tasks and significantly shortened latency of the P300 component of auditory evoked potentials measured by EEG, along with overall topographical modulation of electrical activity.

Two studies have also concomitantly measured glucoregulatory effects and cognitive performance during ‘glucose sensitive’, mentally demanding task performance. In the first of these, Reay et al. (2005) demonstrated significantly reduced fasted blood glucose levels and concomitant improvements in performance and reductions in self-ratings of mental fatigue in healthy young participants following 200 mg or 400 mg of G115. In the second study, Reay et al. (2006) used the same methodology and the most effective dose from the previous study (200 mg) but added a further factor: presence or absence of glucose 75 g. The results directly replicated the cognitive improvements, attenuation of mental fatigue and reduced blood glucose levels seen following ginseng alone in the previous study, but showed that these effects were largely abolished by coadministration with glucose.

The cognitive effects of longer-term dosage with ginseng has not been investigated to a great extent. In two early, double-blind, placebo-controlled studies, D’ Angelo et al. (1986) and Sorensen and Sonne (1996) demonstrated improvements restricted to one or two task outcomes from within a large selection of tasks following ginseng 200 mg and 400 mg/day. Similarly, a recent double-blind, placebo-controlled pilot study (n = 16) using a balanced crossover design in an investigation of 8 weeks’ treatment with 200 mg Korean Panax ginseng demonstrated improvements that were limited to two working memory tasks from within a larger battery, and one (social relations) of four scales from within the World Health Organization – Quality of Life scale.

Panax ginseng monopreparations are rarely associated with adverse events or drug interactions.

Salvia officinalis L. and Salvia lavandulifolia Vahl (Sage)

The most commonly consumed species of the large genus Salvia are Salvia officinalis (garden sage) and Salvia lavandulaefolia (Spanish sage). Indications have traditionally included beneficial central nervous system effects, principally with regards mood and memory.

It has been suggested that the monoterpenoid constituents of sage, e.g. 1,8-cineole, contribute to the physiological activity of the whole herb. Extracts also contain a number of polyphenolic compounds, most notably rosmarinic acid and methyl carnosate. Concentration-dependent inhibition of acetylcholin-esterase in postmortem human brain homogenates was demonstrated by essential oils of both herbs and alcoholic extracts of both fresh and dried Salvia officinalis leaf and dose-dependent inhibition of human acetylcholinesterase by Spanish sage essential oil has also been shown and in vivo in the striatum and hippocampus of aged rats following oral administration.

Acetylcholinesterase inhibition has been shown to involve synergistic interactions and antagonisms. Two studies have also demonstrated inhibition of butyrylcholinesterase in human erythrocytes and others have shown the antioxidant and free-radical scavenging properties of both sages. This latter study also demonstrated anti-inflammatory actions by the extract and its geraniol and α-pinene monoterpenoid constituents.

Several other potentially CNS-relevant properties have also been demonstrated including an oestrogenic activity of Spanish sage and the monoterpenoid component geraniol and benzodiazepine receptor binding by fractions of a methanol extract of Salvia officinalis.

Five double-blind, placebo-controlled, randomised, balanced-crossover studies in healthy humans have assessed the behavioural effects of single doses of sage with in-vitro cholinesterase-inhibiting properties (the number of participants was 20, 24, 20, 30, 36 respectively). Tildesley et al. (2003) assessed the effects of three doses of S. lavandulaefolia essential oil and showed significant memory improvements in 20 healthy young participants following the two lowest doses (50 µL, 100 µL). In a subsequent study, Tildesley et al. (2005) examined the effects of 25 and 50 µL of the same oil in 24 participants and demonstrated that improved memory performance was most marked for the lowest dose of 25µL. Both doses also resulted in significantly increased ratings of ‘contentedness’ and ‘calmness’.

The memory-enhancing effects in a healthy young population have also been confirmed in a recent study into the effects of 50 µL Salvia officinalis essential oil. This study also demonstrated improved mood (alertness) and reduced ratings of mental fatigue during an extended period of cognitive demand. A further study assessed the effects of four separate single doses of an ethanolic extract of Salvia officinalis in an elderly cohort. Once again the results showed clear improvements in memory performance, with this most marked for the lower two doses.

In one further study, Kennedy et al. (2006) also assessed the effects of two doses (300, 600 mg) of dried Salvia officinalis leaf with both acetylcholinesterase and butyrylcholinesterase-inhibitory properties on mood and performance of a psychological stressor multitasking battery. The results showed that the lower dose reduced anxiety and the higher dose increased ratings of ‘alertness’, ‘calmness’ and ‘contentedness’. Task performance was also improved for the higher dose at both post-dose sessions, but reduced for the lower dose at the later testing session.

A single, double-blind, placebo-controlled trial has also assessed the effects of 16 weeks’ administration of an Salvia officinalis alcoholic tincture in 30 patients with Alzheimer’s disease. Those in the verum group were shown to have significantly improved scores on the Alzheimer’s Disease Clinical Assessment Scale cognitive subscale (ADAS-cog) at the study endpoint at 16 weeks. Clinical dementia rating scores were also significantly improved at the end of the study.

Disorders of central nervous system | Tags:

Sleep

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September 4, 2010 at 4:10 pm

Valeriana officinalis L. (Valerian)

Extracts from the roots and rhizomes of Valeriana officinalis L. have a long, cross-cultural tradition of medicinal usage, mainly as mild sedatives and anxiolytics, but they also demonstrate spasmolytic properties. The effects of valerian may be attributable to a number of potentially active constituents, including mono-terpenes and sesquiterpenes, including the genus-specific valepotriates and valerenic acid. Root extracts also contain appreciable levels of GABA, constituents which bind to a variety of neurotransmitter receptors including GABAA, where they perform as an allosteric modulator of subunit specific GABAA channels, adenosine A1 receptors where they also exert a range of allosteric effects, and act on the 5HT1A and the 5-HT5A receptors, which are implicated in circadian rhythms and anxiety.

Research in humans has tended to concentrate on the role of valerian in attenuating sleep disturbance. Stevinson and Ernst (2000) reviewed the 19 randomised, controlled trials that assessed its effects on sleep and insomnia, and concluded from the nine that reached their inclusion criteria, that the efficacy of valerian in this respect was ‘promising but not fully conclusive’.

Similarly, a systematic review of randomised, controlled trials of valerian for improving sleep quality included 16 eligible studies. However, it was noted that the majority of studies had some methodological problems. Allowing for the possibility of a publication bias, the authors concluded that the evidence to date only ‘suggested’ that valerian improved sleep quality.

Valerian has also been reported to have a similar effect to benzodiazepines, with similar positive effects from 6 weeks’ administration of 600 mg/day of valerian extract to those produced by 10 mg/day of oxazepam on sleep quality and waking symptoms in 202 non-organic insomnia outpatients. Additionally a number of studies have reported a benefit to sleep following a valerian/hops combination.

It is also interesting to note that, whereas no effect of valerian on psychomotor performance, alertness or concentration has been reported the morning after administration, acute doses of valerian led to a significant deterioration in performance in vigilance and information-processing tasks 1-2 h after acute daytime administration. Valerian is also often indicated for anxiety, but a recent Cochrane review concluded that there was insufficient evidence of efficacy in this since only one pilot study was found to be eligible for inclusion according to their criteria. Taibi et al. (2007) interpret the literature as failing to show any convincing pattern of behavioural effects but Valeriana officinalis extracts are associated with markedly less negative side-effects than benzodiazepines, with levels similar to placebo across clinical trials.

Disorders of central nervous system | Tags: , ,

Mood

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September 2, 2010 at 4:04 pm

Crocus sativus L. (Saffron)

The stigmas of Crocus sativus L. contain a number of potentially bioactive compounds including a number of carotenoids (crocins), monoterpenes and flavonoids, including quercetin and kaempferol. Rodent behaviour models have demonstrated that Crocus sativus extracts can ameliorate scopolamine-induced memory performance and that crocins can enhance memory performance and attenuate scopolamine-induced memory deficits.

In humans, four double-blind, controlled trials, each with relatively small samples of 40 patients with mild-to-moderate depression, have demonstrated that 6-8 weeks of administration of dried ethanol extracts of Crocus sativus stigmas (15 mg) and petals (30 mg) are more effective than placebo and as effective as fluoxetine (but with no placebo control) in ameliorating the symptoms of depression, as assessed by the Hamilton Depression Rating Scale. While Crocus sativus has been included on the basis that these studies show some promise, the evidence base requires research conducted in larger cohorts.

Hypericum perforatum L. (St John’s wort)

Hypericum perforatum L. has been in recorded medicinal use from the time of the ancient Greeks. Hypericum extracts contain a number of groups of potentially bioactive constituents including flavonoids, phenolic acids, naphthodianthrones and phloroglucinols.

The bioactive properties of St John’s wort include inhibition of the neuronal re-uptake of serotonin, dopamine, noradrenaline, Ύ-aminobutyric acid (GABA) and L-glutamate, and increased neurotransmitter sensitivity and receptor binding. These effects have been variously attributed over time to the naphthodianthrones, e.g. hypericin, pseudohypericin, protohypericin and protopseudohypericin, the phloroglucinol hyperforin and the range of flavonoid constituents.

Given their ability to modulate a wide range of neurotransmitter systems, it is not surprising that extracts and constituents have been shown to exert a plethora of effects relevant to behaviour in animal models. These include neuroprotective effects, an attenuation of cognitive impairment and improved cognitive performance.

In humans the vast majority of research has focused on the antidepressant effects of Hypericum perforatum extracts. In this domain a number of reviews and meta-analyses summarising the evidence have been published in the past 8 or 9 years. The two most recent reviews adequately encompass the considerable body of work in this area. In the first of these meta-analyses, Roder et al, (2004) assessed the evidence from randomised, controlled trials for the efficacy of standardised extracts (dosage: 300-1200 mg/day) in the treatment of mild-to-moderate depression. They concluded that these extracts had a significant effect on symptoms in comparison with placebo, and performed as well as synthetic antidepressants.

A subsequent Cochrane review by Linde et al. (2005) included a total of 37 trials judged to be methodologically adequate that had assessed St John’s wort in comparison with either placebo or standard antidepressants. In common with Roder et al. (2004), the authors conclude that the extracts seems to be more effective than placebo and as effective as standard antidepressants for treating mild-to-moderate depressive symptoms. However, beneficial effects for treating major depression appear minimal, although this latter conclusion may reflect a simple lack of research addressing this question. A subsequent review of reviews and meta-analyses also confirmed the general consensus that St John’s wort is effective in the treatment of depression.

Given evidence of similar levels of efficacy as synthetic antidepressants, a further advantage of Hypericum perforatum extracts is that they are generally found to be better tolerated. However, they can affect the metabolism of several medications resulting in reduced plasma concentrations.

Melissa officinalis L. (Lemon balm)

Melissa officinalis is a perennial, lemon-scented herb, used medicinally for over 2000 years, particularly for improved memory and mental function. Its contemporary usage includes as a mild sedative, in disturbed sleep, and in the attenuation of the symptoms of nervous disorders, including the reduction of excitability, anxiety, and stress.

Potentially active constituents include a number of monoterpenoid aldehydes (including citronellal, neral and geranial), flavonoids and polyphenolic compounds (most notably rosmarinic acid) and monoterpene glycosides.

Extracts have been shown to have both nicotinic and muscarinic cholinergic receptor-binding properties in human brain homogenates and essential oils have appreciable acetylcholinesterase-inhibitory properties. Extracts also have antioxidant properties which are putatively attributable to their flavonoid content.

In behavioural terms, a number of studies involving rodents suggest specific ‘calming’ or sedative effects following both essential oil and an hydroalchoholic extract of Melissa officinalis.

A series of randomised, double-blind, placebo-controlled, balanced-crossover trials have also assessed the cognitive and mood effects of single doses of Melissa officinalis in humans. Two of these studies assessed the effects of a commercial lemon-balm methanolic, which lacked in-vitro nicotinic and muscarinic receptor-binding properties. In the first, three separate, single doses of Melissa officinalis extract (300 mg, 600 mg, and 900 mg) were compared with placebo, with 20 participants undergoing weekly assessments. The results demonstrated a dose-dependent impairment of memory function, with concomitant reductions in ratings of ‘alertness’ restricted to the highest dose and increased ‘calmness’ following the lowest dose.

In the second study, the two lower doses (300 mg, 600 mg) were investigated using a multitasking laboratory stressor paradigm, with the highest dose again leading to reduced ratings of alertness and increased ratings of calmness during the stressor battery. The pattern of results from these two studies is broadly in line with the traditional mildly sedative and calming properties of these extracts.

To assess the effects of Melissa officinalis with cholinergic receptor-binding properties, a further experiment was conducted in two distinct phases. In the first phase, cholinergic receptor-binding properties were established across a number of samples, with the dried leaf with the highest nicotinic and muscarinic receptor-binding properties being administered in a placebo-controlled, double-blind, balanced crossover study assessing the cognitive performance and mood effects of several single doses (600, 1000, 1600 mg dried leaf). In this case, while the lowest of the three doses evinced similar memory decrements as those seen in the previous study, the highest dose both increased ‘calmness’ and improved memory performance. The results from these three studies suggest that lemon balm owes its mildly sedative properties to something other than cholinergic receptor binding.

Two recent double-blind, placebo-controlled studies have also assessed the effects of Melissa officinalis in patients with dementia. Ballard et al. (2003) examined the effect of essential oil aromatherapy (in comparison with vegetable oil) on ratings of agitation and quality of life of 71 patients with severe dementia. After 4 weeks’ treatment, patients in the active treatment group were rated, in comparison with the placebo group, as being less agitated, less socially withdrawn, and as engaging in more time spent in constructive activities. Akhondzadeh et al. (2003) also assessed the effects of 60 drops/day of a tincture in 35 patients with mild-to-moderate dementia (20 verum, 15 placebo) who completed their 16-week trial. At the study endpoint, the results showed a clear cognitive advantage (ADAS-cog and Clinical Dementia Rating) and reduced agitation for the group taking the tincture.

Piper methysticum L.f. (Kava)

Drinks and extracts made from the rhizome and roots of kava have been used for millennia in the South Pacific both recreationally and medicinally to reduce fatigue and induce relaxation and sleep.

The major bioactive constituents of kava are styryl α-pyrones generally referred to as kava-pyrones or, more commonly, kavalactones. Contemporary commercial Kava extracts are generally standardised to contain approximately 30-70% of kavalactones. It should be noted that leaves and stem contain potentially hepatotoxic alkaloids but these are not generally considered to be responsible for the severe liver toxicity in a few individuals reported in recent years, which has led to severe curtailment of its use in many countries.

The exact mechanism underlying the central nervous system effects of kavalactones is poorly delineated to date. Kavalactones have been shown, at the most fundamental level, to modulate neuronal excitability via voltage-dependent calcium channels. They also modulate activity in the serotonergic, glutamatergic and dopaminergic neurotransmitter systems. In addition, kava’s anxyolitic properties have been attributed to interactions with N-methyl-D-aspartic acid and GABA receptors, although the evidence regarding the latter is inconsistent. Modulation of P-adrenergic activity may also play a role in their behavioural effects.

With regards to kava’s anxiolytic effects, Pittler and Ernst’s (2003) Cochrane review meta-analysed the randomised, controlled trials extant at that time. Twelve studies met their inclusion criteria and they concluded that, in comparison with placebo, kava extracts (administered for between 1 day and 24 weeks and containing between 105 and 280 mg of kavalactones) were associated with a significant reduction in anxiety on the Hamilton Anxiety (HAM-A) scale. Witte et al. (2005) went on to meta-analyse the six studies included in the latter analysis that had administered the standardised acetonic extract WS1490, and again found a significant treatment-related anxiolytic effect in comparison with placebo. With regards to behaviour, Cairney et al. (2002) note that a number of small studies have assessed the cognitive effects of kava. However, because of the methodology employed in these studies, the question is largely unresolved.

The focus of recent research has shifted away from efficacy and firmly towards putative negative side-effects and potential drug interactions of kava, since the publication of several case reports of treatment-related liver failure. These reports led to the withdrawal of kava by many national authorities, although the strength of the evidence on which these decisions were based is contested by many. Similary, it has been suggested that kava is capable of a host of theoretical drug interactions, for which hard evidence of specific cases is lacking.

Disorders of central nervous system | Tags: , , ,

Herbs affecting the central nervous system

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September 1, 2010 at 4:36 pm

Herbal medicines have been utilised for their psychoactive and psychotropic properties throughout recorded history. However, in comparatively recent times we have become accustomed to the generally accepted notion that synthetic medicines will be more efficacious than natural products, although this view tends to overlook the fact that many medicinal products derived from nature. However, psychotropic agents comprised only 3 out of 84 new drugs of natural origin.

One of these three is galantamine, originally derived from the Caucasian snowdrop (Galanthus woronowii Losinsk.) and now synthesised. Galantamine is interesting in that, having been initially identified on the basis of traditional ethnic use, it both validates the principles of an ethnopharmacological route to drug discovery, and it also underlines the difficulty in translating most herbal medicines into ‘mainstream’ medicines. The reason for the latter is that although galantamine represents a potential improvement over the other cholinesterase-inhibiting treatments for Alzheimer’s disease, in that it has demonstrated efficacy and is both a competitive inhibitor of acetylcholinesterase and allosteric modulator at nicotinic cholinergic receptor sites, it also represents a single, isolated alkaloid.

In contrast to this, although the mechanisms of action of most established herbal medicines in this domain are far from clear, they could all be described as having multiple potentially active constituents and manifold potential mechanisms of action. It is unlikely that any will provide us with the next ‘galantamine’. However, it is notable that a number of ‘single action’ synthetic psychotropic medications represent a poor cost-benefit profile in terms of efficacy and side-effects (e.g. the cholinesterase inhibitors for Alzheimer’s disease) and the complexity of the central nervous system (CNS) does suggest that the polypharmacology offered by, for instance, Ginkgo biloba, Salvia species, Hypericum perforatum (St John’s wort) or Melissa officinalis, may well provide more efficacious, better-tolerated, alternative treatments for disorders affecting the CNS.

The range of candidate herbal products with CNS effects is substantial. Zhang (2003) reviews the evidence pertaining to traditional medicinal herbal extracts that have undergone screening in animal models pertinent to psychiatric conditions and identifies more than 80 herbal extracts with evidence of potential efficacy. This contrasts with the current evidence base in humans, which is agglomerating around the handful of candidate extracts reviewed below.

The following therefore represents a brief summary of the putative bioactive components and mechanisms, and behavioural effects of the CNS active herbal products that have been subjected to significant research and/or demonstrated some potential efficacy in humans. For brevity it does not include combinations of herbs, or those that have not yet been tested in humans, nor does it include several herbal extracts that have a single, small, human study, and therefore resist any assessment as yet.

The herbal extracts are grouped into those that have predominantly been investigated for their effects on ‘mood‘, ‘sleep‘ and ‘cognitive performance‘.

Disorders of central nervous system | Tags:

Tinnitus

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July 3, 2010 at 10:24 am

Ringing in Ears

Best Single Herb: Gotu kola

Best Combinations: Ginkgo biloba, gotu kola; blessed thistle; Korean ginseng

Other Helpful Supplements: Calcium/magnesium with vitamin D; B-complex vitamins

Possible Causes: High blood pressure; hearing loss; injury

Complementary Help: Ear coning; acupuncture; reflexology; treatments for high blood pressure or cholesterol

For most of us, a high-pitched temporary ringing in the ears goes unnoticed shortly after it passes, and an occasional ringing in the ears is really nothing to be concerned over. However, many folks have a ringing, whooshing, buzzing, or some other constant sound in one or both ears on a consistent basis. This constant ringing in the ears is called tinnitus, and its causes can be linked to several different conditions.

Possible causes of ringing in the ears can include:

  • Head trauma that caused damage to the ear drum
  • Excess wax and debris in the ears (see the “Earaches,” to find a natural way to have the ears cleaned)
  • High blood pressure (see the “Blood Pressure: Easier to Deal with Than Peer Pressure”)
  • Ear infections caused by fungus (see the “Fungus Among Us?”)
  • Excessive exposure to medications, smoking, or noise
  • Temporal mandibular joint problems (the joint where the two jaw bones meet); this can sometimes be corrected by a chiropractor
  • Lack of blood supply to the head area (decreased circulation)
  • Herb Lore: information related to holistic health

To try to help you keep your sense of humor while you find the root cause of your problem, I’ve devised the following questionnaire. How can you tell if you have a problem with tinnitus? (1) Your favorite winter song chorus goes something like this: “Sleigh bells ring, are ya listenin’? In your head, bells are whistlin’.” (2) Earrings have a whole new meaning. (3) Every new name you hear rings a bell. (4) You sheepishly ask people, “Is that noise in my head bothering you?”

Discern what your probable cause for your condition is, look up the corresponding chapters related to your base cause, and then work to clear that problem. If you don’t have any discernable underlying causes, try some of the remedies here.

Gotu Kola: The Real Un-Cola

Gotu kola (Centella asiatica) is another one of my favorite herbs that’s similar to ginkgo biloba in its uses as a brain tonic. These two herbs make a powerful team when taken together. Gotu kola is an herb that, like ginkgo biloba (see the “Alzheimer’s Disease: Don’t Forget to Take Your Herbs,” “A Is for Ailment,” for more on ginkgo), has an affinity for the brain. This means that it is attracted to and nourishes the brain and nervous system.

Gotu kola has been used as an anti-aging regenerative herb because it is thought to stimulate collagen, increase blood circulation, and help detoxify the body of chemicals. You will see some sodas with a gotu kola or ginseng base in many health food stores, and this is a common sight in Asia.

It is said that gotu kola helps to integrate both hemispheres of the brain — how’s that for whole thinking! Gotu kola has been used by those suffering from a nervous breakdown and to help balance and tone the entire glandular system. The old saying about gotu kola sums it up nicely in a catchy phrase that goes something like this: “Gotu kola every day will keep old age away!”

Warnings about the use of herbs

Although gotu kola is a wonderful brain food, too much of a good thing is not necessarily better! In large quantities, gotu kola can give you a headache (too much blood flowing to the brain) or can make you feel itchy, dizzy, or faint

Gotu kola is a favorite food of one of my favorite animals, the wild elephant. The herb is known for its benefits toward longevity and as a brain food. Could munching on this herb be the reason for the long life of an elephant — and the reason why an elephant never forgets?

Other uses for gotu kola include: mental fatigue, nervous breakdowns, fatigue, memory, high blood pressure, concentration, thyroid stimulant, and boosting vitality.

Help for Ringing in the New Ear

Make sure you’re getting the right amount of minerals in your diet. If you are unsure, a safe way to get your daily minerals is by supplementing with alfalfa tablets. We all need calcium and magnesium. Vitamin D helps you absorb the calcium. Magnesium should be about two times more than the calcium intake; this mineral helps regulate your blood pressure, which is sometimes an underlying cause of ear ringing. For more on vitamins and minerals.

The B-complex vitamins are nutrients important to brain and circulatory system function, and these should be considered when you have ringing in the ears. Foods rich in the B vitamins include wheat germ, bananas, avocados, most nuts and legumes, and beef liver.

Disorders of central nervous system

Neuritis

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June 4, 2010 at 1:50 pm

Neuritis: Numb to the Problem

Neuritis (Neuropathy)

Best Single Herb: Devil’s claw

Best Combinations: White willow bark, black cohosh, capsicum, valerian, ginger, hops, wood betony, devil’s claw

Other Helpful Supplements: B-complex vitamins; calcium/magnesium; vitamin E with selenium

Possible Causes: Diabetes; poor circulation

Complementary Help: Reflexology

Neuritis is a disease of the peripheral nerves of the body (usually in the toes and fingers), that causes inflammation and can lead to numbness of these areas. The swelling of the nerves associated with this condition can cause pain (neuralgia), skin sensitivity, paralysis, muscular weakness, and slowed reflexes. The term neuropathy is also used less specifically to refer to this condition.

Terms related to herbs or holistic health

Neuritis, or neuropathy, is a disease of the peripheral nerves of the body (usually in the toes and fingers) that causes inflammation and can lead to numbness of these areas. Neuralgia is nerve pain, usually associated with the swelling of the nerves.

Sometimes neuritis can be caused by diabetes, and it is associated with gout and other diseases affecting the proper functioning of the entire structural system (muscles, tendons, bones, joints).

Warnings about the use of herbs

Devil’s claw may be called a “claw” because of its somewhat abrasive or irritating affect on the digestive tract You will most likely find this herb in a mixture with other herbs that feed the structural system. If you take devil’s claw by itself, try chasing it with an herb that soothes and protects tissues, such as aloe vera.

The Devil’s Claw Made Me Do It

Devil’s claw (Harpagophytum procumbens) is an herb that has been used for a host of painful or inflammatory ailments such as arthritis, rheumatism, acne and allergies, kidney and liver problems, and gout because of its anti-inflammatory properties. Because neuritis is an inflammation of the nerves, devil’s claw may be useful to you for this condition. It works primarily by helping the body eliminate uric acid (see post for more on gout; see post for more on devil’s claw for inflamed knees).

The root of the devil’s claw is taken internally to clean the vascular walls, the blood, and the lymphatic system. It provides iron and magnesium and helps to strengthen the bladder, kidneys, liver, joints, and stomach.

Numb and Number

Stimulating the circulation with herbs will certainly help to prevent the numbness associated with this condition. Capsicum and ginger are both quick to stimulate circulation. Both are very hot and can be toned down a bit to ease digestion when mixed with white willow bark, black cohosh, valerian, and wood betony. If you have diabetes, see post for more pointers on using herbs.

About overcoming an ailment with herbs

Reflexology is an excellent therapy that stimulates points on the feet and hands that connect to all other parts of the body. It also helps increase circulation to the extremities and can be instrumental in protecting you from the effects of neuropathy. Diabetics have been aided with the use of reflexology.

Consider using the B-complex vitamins to feed the nervous system if you have neuritis. Calcium with magnesium will feed the structural system and may be helpful if you are suffering from nerve pain — especially if the body is over-acidic, calcium may ease this pain. Vitamin E with selenium is a powerful antioxidant and aids the circulatory system; up to 1,200 IU may be useful, but always check with your doctor before taking high doses of vitamins. Too high a dose of vitamin E can cause headaches.

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