Ginkgo biloba L

Modern Ayurveda

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In Europe, leaf preparations of Ginkgo biloba L. (Ginkgoaceae) were used for the treatment of circulatory disorders in the 1960s, and they are now a popular herbal remedy with a reputation for alleviating memory problems. In Iran, G. biloba has been used traditionally to improve memory associated with blood circulation abnormalities [249]. The use of G. biloba in TCM dates back for centuries, and the Pharmacopoeia of the People's Republic of China (2005) includes G. biloba seeds as a remedy for cough and asthma and to reduce leukorrhoea and urination [237].

There has been extensive research to determine any pharmacological basis which might explain the reputed effects of G. biloba on memory, and a number of clinical studies have also been conducted. Much of this research has used a standardised extract of G. biloba known as EGb 761, which contains flavonoid glyco-sides and terpenoid lactones amongst various other constituents. This extract has shown a variety of activities relevant to improving cognitive function, particularly neurodegenerative-related disorders such as AD, thus indicating that the extract may have a number of different modes of action. EGb 761 has shown favourable effects on cerebral circulation and neuronal cell metabolism [250, 252, 252] and on the cholinergic system [253], and it has antioxidant activity [254-256]. EGb 761 reduced apoptosis both in vitro and in vivo [257, 258], and it was neuroprotective against NO- and P-amyloid-induced toxicity in vitro [259, 260], with the latter effect being associated with the flavonoid fraction (CP 205) [261]. Ginkgolides, the main constituents of the non-flavonoid fraction of EGb 761, are neuroprotective against hypoxia-induced injury in cortical neurons [262].

EGb 761 also protected mitochondria from P-amyloid-induced toxicity [263] and modulated synaptic and mitochondrial plasticity in vitamin E-deficient rodents [264]. Other studies showed EGb 761 and the terpenoid lactone bilobalide (30) to protect against ischemia-induced neuronal death, and they reduced mitochondrial gene expression in vivo [265]. Furthermore, bilobalide reduced both glutamate and aspartate release in cortical slices [266], indicating a neuroprotective action. One mechanism to explain a neuroprotective action of bilobalide is that it acts as an antagonist at GABAa receptors [267].

Some G. biloba leaf constituents, including some flavonoids (e.g. quercetin (31)) and terpenoids (e.g. bilobalide and ginkgolides A (32), B (33) and C (34)), have been associated with a vasodilatory action [268, 269], which could also benefit memory function. Anti-inflammatory activity is also associated with G. biloba and its components. Ginkgolide B antagonises platelet-activating factor (PAF) [270], ginkgetin (35), a biflavone from G. biloba leaves, inhibits phospholipase A2, and ginkgetin and the biflavone mixture downregulate COX-2 expression [271, 272]. The antioxidant properties of G. biloba extract have shown potential relevance in modulating AD pathology in vivo. An extract reduced oxidative stress resulting from senile plaques in vivo and progressively reversed structural changes in dystrophic neurites associated with senile plaques, thus indicating that neurotoxicity associated with the senile plaques in AD could be partially reversible with antioxidant therapies such as G. biloba extract [273]. Some evidence suggests that G. biloba and its components quercetin, kaempferol and isorhamnetin may also have estrogenic activity in some circumstances [274, 275], but any physiological relevance of this effect is unclear.

These activities, and perhaps other modes of action yet to be elucidated, might explain the effects on cognition observed when G. biloba extracts have been tested in vivo. Extracts have been shown to enhance cognition in both young and old rats [276, 277], to improve short-term memory in mice [278] and spatial learning and memory in rats with aluminium-induced brain dysfunction [279], to reduce cognitive impairment and hippocampal damage after ischemia in rats [280] and to attenuate scopolamine-induced amnesia in rats [281], perhaps indicating modulation of cholinergic function. This hypothesis is supported by another study in which a standardised G. biloba extract containing 24% flavone glycosides inhibited AChE activity both in vitro and ex vivo at doses which correlated with effects against scopolamine-induced deficits in a passive avoidance test in mice [129]. In another study, the antagonistic effect of G. biloba extract on spatial memory deficits in rodents was attributed to cholinergic activity but was also suggested to be partly due to a histaminergic mechanism of action [282].

The clinical efficacy of G. biloba extracts (including EGb 761) has been evaluated in several studies including double-blind, placebo-controlled, multicentre trials

with administration to both AD and healthy subjects [283-292]. Although these trials have indicated that G. biloba can modestly improve cognitive ability, some of the data need to be interpreted with caution since some results were based on self-assessment questionnaires rather than more objective methods of analysis. G. biloba extract is also being investigated for any role it may have in the prevention of AD [293]. In another randomised, double-blind, placebo-controlled trial, 120 mg G. biloba extract was administered twice daily to assess if it could improve cognitive performance in multiple sclerosis patients. Although this extract was not found to significantly improve cognition in this study, it was suggested to influence some cognitive processes such as mental flexibility [294].

G. biloba is probably one of the most studied herbal remedies for alleviating memory problems, and there is substantial evidence, both pharmacological and clinical, to encourage further study on its potential in the treatment of some cognitive disorders. As is often typical with herbal products, the active compounds need to be characterised, appropriate doses need to be established and both short-and long-term safety needs to be evaluated. Clinical trials to date have generally shown oral administration of G. biloba to be well tolerated, with no serious adverse effects [287, 295]. It is also important to consider potential drug interactions, particularly as patients requiring therapies to improve cognition may be already taking a number of other medicines. One study showed that G. biloba supplementation in AD patients taking donepezil (8) (5 mg/d) did not have a major impact on the pharmacokinetics and pharmacodynamics of donepezil [296], although the use of G. biloba with antiplatelet or anticoagulant medicines may increase the risk of haemorrhage [297].

15.5.3 Huperzia serrata (Thunb.) Trevis.

In TCM a prescription prepared from Huperzia serrata (Thunb.) Trevis. (Lycopo-diaceae) has been a treatment for memory loss [298, 299]. Of the alkaloids isolated from H. serrata, huperzine A (36) has been extensively studied for pharmacological and clinical effects in relation to treatment of cognitive disorders.

A range of studies in animals have shown this alkaloid to improve memory-retention processes in cognitively impaired aged and adult rats [300] and to attenuate cognitive deficits in chronically hypoperfused rats [301] and in gerbils following ischemia [302]. The principal mechanism of action thought to be responsible for the cognitive-enhancing effects of huperzine A is modulation of cholinergic function by inhibition of ChE; it reversibly inhibits AChE both in vitro and in vivo [303305]. Huperzine A is more selective for AChE than BChE, was less toxic than the synthetic AChE inhibitors donepezil (8) and tacrine (7) and significantly improved memory and behaviour in AD patients in a multicentre, double-blind trial [306, 307]. In phase IV clinical trials in China, huperzine A improved memory in elderly, AD and vascular dementia patients, with limited adverse effects [308]. Pharmacokinetic studies have indicated that huperzine A is rapidly absorbed, widely distributed in the body and eliminated at a moderate rate [308].

In addition to ChE inhibition, other effects may contribute to the cognitive benefits of this remedy. Huperzine A also favourably affects other neurotransmitter systems to improve memory [309]. It was also neuroprotective against ^-amyloid peptide [310], oxygen-glucose deprivation [311], free-radical-induced cytotoxicity [312] and glutamate [313] and it acts as an NMDA receptor antagonist in the cerebral cortex [314]. The enantiomers of huperzine A concentration-dependently inhibit NMDA receptor binding without stereoselectivity, although stereoselectivity is reported in the inhibition of AChE, with the (+)-isomer of huperzine A being less potent than the natural (—)-isomer [315]. Huperzine A is also suggested to attenuate apoptosis by inhibiting the mitochondria-capase pathway [316] and to have neurotrophic effects [308]. Huperzine B (37), also from H. serrata, attenuates H2O2-and oxygen-glucose-deprivation-induced injury in the rat pheochromocytoma cell line PC12, indicating that it has a neuroprotective action [317, 318].

Huperzine A appears to be therapeutically advantageous over some other known ChE inhibitors since it is a potent, reversible and relatively selective inhibitor of AChE, it shows other activities that may be relevant in alleviating cognitive dysfunction and it has shown efficacy in clinical trials in cognitively impaired patients with few adverse effects. It is therefore not surprising that the structures of huperzines A

36 Huperzine A 37 Huperzine B

and B have been used as templates for the synthesis of new compounds, with the aim of developing potentially new drugs with improved efficacy and safety.

One study involved an attempt to develop a compound, (±)-14-fluorohuperzine A, to enhance the H-bond between the C-14 methyl of huperzine A and the backbone carbonyl of His440 on AChE. The racemic form of 14-fluorohuperzine A inhibited AChE in vitro with a potency that was 62-times less than huperzine A [319]. Other attempts to develop fluorinated analogues of huperzine A ((±)-12,12,12-trifluorohuperzine A, (±)-14,14,14-trifluorohuperzine A, (±)-12,12,12,14,14,14-hexafluorohuperzine A and (±)-12-fluorohuperzine A) have been unsuccessful as these compounds did not inhibit AChE more potently than huperzine A [320, 321].

Analogues of huperzine A synthesised to achieve 5-substitution with either a hydroxyl group, a fluoro group or an acetoxyl group were assessed for their anti-AChE activity in vitro. The AChE inhibitory activities of these 5-substituted hu-perzine A analogues were also less potent than huperzine A when tested in vitro, indicating that the C-5 amino group in huperzine A (which can form a quaternary ammonium under physiological conditions to imitate ACh (1)) is an important structural feature for AChE inhibition [322]. Other compounds synthesised are the (E)- and (Z)-5-desamino huperzine A derivatives, which, although more potent than the 5-fluoro and 5-hydroxyl derivatives in the inhibition of AChE in vitro, were still less potent than huperzine A [322, 323]. Another synthetic derivative of huperzine A, (—)-dimethylhuperzine A (DMHA), showed AChE inhibitory activity comparable to (—)-huperzine A, and although the enantiomer (+)-DMHA was inactive against AChE activity, both enantiomers were equally effective in protecting against glutamate-induced neurotoxicity [324]. Analogues of huperzine B have also been synthesised with the aim of improving AChE inhibitory potency, but although some of these analogues are reported to be up to four-fold more potent than huperzine B, they were not as potent as huperzine A in the inhibition of AChE [325].

Other studies have involved synthesis of hybrid compounds, containing structural features of both huperzine A and other known ChE inhibitors. Pharmacomod-ulation of huperzine A and tacrine has produced compounds that include a combination of the carbobicyclic substructure of huperzine A and the 4-aminoquinoline substructure of tacrine [326, 327]. One of these compounds, rac-(£>12-amino-13-ethylidene-6,7,10,11-tetrahydro-9-methyl-7-11-methanocycloocta[b]quinoline hy-drochloride, was less potent than tacrine in the inhibition of AChE, but it was more active than the (Z)-stereoisomer [326]. Other derivatives synthesised which lack the ethylidene substituent (rac-12-amino-6,7,10,11-tetrahydro-9-methyl-7,11-methanocycloocta[b]quinoline hydrochloride and rac-12-amino-9-ethyl-6,7,10,11-tetrahydro-7,11-methanocycloocta[b]quinoline hydrochloride) inhibited AChE more potently than tacrine [326].

Other synthetic compounds are thehuprines. HuprineX ((—)-12-amino-3-chloro-9-ethyl-6,7,10,11-tetrahydro-7,11-methanocycloocta[b]quinoline hydrochloride) (38) was found to bind to AChE in a similar manner to huperzine A and tacrine at the acylation site in the active site gorge; it also interferes with the binding of peripheral-

site ligands [328]. Huprine X also had an affinity for AChE that was 180 times that of huperzine A, 1200 times that of tacrine and 40 times that of donepezil [328], and it may act as an agonist at muscarinic Mi and M2 and at nicotinic receptors [329]. Both (±)-huprine X and (±)-huprine Y ((±)-12-amino-3-chloro-9-methyl-6,7,10,11-tetrahydro-7,11-methanocycloocta[b]quinoline hydrochloride) (39) increased the level of ACh in the synaptic cleft more effectively than tacrine, and the interaction of (±)-huprine X with nicotinic receptors was weaker than that of (±)-huprine Y [330], although the nicotinic receptor binding effect of huprine X was not shown in a separate study [331]. (±)-Huprines Y and Z (40), which differ in structure by the halogen at position 3 (chlorine and fluorine, respectively), are more potent inhibitors of AChE than BChE and both compounds inhibited brain AChE (ex vivo), with (±)-huprine Y being approximately five times more potent than (±)-huprine Z [332].

h2n h2n

Other huperzine A hybrids that have been synthesised include structural features of both huperzine A and E2020 (donepezil). These hybrid compounds were synthesised with the aim of enabling an interaction between the 5,6,7,8-tetrahy-droquinolinone of huperzine A and the active site of AChE, and an interaction between the benzyl piperidine of E2020 and the peripheral binding site of AChE, but these derivatives were less potent than E2020 in the inhibition of AChE in vitro [333].

15.5.4 Magnolia officinalis Rehder & E.H.Wilson

In TCM, the bark of the root and stem of Magnolia officinalis Rehder & E.H.Wilson (Magnoliaceae) has been used as a remedy for alleviating anxiety and nervous disturbances. Many of the more recent studies investigating any basis for the CNS effects of M. officinalis have focused on the biphenolic lignans isolated from M. officinalis, honokiol (41) and magnolol (42), and although a variety of in vitro tests and some in vivo studies have been undertaken that may explain the reputed effects, there is a lack of clinical evidence for efficacy.

Modulation of cholinergic function could explain any favourable effects of this remedy on memory, as both honokiol and magnolol increase ChAT activity, they inhibit AChE activity in vitro and they increase hippocampal ACh (1) release in vivo [334]. Other activities that may preserve cognitive function have also been associated with M. officinalis and the component lignans. An extract [335], mag-nolol [336, 337] and honokiol [337, 338] showed antioxidant activity, and magnolol was neuroprotective in vitro [339]. In another study, both magnolol and honokiol, the latter being the most potent, were neuroprotective against glutamate-, NMDA-and H2O2-induced mitochondrial dysfunction in vitro, effects associated with an antioxidant action and antagonism of excitatory amino-acid-induced toxicity; these two compounds are suggested to differ in some mechanisms by which they are neu-roprotective [340, 341]. The anti-inflammatory activity of magnolol both in vitro and in vivo could be explained by its ability to inhibit COX and 5-LOX [342, 343] or by regulating the NF-kB pathway [344]. Modulation of the NF-kB pathway has also been shown to occur with honokiol [345] and it protected against cerebral ischemia-reperfusion injury in rodents, which was attributed to its antioxidant, anti-inflammatory and antiplatelet aggregation properties [346, 347]. Also from the bark of M. officinalis are the (+)- and (—)-enantiomers of syringaresinol and a mixture of their glucosides; these compounds promoted dose-dependent neuritogenesis in vitro [348]. These potential neurotrophins and the lignans honokiol and magnolol appear to show some activities that could be relevant in disorders in which cognition is impaired, but more in-depth studies, particularly those assessing their clinical relevance and safety, are needed.

15.5.5 Polygala tenuifolia Willd.

Polygala tenuifolia Willd. (Polygalaceae) root is a remedy used in TCM for cardiotonic and cerebrotonic effects and is considered to act as a sedative and tranquilliser and to alleviate amnesia, neuritis and insomnia [349, 350]. According to the Chinese Materia Medica, the root is supposed to produce an effect upon the will and mental powers, improving understanding and strengthening memory, and the Pharmacopoeia of the People's Republic of China (2005) includes P tenuifolia root as a remedy to anchor the mind and for forgetfulness [237].

Since in TCM a mixture of herbs, rather than one single herb or other substance, is commonly prescribed, a number of studies have investigated a traditional Chinese prescription, known as DX-9386, for any activities that could have relevance in improving cognitive processes. DX-9386 is composed of P. tenuifolia in addition to Panax ginseng C.A. Mey. (Araliaceae), Acorus gramineus [Soland.] (Acoraceae) and Poria cocos (Schwein.) F.A. Wolf (Fomitopsidaceae) (in the ratio 1:1:25:50 dry weight). Although this prescription has shown a number of favourable biological activities in relation to treating cognitive dysfunction, the contribution of each of the components in the prescription to the observed effects is unclear. Studies conducted have shown that DX-9386 may slow the ageing process as it ameliorated memory impairment and reduced lipid peroxide levels [351] and prolonged lifespan [352] in senescence-accelerated mice, and it ameliorated ethanol-induced memory impairment in rodents [353]. The enhancement of hippocampal long-term potentiation of synaptic transmission by DX-9386 was attributed to P. ginseng and P. cocos, with P. tenuifolia only producing a minor effect [354].

Other studies have also investigated P. tenuifolia amongst a mixture of 12 prescription components in a formula known as kami-utan-to (KUT), a remedy used in traditional Japanese medicine to treat psychoneurological diseases. Studies have shown KUT to dose-dependently upregulate ChAT activity and increase NGF secretion in vitro, and to improve passive avoidance behaviour and induce ChAT activity in the cerebral cortex of aged rats and in scopolamine-induced memory impaired rats [355, 356]. These activities were mainly attributed to the P. tenuifolia content of the prescription, since the effects on ChAT activity and NGF secretion were not as pronounced when treated with KUT in the absence of P. tenuifolia root, and P. tenuifolia root extract alone was shown to upregulate ChAT activity and increase NGF secretion in vitro [355, 356]. The clinical potential of KUT in cognitive disorders has shown some promise, as KUT treatment improved memory-related behaviour in AD patients [356].

Some studies on P. tenuifolia root extract alone in the absence of other traditional remedies have provided more evidence to explain the use of this plant in TCM for CNS effects. Extracts reversed scopolamine-induced cognitive impairment and, to some extent, improved memory and behavioural disorders induced by CNS lesions in rodents; in addition, they showed a neuroprotective action against glutamate and amyloid precursor protein (APP) in vitro and dose-dependently inhibited AChE activity in vitro [357-359], indicating an effect on cholinergic function in addition to other modes of action. Although extracts of P. tenuifolia have been associated with a neuroprotective action and an aqueous extract enhanced axonal length in cortical neurons treated with amyloid in vitro, the aqueous extract was not effective in recovering dendritic atrophy and synaptic loss [360]. Anti-inflammatory activity could also contribute to the favourable CNS effects associated with this plant. An aqueous extract of P. tenuifolia root inhibited IL-1 mediated TNF secretion by astrocytes [361] and dose-dependently inhibited ethanol-induced IL-1 secretion in vitro [362].

The compounds responsible for the effects of P. tenuifolia are unknown, although some cinnamic acid derivatives may explain the suggested cholinergic action as sinapic acid, a cinnamic acid derivative from P. tenuifolia root, increased ChAT activity in the frontal cortex in brain-lesioned rats [355]. Also from P. tenuifolia root is the acylated oligosaccharide tenuifoliside B, which has a sinapoyl moiety in its structure. This compound showed a cerebral protective effect on KCN-induced anoxia, and it ameliorated the scopolamine-induced impairment of performance in a passive avoidance task in rodents [363]. It is suggested that sinapic acid, or a sinapoyl moiety, could be an important structural feature for the molecular interactions that modulate cognitve function. To support this theory, a further study was conducted which showed that sinapic acid also inhibited KCN-induced hypoxia and scopolamine-induced memory impairment and it inhibited basal-forebrain-lesion-induced cerebral cholinergic dysfunction in rodents [364]. Tenuigenin, extracted from P. tenuifolia, inhibited P-amyloid secretion via P-secretase (BACE) inhibition in vitro [365]. Other compounds that have been associated with some of the in vitro effects observed with P. tenuifolia extracts include saponins with the aglycone pre-senegenin (onjisaponins A, B, E, F and G), which increased NGF levels in astrocyte cultures, with onjisaponin F also inducing the ChAT mRNA level in rat basal fore-brain cells [366].

15.5.6 Salvia miltiorhiza Bunge

The dried root of Salvia miltiorhiza Bunge (Lamiaceae), also known as Chinese sage or 'dan shen', is red in colour and was therefore believed to be a treatment for blood disorders in folk medicine. In TCM the root has been used as a remedy to stabilise the heart and calm the nerves and to treat circulatory disorders, insomnia and neurasthenia, and to alleviate inflammation [151, 367]. The Pharmacopoeia of the People's Republic of China (2005) includes S. miltiorhiza root as a remedy for fidgets and insomnia, amongst other indications [237]. S. miltiorhiza root extracts have been investigated for a wide range of activities in relation to effects on the cardiovascular system but also for effects on the CNS, and in cerebral ischemia in particular. Some of the biological activities associated with S. miltiorhiza could also be relevant to the modulation of cognitive function and may provide some explanation for the traditional uses of this plant in some neural disorders.

S. miltiorhiza extracts have been shown to modulate the action of some neuropep-tides, although studies on this subject are relatively limited and the pharmacological activities reported often provide theoretical explanations for their clinical relevance in CNS disorders. S. miltiorhiza has been suggested to modify the actions of vasoactive intestinal peptide (VIP), a neuropeptide distributed within the gastrointestinal tract and CNS [368], and somatostatin [369], a CNS neuropeptide that has been implicated in learning and memory [370, 371]; both neuropeptides are considered to play a role in changes involved in cerebral ischemia. S. miltiorhiza has also been suggested to influence the action of substance P, which is associated with neuronal damage following cerebral ischemia [372] and which is decreased in the brains of AD patients [373]. The compounds in S. miltiorhiza that protect against ischemic damage in the CNS appear to be the tanshinones [374], including tanshinone IIb, which was effective in reducing stroke-induced brain damage [375].

S. miltiorhiza may modify ischemic damage to the CNS by antioxidant effects. Since the metabolism of free fatty acids from the breakdown of lipid membranes and the generation of oxygen free radicals occur in ischemia, further brain injury occurs [376] and cognitive ability may be affected. S. miltiorhiza reduces lipid peroxidation and could therefore protect against these effects on the CNS during ischemia [377-379]. The herbal mixture known as 'Salvia compositus', composed of Dalbergia odorifera T.C.Chen (Leguminosae) and S. miltiorhiza, is reported to modulate electrical activities of the cerebral cortex [380], to ameliorate cerebral oedema [381] and to inhibit oxidation of lipids [382].

Several compounds isolated from S. miltiorhiza root have shown antioxidant effects, which may explain any protective effects this plant may have against ischemic damage, and could also be relevant in modifying the progression of some cognitive disorders. The antioxidant modes of action of compounds from S. miltiorhiza are well documented [383]. Caffeic acid dimers, trimers and tetramers are some of the antioxidant compounds from the root of this plant and include rosmarinic acid (43) and salvianolic acids A (44) and B (45) [378, 384], with the latter two compounds also protecting against memory impairment induced by cerebral ischemia in rodents [385, 386]. Salvianolic acid B also protects against amyloid-induced neurotoxicity in vitro, which was associated with an antioxidant effect [387]. A series of quinones from the root of S. miltiorhiza have shown antioxidant activity in vitro [388, 389]. The antioxidant potency of these compounds was rosmariquinone, dihydrotanshinone (46), miltirone 1 > dehydrorosmariquinone > cryptotanshinone (47) > tanshinone Ila (48), which suggested that the structural features important

43 Rosmarinic acid

44 Salvianolic acid A

43 Rosmarinic acid

44 Salvianolic acid A

45 Salvianolic acid B

45 Salvianolic acid B

for the antioxidant activity were additional conjugated double bonds in the A ring, a dihydrofuran ring rather than a furan ring and an isopropyl substituent ortho to a quinone carbonyl rather than a dihydrofuran ring [388].

The anti-inflammatory effects of some S. miltiorhiza components could perhaps be exploited for use in cognitive disorders. Tanshinones from S. miltiorhiza root were anti-inflammatory in vivo and were active against 5-LOX in vitro, although they were not as active as the crude extracts [349, 390], suggesting that other compounds from the root may be more potent against LOX activity, or perhaps a synergistic effect might occur with the crude extract. In addition to an anti-inflammatory action in vivo, tanshinone I (49) inhibited phospholipase A2 and prostaglandin (PG) E2 formation in vitro, but did not affect COX-2 activity or expression [391], but cryptotanshinone does inhibit COX-2 activity [392]. These studies suggest that cryptotanshinone, but not tanshinone I, may have potential in modulating inflammatory processes in cognitive disorders such as AD, since many studies suggest that COX-inhibiting drugs prevent or delay the onset of AD [58-62].

Other, perhaps more relevant, activities of S. miltiorhiza root are inhibition of neuronal cell death by inhibition of presynaptic glutamate release, currently a therapeutic target in AD, and protection against (i-amyloid-induced neuropathological changes in the hippocampus in vivo, effects observed with an extract and tanshinone, respectively [393, 394]. Also significant is that the first diterpenoids to show AChE inhibitory activity were isolated from S. miltiorhiza root, with dihydrotanshi-none and cryptotanshinone being the most active [395]. These dihydrofurans were more active than the furans tanshinones I and Ila [395], suggesting that the more flexible dihydrofuran improves the binding affinity to the active site of the enzyme.

46 Dihydrotanshinone

47 Cryptotanshinone

46 Dihydrotanshinone

47 Cryptotanshinone

48 Tanshinone IIa

49 Tanshinone I

48 Tanshinone IIa

49 Tanshinone I

Although many activities associated with the treatment of cognitive disorders have been associated with numerous traditional remedies, studies to determine the bioavailability and if active compounds reach the site of action in the CNS are very limited. Studies on S. miltiorhiza compounds with regard to these parameters have shown that the bioavailability of salvianolic acid B [396] and tanshinone IIa [397] is low, and that penetration of cryptotanshinone across the blood-brain barrier may be limited in vivo [398], effects which may affect efficacy. In addition, an extract of S. miltiorhiza induced cytochrome P450 [399], which raises the possibility of drug interactions, and treatment with a preparation of S. miltiorhiza in patients on long-term warfarin therapy increased haemorrhage risk [400].

15.6 Plants Used in Traditional European Medicine

The practice of herbal medicine in Europe has been influenced by the remedies used and described by the ancient Greeks and by the traditions of Middle Eastern countries. Also often used are those herbal remedies used in North American traditional medicine, whose uses were learnt from the native Americans by the European settlers largely in the period between the 17th and 19th centuries.

15.6.1 Galanthus and Narcissus Species

Galanthus species (Amaryllidaceae) were used traditionally in Bulgaria and Turkey for neurological conditions [401]. The alkaloid galantamine (50) was originally isolated in the mid-20th century from G. woronowii Losinsk., commonly known as the 'snowdrop', but has now also been isolated from some species of Narcissus (Amaryllidaceae) and Leucojum aestivum L. (Amaryllidaceae) [401]. Galantamine is one of the few drugs of natural origin used to alleviate symptoms in AD, and it is now a licensed drug in Europe for this purpose.

The mode of action of galantamine is principally by inhibition of AChE. It is reported to bind at the base of the active site gorge of the enzyme (Torpedo cali-fornica AChE), interacting with both the choline-binding site and the acyl-binding pocket, and the tertiary amine is suggested to form an H-bond (via the N-methyl group) near the top of the gorge (to Asp-72) [402]. Galantamine is more selective for AChE than BChE and provides complete oral bioavailability [403, 404].

In clinical, multicentre, randomised, controlled trials, galantamine was well tolerated and significantly improved cognitive function when administered to AD patients [405, 406]. The cognitive benefits produced with galantamine treatment appear to be sustained for at least 3 years, which is a much longer time than for other drugs of this type [407]. Galantamine could have advantages over some other known AChE inhibitors in clinical use, as it is also a positive allosteric modulator of nicotinic receptors [408, 409], another activity that could modulate cholinergic and therefore cognitive function. There is also evidence to suggest that galantamine may be of some therapeutic value in vascular dementia and in dementia with Lewy bodies, as well as AD patients [410, 411], and it also improved memory and attention in patients with schizophrenia who were stabilised on risperidone [412].

In view of the success of galantamine as a naturally derived drug, it is not surprising that other alkaloids from species of Narcissus have been investigated for their anti-ChE activity. In one study, 26 extracts from different species of Narcissus and 23 Amaryllidaceae alkaloids were evaluated, but only 7 of these alkaloids, those with galantamine and lycorine (51) structural skeleton types, inhibited AChE [413]. In this study, 11-hydroxygalantamine (52) had similar potency to galantamine in the inhibition of AChE, epinorgalantamine (53) was less potent and sanguinine (54) was even more potent than galantamine, an effect attributed to the additional hydroxyl group in this structure, for interaction with AChE [413]. Among the lycorine type alkaloids, assoanine (55) was the most active AChE inhibitor in this study, but it was still four-fold less potent than galantamine [413]. Another study identified the alkaloid ungiminorine as an AChE inhibitory component, although the activity was relatively weak [414].

50 Galantamine 51 Lycorine 52 11-Hydroxygalantamine
53 Epinorgalantamine 54 Sanguinine 55 Assoanine

15.6.2 Melissa officinalis L.

In traditional European medicine Melissa officinalis L. (Lamiaceae) has been used as a remedy for over 2000 years, and it is reputed to treat melancholia, neuroses and hysteria, and the plant has been acclaimed for promoting long life and for restoring memory [415-417]. John Hill (1751) reported that M. officinalis was 'Good for disorders of the head and stomach' [418]. M. officinalis has also been used in other traditional practices of medicine and was considered as a treatment for depression in Arabic medicine [417] and used to treat hysteria in traditional Greek medicine [419].

Some clinical studies have investigated the reputed cognitive effects of M. officinalis. Some improvement in cognitive performance has been reported in healthy (non-AD) participants in randomised, placebo-controlled, double-blind, crossover studies, following treatment with cholinergically active (determined using in vitro studies) M. officinalis dried leaf [420] or a standardised extract [421], and cognitive improvements and a positive effect on agitation were also reported in AD patients administered an extract of M. officinalis for 4 months in a double-blind, randomised, placebo-controlled trial [422]. The results of a double-blind, placebo-controlled trial to investigate the effects of aromatherapy with M. officinalis oil in patients with clinically significant agitation associated with dementia indicated that M. officinalis oil may be a safe and effective treatment for agitation in people with AD [423].

Some investigations have been conducted to ascertain a pharmacological basis for the reputed cognitive enhancing effects of M. officinalis and to explain the favourable effects observed in some clinical trials. The essential oil and an ethano-lic extract from M. officinalis weakly inhibit AChE [424] and some monoterpenoids that have been identified in the essential oil of M. officinalis including citral (a mixture of the isomers geranial and neral) [415, 425, 426] are also weak inhibitors of AChE [155]. Another study showed no AChE inhibitory effect to be associated with aqueous and methanolic extracts of M. officinalis [427].

Other activities of M. officinalis that may be relevant in AD therapy and that may explain the reported cognitive improvements include antioxidant effects [425, 428, 429], possible estrogenic effects [97] and binding to muscarinic and nicotinic receptors in vitro [430,431]. However, the randomised, placebo-controlled, doubleblind, balanced-crossover study which investigated the acute effects on cognition and mood of a standardised extract of M. officinalis did not correlate the modulation of cognitive function observed with an effect on cholinergic neurotransmission [421]. It was proposed that the low cholinergic binding properties shown in this study could be a result of a loss of volatile components in this particular extract [421]. Other studies indicate that different M. officinalis extracts may vary in their cholinergic receptor binding properties [431]. The differences observed in the cholinergic binding effects of M. officinalis preparations could be due to natural chemical variation in the M. officinalis used or different extraction methods; chemical variation can occur in M. officinalis essential oils due to various factors [426, 432-434]. These possibilities emphasise the need for quality control in the production of herbal remedies for therapeutic purposes. Continued investigation on the modes of action, including modulation of neurotransmitter systems in the CNS, would be useful to further assess the potential of compounds from M. offici-nalis extracts and essential oil for use in cognitive disorders.

15.6.3 Salvia officinalis L. and S. lavandulifolia Vahl

Research into the historical literature has identified several quotes in 16th- and 17th-century English herbals, describing sage (species of Salvia (Lamiaceae)) to improve memory [98]. In his late-16th-century English herbal, Gerard writes about sage: 'It is singularly good for the head and brain and quickenethe the nerves and memory', and Culpeper, writing about 50 years later, says that 'It also heals the memory, warming and quickening the senses', whilst Hill in 1756 poignantly describes the tragic effects associated with ageing by stating, 'Sage will retard that rapid progress of decay that treads upon our heels so fast in latter years of life, will preserve faculty and memory more valuable to the rational mind than life itself' [98]. Effects on the CNS have been reported for a number of species of Salvia, including sedative and hypnotic, hallucinogenic, memory-enhancing, anticonvulsant, neuroprotective and anti-Parkinsonian activities [435, 436].

In recent years a variety of studies have been conducted to investigate if there is any scientific evidence to explain the traditional uses of sage for improving memory, with many studies focusing on extracts and essential oils from S. officinalis L. and S. lavandulifolia Vahl. An ethanolic extract and the steam-distilled oil of S. officinalis, and the oil of S. lavandulifolia gave inhibition of AChE at relatively low concentrations in vitro [430]. The cyclic monoterpenoids 1,8-cineole (56) and a-pinene (57) were shown to inhibit AChE in vitro and were considered to explain the anti-ChE activity of the S. lavandulifolia oil, although other constituents of the oil may also have contributed, perhaps synergistically [154, 437].

Although the observed anti-ChE activity of the monoterpenoids is particularly interesting, since many of the previously reported AChE inhibitors of natural origin were amines, the monoterpenoids were considerably less potent by a factor of at least 103 than the alkaloid inhibitors such as physostigmine [154]. The relevance of in vitro test results with sage extracts and oils has been explored by further tests in vivo. One study showed that oral administration of S. lavandulifolia oil to rats decreased AChE activity in both the striatum and the hippocampus, compared to the control rats, suggesting that one or more oil constituents or their metabolites reach the brain and inhibit AChE in select brain areas, which is consistent with evidence of inhibition of AChE in vitro [430, 438]. Another study assessed the effect of an ethanolic extract of S. officinalis on memory retention of passive avoidance learning in rodents; the potentiation of memory retention observed with this treatment may have been associated with an interaction with the muscarinic and nicotinic cholin-ergic systems [439].

Extracts from some species of Salvia, including from both S. officinalis and S. lavandulifolia, have also shown antioxidant effects [98, 428, 440]. An aqueous methanolic extract of S. officinalis dose-dependently inhibited lipid peroxidation [428], and antioxidant effects were also shown with an ethanolic extract of S. lavandulifolia; both the water-soluble and chloroform-soluble fractions of the latter extract gave similar activity [98]. Compounds isolated from species of Salvia that have shown antioxidant effects include salvianolic acids I, K and L and various other phenolic compounds [441,442].

Species of Salvia have also been investigated for activities relevant to producing an anti-inflammatory action. Inhibition of eicosanoid synthesis was observed with an ethanol extract of S. lavandulifolia, although this effect was relatively weak [98]. Some essential oil constituents from S. lavandulifolia have also been assessed for their effects on eicosanoid synthesis, but only the monoterpenoid a-pinene (comprising 5% of the essential oil) produced significant activity, although it did show some weak selectivity for inhibition of leukotriene B4 (LTB4) generation [98]. Ursolic acid, from S. officinalis, has anti-inflammatory activity in vivo [443].

Some other, perhaps relevant, activities have also been reported for sage. A standardised extract of S. officinalis and one of its components rosmarinic acid (43) were neuroprotective against P-amyloid-induced toxicity in vitro [444]. In addition, dose-dependent estrogenic activity was observed in vitro with an ethanolic extract from S. lavandulifolia [98], and although the possible benefits of estrogenic compounds on cognition are still unclear, an estrogenic effect of sage might also provide some explanation for the reputed effects in traditional medicine.

Some clinical studies with human volunteers, including AD patients, have also been reported. In a placebo-controlled, double-blind, balanced, crossover study, subjects (healthy young adults) received a standardised oil extract of S. lavandulifolia and vehicle (sunflower oil) alone, with a 7-d washout period between each treatment [445]. The sage treatment was associated with significant effects on cognitive ability, including improvements in immediate word-recall scores [445]. A similar study also showed a positive modulation of mood and cognition in healthy young adults when given doses of a standardised essential oil of S. lavandulifolia in a placebo-controlled, double-blind, balanced, crossover study [446]. In a small pilot trial, 11 patients showing mild to moderate symptoms of AD were orally administered S. lavandulifolia oil, which significantly improved cognitive function; a reduction in neuropsychiatric symptoms and an improvement in attention were observed [447]. Further evidence for the cognitive enhancing effects of sage was shown in a multicentre, double-blind, randomised, placebo-controlled trial. In this study, patients showing some typical AD symptoms were treated with an extract of S. officinalis and significantly better outcomes in measurements of cognitive function were observed; there was no significant difference in side-effects between the treated and placebo groups, but a greater incidence of agitation in the placebo group was observed [448], suggesting the sage treatment may have also alleviated agitation.

15.7 Plants Used in African and South American Traditional Medicine

African traditional medicine, which is diverse because of the vast range of habitats, languages and cultural groups, has a long history of use, and in some countries up to 90% of the population relies on plants as the only source of medicines [449]. Countries north of the Sahara have a similar ethnopharmacology because of an influence from Islamic cultures over many centuries. Sub-Saharan cultures are more diverse but do share some common features, such as the consideration of spiritual influences and beings in the disease and healing process. In sub-Saharan Africa, the influence of European culture came quite late and was diversified because of the different colonial powers and the climate being generally not very amenable to growing some of the traditional European plants. Therefore, the endemic medical systems were arguably more preserved than in many parts of South America, where European domination occurred two or three centuries earlier. However, in the more remote parts of the continent, especially where there was also considerable biodiversity, extensive knowledge about the medicinal uses of the local plants remained, and consequently, several drugs have been included in European medicine over the years.

15.7.1 Physostigma venenosum Balf.

The calabar bean, the seeds of Physostigma venenosum Balf. (Leguminosae), was used traditionally in Africa, particularly south-eastern Nigeria, for ritual deaths associated with the funeral of a chief and as an ordeal poison, claimed to determine the guilt or innocence of persons accused of a crime [450-452]. Rapid death was an indication that the suspect was guilty and innocence was shown by survival. This logic does appear to have some scientific basis, as differences in absorption might arise due to psychosomatic influences, with nervous sipping by guilty suspects enabling greater absorption [453]. The toxic effects of the calabar bean extract were found to be due to excessive cholinergic stimulation resulting in increased salivation, nausea, bradycardia, muscle cramps and respiratory failure, as well as CNS effects. This effect was attributed to the presence of an alkaloid with an unusual pyrroloindole skeleton, physostigmine (58), also known as eserine [454], which potently inhibits AChE [455]. Physostigmine has been shown to inhibit both G1 and G4 AChE forms, the major AChE isoenzymes present in mammalian CNS [456]. Physostigmine also inhibits with similar potency BChE, an enzyme that has been implicated in the etiology and progression of AD [457].

Physostigmine protects mice against cognitive impairment caused by oxygen deficit, and it improves learning [452] and antagonises scopolamine-induced impairment of cognitive function in rats [458]. Physostigmine, a short-acting reversible AChE inhibitor, is also reported to have shown significant cognitive benefits in both normal and AD patients [306, 459], but clinical use may be limited by its short half-life, which would require frequent dosing. To develop compounds which are lipophilic, and so able to cross the blood-brain barrier, and which can improve on the pharmacokinetic profile of physostigmine, a number of compounds structurally related to physostigmine that inhibit AChE have been synthesised with the aim of developing new drugs to alleviate cognitive dysfunction in AD.

The most therapeutically successful of these compounds to date is rivastigmine (59), an AChE inhibitor that is now licensed for use in Europe for the symptomatic treatment of mild to moderate dementia in AD or Parkinson's disease. Rivastig-mine inhibits AChE in the cortex and hippocampus and preferentially inhibits the Gi form of AChE [460], and it improves cognition in AD patients, an effect that has been correlated with the level of AChE inhibition [461-465]. It also potently inhibits AChE and BChE in Alzheimer's plaques and tangles [466]. Other synthetic compounds being investigated include cymserine (60), which has a structure based on the backbone of physostigmine and which potently and concentration-dependently binds with human BChE [467], and a structural analogue of cymserine, bisnorcymserine, which also potently inhibits BChE in vitro [468]. Another derivative of physostigmine is eptastigmine (heptyl-physostigmine tartrate) (61), in which the carbamoylmethyl group in position 5 of the side chain has been substituted with a carbamoylheptyl group [469]. Although it is an effective inhibitor of both AChE and BChE and it improves cognitive performance in AD patients, this compound caused haematologic adverse effects, resulting in the suspension of any further clinical trials [469].

58 Physostigmine

59 Rivastigmine

58 Physostigmine

59 Rivastigmine

60 Cymserine

60 Cymserine

61 Eptastigmine

15.7.2 Pilocarpus Species

Jaborandi leaves are obtained from various species of Pilocarpus (Rutaceae), found in South America, but members of this genus are also found in the West Indies and Central America, although to a lesser extent. The leaves from species of

Pilocarpus, including P. microphyllus Stapf, have been used traditionally in South America to induce sweating and urination, considered to eliminate toxins from the body. The leaves contain a number of imidazole alkaloids including pilocarpine (62) [450], which has structural similarities to ACh (1) and is a muscarinic receptor agonist [116].

Chewing the leaves of Jaborandi therefore produces cholinergic effects such as contraction of the pupils and excessive salivation. It is for this action that salts of pilocarpine have been used as topical treatments to reduce the raised intra-ocular pressure that occurs in glaucoma. Since modulation of the cholinergic system is considered to be involved in learning and memory processes, muscarinic receptor modulators could be used clinically to achieve cognitive improvements. Pilocarpine has been shown to enhance cognitive performance in rodents [470-472], although studies to investigate cognitive effects in humans are lacking, probably due to its poor pharmacokinetic profile as it poorly penetrates the blood-brain barrier, in addition to having undesirable side-effects, such as nausea and vomiting, sweating and bradycardia. Although, it has been suggested that co-administration of a compound that blocks peripheral muscarinic receptors with pilocarpine, or with other muscarinic receptor agonists, may reduce the potential for adverse effects [473]. It should also be noted that CNS symptoms may be induced or exacerbated with the use of pilocarpine eye drops in patients with AD [474, 475].

15.7.3 Ptychopetalum olacoides Benth.

Ptychopetalum olacoides Benth. (Olacaceae) originates from the Amazon and the roots have been used as a traditional remedy for a variety of ailments of the CNS and stress, particularly age-related conditions. The roots are known commonly as 'mara-puama', 'muirapuama' or 'miranta' and are now internationally available in general health-food stores. An ethanol extract of the roots of this plant improved memory retrieval when administered to both young and ageing rodents [476, 477]. The mechanisms of action to explain these effects and the active compounds are unknown. Some studies show root extracts of P. olacoides to have antioxidant [478], AChE inhibitory [479] and neuroprotective activities [480], effects that could explain the experimental and reputed effects on memory function. More studies are necessary to investigate further the underlying modes of action that the compounds

62 Pilocarpine

62 Pilocarpine from the roots of this plant have on the CNS and any clinical relevance this remedy may have in cognitive disorders.

15.8 Conclusions

Many plants have a reputation in a variety of traditional practices of medicine for alleviating symptoms of cognitive disorders such as memory decline; such plants have been used for medicinal purposes for a long time and in some cases continue to be used. There have been numerous scientific studies on a number of these plants to establish any pharmacological basis for their historical uses, although the extent to which each species has been investigated varies considerably. Very few of the plants that have a reputation for modifying cognitive abilities have been extensively studied, and there is frequently a lack of knowledge about the compounds responsible for the observed activities, and reliable clinical studies are also uncommon. Amongst those plants which have been subjected to more thorough investigations is Ginkgo biloba, which has shown biological activities relevant to modulation of cognitive function both in vitro and in vivo, and there is some evidence of efficacy in both healthy and AD subjects.

It is particularly interesting that of the four main currently licensed drugs (donepezil (8), galantamine (50), memantine (13) and rivastigmine (59)) used to treat cognitive symptoms in AD, and which have been investigated for their potential for use in other cognitive disorders, two of these (galantamine and rivastigmine) were derived from plant sources. Some of the therapeutic single chemical entities that have been developed for clinical use have arisen from toxicological investigations, very often combined with chemical modification of the active toxic compound once its structure has been determined; rivastigmine, which is based on the structure of physostigmine (58), is an example of this. In other cases, a compound useful in the treatment of a cognitive disorder has been discovered by studies on a plant species which has attracted interest because of its traditional use for some other purposes, such as galantamine.

It should also be considered that, although the development of new and effective 'orthodox' drugs as single chemical entities for some cognitive disorders is one aim, the use of plant extracts can still be valuable, particularly as in many cases more than one constituent in a plant is responsible for the overall effect, and it is too simplistic to conceive that a single compound has the same effect or efficacy. Herbal preparations consisting of complex mixtures for therapeutic purposes are generally not accepted in modern Western medicine, and consequently many potentially useful plants will not be accepted for clinical use, although they may be extensively used in complementary and alternative therapies. In these circumstances, the role of scientific research is to provide evidence for their therapeutic applications in conventional Western medicine and to identify compounds responsible for the activity so that herbal products with the appropriate qualitative and quantitative chemical profile can be made available, with greater assurance of safety and efficacy.

In addition to concerns regarding the quality control issues associated with herbal medicinal products, the potential for their interactions with other medicines has not been widely studied and these issues need to be addressed.

In conclusion, it is apparent that the pharmacological activities of plants and their compounds often appear to reflect their uses in traditional medicine, although traditional medicines used to treat other disorders and poisons can also provide leads to develop herbal medicines and drugs to alleviate symptoms in cognitive disorders.

Acknowledgements We would like to thank Dr N. C. Veitch (Royal Botanic Gardens, Kew) for drawing the chemical structures.

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