Celastrus paniculatus Willd

Modern Ayurveda

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Celastrus paniculatus Willd. (Celastraceae) seeds and seed oil have been used in Ayurvedic medicine to stimulate intellect and to sharpen the memory [169, 170]. Many of the studies undertaken to establish any pharmacological basis for the reputed effects of C. paniculatus have focused on the seeds and seed oil. When administered orally to rats, the seed oil decreased levels of noradrenaline, dopamine and 5-HT in the brain, which was correlated with an improvement in learning and memory processes, without inducing neurotoxic effects [171]. Administration of the seed oil to rats also reversed a scopolamine-induced task deficit, but this effect was not associated with anti-ChE activity [172]. Other studies have explored more polar extracts from the seeds of C. paniculatus rather than the seed oil. An aqueous seed extract showed an antioxidant effect in the CNS, which may provide some explanation for the reputed benefits on memory, since this extract enhanced cognition in vivo [173]. A seed extract is also reported to increase brain phospholipid content in vivo, possibly as a consequence of increased myelination [174]. Aqueous seed extracts protected neuronal cells against glutamate-induced toxicity [175] and H2O2-induced toxicity [176], with methanol and ethanol extracts in addition to the seed oil also showing the latter effect [177]. Although the neuroprotective effect of the polar extracts was attributed to their antioxidant properties, the seed oil, which was the most potent neuroprotector, was suggested to act via a different mechanism [177].

Another C. paniculatus extract was evaluated for NMDA and y-aminobutyric acid (GABA) receptor binding and NGF effects, but did not produce any response [178]. Studies on the flowers from C. paniculatus have shown a methanol extract to be anti-inflammatory [179], which may also have some relevance in the management of neurodegenerative disorders. A polyherbal formula (Abana) containing C. paniculatus as a component amongst other herbs is used in Ayurvedic medicine, and dose-dependently improved memory in both young and aged rodents and reversed scopolamine- and diazepam-induced amnesia and reduced brain ChE activity [180]. The contribution of each of the component herbs of this formula to the observed effects, or if any synergistic effect occurred, is unknown. Although a number of studies have attempted to elucidate the mechanisms of action to explain the reputed effects of C. paniculatus on cognitive function, the compounds responsible for the observed activities have yet to be established.

15.4.5 Clitoria ternatea L.

The roots of the Indian medicinal plant Clitoria ternatea L. (Leguminosae) have a reputation for promoting intellect [170, 181]. This reputed effect may be related to effects on cholinergic activity in the CNS, as some studies have shown. A study investigating both the aerial parts and roots of C. ternatea showed that alcoholic root extracts were more effective than extracts of the aerial parts in attenuating memory deficits in rats [182]. Enhanced memory retention following oral administration of C. ternatea root extract was associated with increased levels of ACh (1) and ChAT in rat brain, but no relationship with inhibition of AChE activity was established, and cortical AChE activity was actually found to be increased [182]. However, another study showed that the triterpenoid taraxerol (17) from C. ternatea inhibited AChE both in vitro and in the brain of rodents in vivo, but it was not as potent as physostigmine [183]. An aqueous extract of the root also increased ACh levels in rat hippocampus following oral administration, and it was hypothesised that this effect may be due to an increase in ACh synthetic enzymes [184]. Other studies have indicated that C. ternatea extract can act as a nootropic, an anxiolytic, an antidepressant and an anticonvulsant and has antistress [185] and anti-inflammatory activities [186].

Further studies are necessary to establish the mechanism of action to explain the observed effects of the root extract on the CNS, and also to identify the compounds responsible for activity. It has been suggested that memory enhancement in vivo could be explained by an increase in functional growth of neurons of the amygdala, since this effect was observed in rodents orally administered with an aqueous root extract of C. ternatea [187].

16 Asiatic acid 17 Taraxerol

15.4.6 Curcuma longa L.

Regarded as a 'Rasayana' herb in Ayurveda to counteract ageing processes, Curcuma longa L. (Zingiberaceae) has also been used for culinary purposes and in the textile industry. Much research has focused on curcumin (18), a curcuminoid from C. longa rhizomes, and it has been shown to modulate a variety of molecular targets. In particular, studies have shown that some curcuminoids are associated with antioxidant and anti-inflammatory activities, but in general, studies with particular attention to cognitive disorders and any clinical relevance are lacking. In addition, further evaluation of potentially active compounds from C. longa, other than the curcuminoids, may contribute to the understanding of the traditional uses of this herb.

The antioxidant activity of curcumin is well documented [188, 189], and it is suggested to be the underlying mechanism to explain a number of beneficial effects on cognition. Curcumin was shown to be neuroprotective in vitro [190] and protected against ethanol-induced brain injury in vivo following oral administration, an effect that was related to a reduction in lipid peroxide levels and enhancement of glutathione in rat brain [191]. A neuroprotective action of curcumin was also observed in an animal model of Parkinson's disease, an effect also attributed to its antioxidant properties [192]. It also dose-dependently improved motor and cognitive impairment and significantly attenuated the associated oxidative stress in the brain when orally administered to rodents [193]. Some compounds from C. longa, including curcumin, demethoxycurcumin (19), bisdemethoxycurcumin (20) and calebin A (21) (and some synthetic analogues), were shown to protect PC12 cells from (P-amyloid insult in vitro [194, 195]; this activity was also suggested to be due to an antioxidant effect [196]. It is proposed that the hydrophobic bridge of the conjugated network in the curcumin structure enables penetration into the blood-brain barrier, and the more hydrophilic phenolic polar groups are important for its binding to p-amyloid [197].

19 = OMe, R2 = H; Demethoxycurcumin

20 R-i = R2 = H; Bisdemethoxycurcumin

19 = OMe, R2 = H; Demethoxycurcumin

20 R-i = R2 = H; Bisdemethoxycurcumin

Curcumin is also reported to be anti-inflammatory [65, 198] and has been suggested to modulate eicosanoid biosynthesis and COX-1, COX-2 and lipoxygenase (LOX) activities [199-202]. It also inhibits nuclear transcription factor kB (NF-kB) activation [65], although the clinical significance of the latter action in cognitive disorders is unclear. Attempts to improve selectivity for the COX enzymes and efficacy by developing compounds based on the structures of the curcumi-noids could be a route to new anti-inflammatory drugs. Some curcuminoid pyrazole and isoxazole analogues have been synthesised and are reported to inhibit COX and to be anti-inflammatory in vivo, and it was shown that replacement of the P-diketo in the curcumin structure with a pyrazole ring enhanced the COX-2/COX-1 selectivity [203].

15.4.7 Withania somnifera (L.) Dunal

Withania somnifera (L.) Dunal (Solanaceae) root, known as 'ashwagandha' in Sanskrit, is classed among 'Rasayanas', the rejuvenative tonics, and its use dates back almost 4000 years. It is considered to be one of the most highly regarded herbs in Ayurvedic medicine. The Ayurvedic scholar Charaka (10 BC) described the reputed effects associated with W somnifera: 'One obtains longevity, regains youth, gets a sharp memory and intellect and freedom from diseases, gets a lustrous complexion and strength of a horse' [204]. It has also traditionally been used to treat some inflammatory conditions such as arthritis.

Numerous studies provide experimental evidence to support the traditional uses of W somnifera, and many of these have associated the biological activities with various steroidal derivatives found in the root. The sitoindosides IX (22) and X

isolated from the root augmented learning acquisition and memory in both young and old rats [205]. This observation could be explained by a modulatory effect on cholinergic function, since another study with an extract of W. somnifera containing the sitoindosides VII-X and withaferin A (23) resulted in enhanced AChE activity in the lateral septum and globus pallidus and decreased AChE activity in the vertical diagonal band, enhanced muscarinic M1 receptor binding in the lateral and medial septum and the frontal cortices, and increased muscarinic M2 receptor binding sites in cortical regions, when administered to rodents [206]. However, it was not shown to affect GABAa, benzodiazepine receptor binding, or NMDA or amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) glutamate receptor subtypes in this study [206]. Another study showed a similar extract containing the same sitoindosides and withaferin A to reverse the ibotenic acid-induced cognitive deficit and the reduction in cholinergic markers (e.g. ACh (1), ChAT) in rodents [207]. Tests in vitro have shown a methanol extract of W. somnifera to inhibit AChE [208] and some withanolides inhibit AChE and BChE, with withaferin A, 2,3-dihydrowithaferin A (24) and 5P,6P-epoxy-4^-hydroxy-1-oxowitha-2,14,24-trienolide (25) being more active against AChE activity [209, 210]. These studies indicate that W. somnifera and some of its components, particularly some withanolides and sitoindosides, may improve cognition by influencing cholinergic neurotransmission, although other mechanisms of action have also been suggested.

Withanolides Mechanisms
22 Sitoindoside IX 25 R = H; A2'3, A14'15

A reversal of scopolamine-induced disruption of acquisition and attention and attenuation of amnesia was observed when a root extract of W. somnifera was administered to mice, and these effects were suggested to be due to a nootropic effect [211]. Other studies have shown that W. somnifera root (methanol extract), and some of the withanolide derivatives in particular, could dose-dependently promote dendrite formation in human neuroblastoma cells in vitro [212, 213]. Withanolide A and withanosides IV and VI are also reported to extend axons and dendrites, respectively, in vitro [214], and withanolide A is considered to reconstruct neuronal networks in vivo [215]. The clinical relevance of these effects is unknown, but cholinergic function could be modulated if neurite outgrowth were to occur in the CNS at therapeutic doses and with consideration of pharmacokinetic profiles of the relevant compounds in vivo. The main metabolite of withanoside IV following oral administration was identified as the aglycone sominone, which induced ax-onal and dendritic regeneration and synaptic reconstruction in cultured rat cortical neurons [216]. The use of W. somnifera to improve some memory disorders shows promise, if compounds demonstrate a suitable pharmacokinetic profile for efficacy. A neuroprotective action has also been considered as an explanation for the reputed effects of the root of this medicinal plant, since a root extract significantly reduced the number of hippocampal degenerating cells in the brains of stressed rodents [217] and was neuroprotective in an animal model of Parkinson's disease [218].

In addition to the steroidal derivatives, other compounds may contribute to the reputed and pharmacological effects of W somnifera root preparations. The cognitive benefits associated with nicotine (4) [37-39] could also explain the effects on memory observed with W. somnifera, since this alkaloid is reported to occur in W. somnifera root [148]. However, other studies have not reported it to be present [219, 220]. Chemical variation in W somnifera plants has been reported to occur [221], which emphasises the need for standardisation of plant-derived products for therapeutic use.

Other activities that may be advantageous in the alleviation of some cognitive disorders are anti-inflammatory and antioxidant effects, both of which have been associated with W somnifera. Inhibition of lipid peroxidation both in vitro and in vivo has been observed with extracts of the root [222, 223], with the root extract and the glycowithanolides (containing equimolar concentrations of sitoindosides VII-X and withaferin A) protecting against lipid peroxidation due to an antioxidant action [224, 225]. In addition to the withanolides being antioxidant [189, 226-228] and decreasing lipid peroxidation in rodent brains, withanolides and sitoindosides (VII-X) also enhanced catalase and glutathione peroxidase activities in rat frontal cortex and striatum [225, 226, 229]. Phenolic compounds from W somnifera root might also contribute to the overall antioxidant properties of this plant [230].

Evidence for the anti-inflammatory effects of W somnifera is apparent in several studies. Root extracts were effective against arthritis and associated biochemical markers in rodents [231,232]; they reduced serum protein levels (a2-macroglobulin, an indicator of inflammatory conditions) [233, 234] and also reduced interleukin-1 (IL-1) and tumour necrosis factor (TNF)-a levels in vivo [235], which may be of some clinical relevance as some inflammatory mediators have been linked with senile plaque formation in some cognitive disorders. The compounds responsible for these observations require further study, although a dimeric withanolide, ashwa-gandhanolide, is an inhibitor of COX-2 activity [228]. The leaves of W somnifera leaves are also reported to have anti-inflammatory activity [236].

W somnifera root has been extensively studied and shown to possess a variety of activities that could be relevant to improve cognitive impairment. It appears to have therapeutic potential for treating memory-related disorders, but further evidence of clinical safety and efficacy is still needed before this promising herbal drug could be considered for wider use in cognitive disorders.

15.5 Plants Used in Traditional Chinese Medicine (TCM)

The practice of TCM has been documented for thousands of years, and the medicinal preparations used include various substances of animal, fungal and plant origin. TCM has also influenced the traditional medicine practiced in neighbouring regions, such as Japan, Korea and Vietnam.

15.5.1 Evodia rutaecarpa (Juss.) Benth.

The plant described in the Pharmacopoeia of the People's Republic of China (2005) as Evodia rutaecarpa (Juss.) Benth. (Rutaceae) is used in TCM for its reputed cardiotonic, restorative and analgesic effects [237]. Extracts and alkaloids isolated from this plant have been investigated for activities that might help to explain the reputed restorative effects. An ethanol extract of this plant and four compounds present, dehydroevodiamine (26), evodiamine (27), rutaecarpine (28) and synephrine (29), have been shown to be anti-inflammatory in vitro [238], an action that has been implicated as potential therapy in some cognitive disorders.

Gaba Nmda Balance
28 Rutaecarpine 29 Synephrine

The alkaloid rutaecarpine is also reported to inhibit COX-2 activity in vitro and to be anti-inflammatory in vivo [239], although another study showed evodiamine to inhibit COX-2 induction and NF-kB activation, whilst rutaecarpine did not show these effects [240]. Evodiamine has also been shown to inhibit both constitutive and induced NF-kB activation and NF-KB-regulated gene expression [241]. Dehydroevodiamine increases cerebral blood flow in vivo [242], an action that might also improve cognitive function, and it may have a neuroprotective action, since it inhibited glutamate uptake and release in vitro [243]. Dehydroevodiamine (hy-drochloride) also prevents impairment of learning and memory and neuronal loss

[244] and is not considered to be associated with any serious adverse effects [245]. E. rutaecarpa extract and dehydroevodiamine both inhibited AChE in vitro and reversed scopolamine-induced memory impairment in rats [246]. In addition to reversing scopolamine-induced amnesia, dehydroevodiamine is reported to be even more effective in the reversal of P-amyloid-peptide-induced amnesia in vivo [247], indicating that it may improve cognitive ability by influencing cholinergic function and by other mechanisms.

Since the alkaloids rutaecarpine and dehydroevodiamine are inhibitors of ChE, their chemical structures have been used as a basis for the development of new ChE inhibitors, including synthetic compounds which combine the structural features of these alkaloids with tacrine (7). Inhibition of both AChE and BChE in vitro occurred with the synthetic analogues (8Z)-5,6-dihydro-8H-isoquino[1,2-b]quinazolin-8-imine, 5,8-dihydro-6H-isoquino[1,2-b]quinazoline, 5,7,8,13-tetra-hydroindolo [2',3':3,4]pyrido[2,1-b]quinazoline and N-(2-phenylethyl)-N-[(12Z)-7,8,9,10-tetrahydroazepino [2,1-b]quinazolin-12(6H)-ylidene]amine, with 5,7,8,13-tetrahydroindolo [2',3':3,4]pyrido[2,1-b]quinazoline and N-(2-phenylethyl)-N-[(12Z)-7,8,9,10-tetrahydroazepino [2,1-b]quinazolin-12(6H)-ylidene]amine showing higher affinity for BChE, but the dibenzo-analogue of dehydroevodiamine (13-methyl-5,8-dihydro-6H-isoquino[1,2-b]quinazolin-13-ium chloride) showed greater selectivity for AChE compared to BChE [248].

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