Ayurvedic medicine is the oldest medical system in the world with written records in Sanskrit dating back at least 5000 years. It originates from the Indian subcontinent and has also influenced the traditional medical system in Thailand. The practice of Ayurvedic medicine is now widely used throughout the world as a complementary medicine.
Areca catechu L.
Arecoline is the major alkaloid of those present in betel or areca nuts, the fruit of the palm tree Areca catechu L. (Arecaceae), which is extensively chewed to induce salivation and euphoria throughout the Indian subcontinent and other parts of southeast Asia. It is estimated that 500 million people regularly chew betel nut (often referred to as ‘pan’ or ‘paan’ in India) in a form which is usually shredded, mixed with lime and wrapped in a leaf from the Piper betel Blanco (Piperaceae) plant, although chewing of betel nuts has been positively correlated with an incidence of oral cancer. As a direct result of the cholinergic activity induced by this plant, excessive salivation occurs, which is associated with a muscarinic effect, and CNS stimulatory and euphoric effects develop, which is considered to be associated with a nicotinic receptor stimulant effect.
Arecoline has been reported as an M1/M3 partial agonist and was shown to bind to M2 muscarinic receptors. Arecoline has been considered as a treatment for cognitive impairment since it showed improvement in scopolamine-induced cognitive impairment and passive avoidance performance in vivo, indicating a cholinergic action. When arecoline was administered to Alzheimer’s disease patients, it enhanced verbal memory and moderately improved cognitive function and recognition skills.
Derivatives of arecoline have been synthesised in order to improve selectivity for cortical muscarinic receptors. Examples of arecoline derivatives include xanomeline, reported to be functionally selective for the M1 receptor, which delayed cognitive decline and reduced hallucinations and delusions when given to Alzheimer’s disease patients. Other derivatives of arecoline are Lu 25-109-T and talsaclidine, which are also M1 functionally selective receptor agonists. Although Lu 25-109-T showed encouraging results in vitro, it failed to improve cognition when tested clinically in patients with mild to moderate Alzheimer’s disease. Talsaclidine has been shown to increase cholinomimetic central activation in animals and humans without some of the side-effects observed with acetylcholinesterase inhibitor therapy, but higher doses are linked with adverse effects including salivation and sweating, and, disappointingly, cognitive function was not significantly improved with this compound. Other tests on rhesus monkeys did show some improvement in memory-related tasks, but at doses which produced unacceptable adverse effects.
Celastrus paniculatus Willd.
Celastrus paniculatus Willd. (Celastraceae) seeds and seed oil have been used in Ayurvedic medicine to stimulate intellect and to sharpen the memory. Many of the studies undertaken to establish any pharmacological basis for the reputed effects of Celastrus 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. Administration of the seed oil to rats also reversed a scopolamine-induced task deficit, but this effect was not associated with anti-cholinesterase activity. Other studies have explored more polar extracts from the seeds of Celastrus 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. A seed extract is also reported to increase brain phospholipid content in vivo, possibly as a consequence of increased myelination. Aqueous seed extracts protected neuronal cells against glutamate-induced toxicity and H2O2-induced toxicity, with methanol and ethanol extracts in addition to the seed oil also showing the latter effect. 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.
Another Celastrus paniculatus extract was evaluated for NMDA and y-aminobutyric acid (GABA) receptor binding and NGF effects, but did not produce any response. Studies on the flowers from Celastrus paniculatus have shown a methanol extract to be anti-inflammatory, which may also have some relevance in the management of neurodegenerative disorders. A polyherbal formula (Abana) containing Celastrus 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 cholinesterase activity. 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 Celastrus paniculatus on cognitive function, the compounds responsible for the observed activities have yet to be established.
Clitoria ternatea L.
The roots of the Indian medicinal plant Clitoria ternatea L. (Leguminosae) have a reputation for promoting intellect. 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 Clitoria ternatea showed that alcoholic root extracts were more effective than extracts of the aerial parts in attenuating memory deficits in rats. Enhanced memory retention following oral administration of Clitoria ternatea root extract was associated with increased levels of acetylcholine and choline acetyltransferase in rat brain, but no relationship with inhibition of acetylcholinesterase activity was established, and cortical acetylcholinesterase activity was actually found to be increased. However, another study showed that the triterpenoid taraxerol from Clitoria ternatea inhibited acetylcholinesterase both in vitro and in the brain of rodents in vivo, but it was not as potent as physostigmine. An aqueous extract of the root also increased acetylcholine levels in rat hippocampus following oral administration, and it was hypothesised that this effect may be due to an increase in acetylcholine synthetic enzymes. Other studies have indicated that Clitoria ternatea extract can act as a nootropic, an anxiolytic, an an-tidepressant and an anticonvulsant and has antistress and anti-inflammatory activities.
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 Clitoria ternatea.