Precursors of Acetylcholine
Adequate availability of choline has been proposed to enable sufficient acetylcholine synthesis for neurotransmission. Precursors of acetylcholine (e.g. choline and lecithin) have been investigated for their effects on synthesis and release of acetylcholine, with a view to increasing acetylcholine release and cholinergic activity. Few clinical or animal studies have reported any significant beneficial effects on cognitive function with these compounds. Therapy failure may be due to impaired uptake mechanisms of choline causing the reduction in acetylcholine synthesis, and not due to insufficient choline supply. This is apparent as it has been reported that more choline occurs in the cerebrospinal fluid of Alzheimer’s disease patients than in patients without Alzheimer’s disease, and that choline levels increase with disease progression. Therapy with acetylcholine precursors may be limited by side-effects, including gastrointestinal disturbances such as nausea, vomiting and diarrhoea.
Muscarinic Receptor Stimulation
Direct cholinergic receptor stimulation has been explored as one therapeutic target to enhance cognitive function. Cholinergic agonists are reported to facilitate learning and memory, but cholinergic antagonists impair learning and memory; thus cholinergic agonists may be useful in cognitive disorders. Direct stimulation of the M1 muscarinic receptor with agonists such as xanomeline, which is an analogue of the natural compound arecoline, is reported to improve cognition both in animal models and in Alzheimer’s disease patients, and antagonists of central presynaptic M2 receptors, which include analogues of the naturally derived himbacine, also enhance cognitive ability by increasing the release of acetylcholine. To date, treatment with compounds that directly interact with muscarinic receptors has not been a major approach to alleviate cognitive disorders such as Alzheimer’s disease, perhaps due to the unpleasant cholinergic side-effects such as gastrointestinal contraction and sweating, reported to be associated with muscarinic receptor modulators.
Nicotinic Receptor Stimulation/Nicotinic Agonists
Behavioural studies have shown that nicotinic receptors participate in cognitive functions. Nicotinic receptors are reduced in cortical brain areas in Alzheimer’s disease, and nicotine upregulates nicotinic receptors and increases acetylcholine release. Nicotine treatment in various in vivo studies, including administration to rats with cholinergic brain lesions and in aged monkeys, has been shown to improve cognitive function.
Thus, nicotinic agonists may enhance cholinergic neurotransmission and therefore cognitive function in some disorders that feature memory impairment. In support of this, some studies suggest smoking may protect against Alzheimer’s disease development, and administration of nicotine to Alzheimer’s disease patients and to healthy (non-Alzheimer’s disease) elderly people improved cognitive function. However, some cohort studies have shown that smoking shows either no association with Alzheimer’s disease risk or moderately increases Alzheimer’s disease risk. Although the effects of smoking on memory and Alzheimer’s disease risk are inconclusive, the effects of nicotine on cognitive ability are still of interest. In addition to modulating cholinergic activity, nicotine has shown other activities which may be relevant in some neurodegenerative diseases featuring memory loss. Nicotine inhibits beta-amyloid formation in vitro, inhibits the neurotoxic effects of glutamate and also enhances the effects of nerve growth factor (NGF).
A number of other alkaloids are reported to be nicotinic agonists and could therefore be investigated, or their structures modified, to develop new therapeutic compounds. Alkaloids including lobeline from Lobelia inflata L. (Campanulaceae) and cytisine, found in a number of plants including species of Sophora (Leguminosae), have binding affinity for nicotinic receptors, but these compounds do not appear to have been developed for any pharmaceutical purposes, perhaps due to toxicity.
Inhibition of acetylcholine hydrolysis by acetylcholinesterase, through the use of acetylcholinesterase inhibitors, has been a more successful approach than attempts to use compounds which directly stimulate cholinergic receptors to modulate cholinergic function, as acetylcholinesterase inhibitors prolong the half-life of acetylcholine, and therefore the availability of acetylcholine released into the neuronal synaptic cleft.
Over the last decade, some acetylcholinesterase inhibitors have been licensed for clinical use for the symptomatic relief of mild to moderately severe Alzheimer’s disease. However, these drugs only alleviate some of the cognitive symptoms of the disease, rather than treat the disease, and may not be effective in some patients. The synthetic drug tacrine (Cognex) was the first acetylcholinesterase inhibitor to be licensed, but its use was limited by adverse effects, including hepatotoxicity. The current acetylcholinesterase inhibitors licensed for use in Alzheimer’s disease include donepezil (Aricept), rivastigmine (Exelon) and galantamine (Reminyl), with the latter two drugs based on naturally derived compounds. In addition to modulating cholinergic function, some acetylcholinesterase inhibitors are reported to interfere with beta-amyloid metabolism and thus could reduce senile plaque formation, one of the pathological occurrences in Alzheimer’s disease.
Glutamate may induce neuronal degeneration by overstimulation of NMDA receptors. NMDA receptor modulators may have potential use in some CNS disorders including schizophrenia, stroke, epilepsy, Parkinson’s disease, Huntington’s disease and Alzheimer’s disease. Memantine (Ebixa), an uncompetitive NMDA receptor antagonist, is reported to be neuroprotective, is a licensed drug for the treatment of Alzheimer’s disease symptoms and has been shown to be therapeutically effective in Alzheimer’s disease patients.