The pharmacotherapy of Alzheimer's disease based on the cholinergic hypothesis: an update.
Alzheimer's disease (AD) is a neurodegenerative disorder with impairment of cognitive function and personality. The synaptic loss, neuronal atrophy and degeneration of cholinergic nuclei in the basal forebrain may be associated with a reduction in oxidative metabolism of glucose, a fall in acetyl CoA and ATP. Current pharmacological strategies, aimed at increasing cholinergic activity include acetylcholinesterase (AChE) inhibitors, cholinergic agonists, acetylcholine (ACh) releasers and stimulants of nerve growth factors (NGF). AChE inhibitors, physostigmine and Tacrine can slow the decline of cognitive function and memory in some patients with mild or moderate AD, if given for at least 3-6 months in sufficient doses to inhibit brain AChE. Their main disadvantages are low oral bioavailability, peripheral cholinergic hyperactivity and liver toxicity with Tacrine. Newer, less toxic AChE inhibitors, with selective central activity, formulations of physostigmine, selective Ml and nicotinic agonists are becoming available with improved bioavailability and pharmacokinetics. These may increase the likelihood of therapeutic benefit in AD. Nootropic drugs, e.g. piracetam, which release ACh and are relatively non-toxic could possibly slow the progression of the disease. A combination of an AChE inhibitor, piracetam and a stimulator of NGF may show additive effects on memory processes but with a lower incidence of untoward effects.
Weinstock
M
M
Department of Pharmacology, Hebrew University Hadassah Medical Centre, Jerusalem, Israel.
D000544:Alzheimer Disease / Q000188:drug therapy* / Q000503:physiopathology; D018679:Cholinergic Agonists / Q000627:therapeutic use*; D002800:Cholinesterase Inhibitors / Q000627:therapeutic use*; D006801:Humans; D009410:Nerve Degeneration / Q000187:drug effects*; D009414:Nerve Growth Factors / Q000187:drug effects; D009435:Synaptic Transmission / Q000187:drug effects
D018679:Cholinergic Agonists; D002800:Cholinesterase Inhibitors; D009414:Nerve Growth Factors