Cholinergic Basis for Alzheimer Therapy

Reversal of cognitive impairment by heptyl physostigmine, a long-lasting cholinesterase inhibitor, in primates.

Comparison of the effects of selective and nonselective muscarinic agonists on cognition and thermoregulation in primates.

Effect of repeated nicotine exposure on core temperature and motor activity in male and female rats

The discovery in the 1970’s that choline acetyltransferase (ChAT) is markedly reduced in the brains of patients with Alzheimer’s disease (AD) compared with those of age-matched controls (Bowen et al., 1976) prompted a number of attempts to improve cholinergic transmission in patients with the disease. Initial studies with cholinesterase inhibitors were encouraging. Treatment with physostigmine alone (Davidson et al., 1986) or in combination with lecithin (Peters and Levin, 1979) suggested that cholinesterase inhibitors may be an effective treatment for AD. However, the therapeutic usefulness of physostigmine is limited by its short half-life, poor bioavailability and narrow therapeutic window (Davis et al., 1983). In recent years attempts have been made to treat patients with longer duration cholinesterase inhibitors such as 9-amino-1,2,3,4- tetrahydroaminoacridine (THA). Unfortunately, the relatively high doses of THA used in these studies are also known to cause hepatocellular injury (Food and Drug Administration, 1991), which limits its long-term therapeutic utility.

Heptylphysostigmine — Novel Acetylcholinesterase Inhibitor: Biochemical and Behavioral Pharmacology

The influence of various cholinergic drugs on rectal temperature of rats under controlled laboratory conditions was examined. Animals were anaesthetized by intraperitoneal injection of thiopental. Three hours later acetylcholine, methacholine, arecoline, nicotine, neostigmine, atropine, methylatropine, mecamylamine or hemicholinium were injected intrahypothalamically (i.h.), intracerebroventricularly (i.c.v.) or intraperitoneally (i.p.). Rectal temperature was measured at 15 min-intervals for 1 hr after the substances were injected. Our results indicate that the cholinergic mechanisms play an important role in thermoregulatory processes in rats. Cholinergic activation decreases rectal temperature, due to an increased activity of central, and not of peripheral cholinergic neurotransmission. The hypothermic effect of cholinomimetics is mediated through an activation of muscarinic cholinergic receptors.

Roganović-Dordević J

Papers

Influence of various cholinergic and anticholinergic drugs on rectal temperature in rats.