Tetrahydroaminoacridine (tacrine) stimulates neurosecretion at mammalian motor endplates

Abstract

1 Tacrine (20pM) induced, like 4-aminoquinoline (4-AQ, 2O0pM), the appearance of a population of miniature endplate potentials (m.e.p.ps) with more than twice the normal amplitude or time-to-peak. The times-to-peak of nerve impulse-evoked endplate potentials were not similarly affected. 2 Cholinesterase inhibition by edrophonium (25 UM) did not prevent tacrine or 4-AQ from inducing this population of m.e.p.ps. 3 Nerve-muscle preparations in which the normal calcium-sensitive quantal release of acetylcholine had been blocked by botulinum neurotoxin type A also responded to tacrine by an increase in the frequency of giant or slow m.e.p.ps. 4 Reduction of the temperature from 300 to 14°C reduced the frequency of giant or slow m.e.p.ps induced either by tacrine or by 4-AQ. A similar effect was obtained by colchicine (5 mM). This supports the idea that proximo-distal axonal transport is required for the secretory activity. 5 The neurosecretion evoked by tacrine could explain the therapeutic effects of the drug claimed in the treatment of Alzheimer's type of dementia.

Effectiveness of 1,2,3,4-Tetrahydro-9-aminoacridine (THA) as a pretreatment drug for protection of mice from acute diisopropylfluorophosphate (DFP) intoxication

“…Finally, also the possibility that mechanism(s) other than AChE protection may be involved in THA antidotal action, deserves attention. It is well known that THA has a complicated pharmacology and exerts several actions besides interacting with cholinesterases (Rogawski 1987;Albin et al 1988;Davenport et al 1988;Hunter et al 1989;Robinson et al 1989;Peterson 1990;Thesleff et al 1990). …”

“…Interest in this drug arises mainly from reports indicating that is effective in improving the clinical condition of certain patients with Alzheimer's disease (Summers et al 1989). Although there is growing evidence for other than AChE inhibitory actions (Albin et al 1988;Hunter et al 1989;Robinson et al 1989;Peterson 1990;Thesleff et al 1990), the opinion that THA exerts its beneficial effects primarily by temporarily inhibiting central AChE still seems to prevail over other hypotheses at the moment (Nielsen et al 1989). Previous studies have shown that THA and THA derivatives may exert direct protective action on AChE from various sources against inhibition by organophosphorus compounds (Patocka et al 1976;Bajgar et al 1983;Wu and Yang 1989).…”

Synthesis, in Vitro Pharmacology, and Molecular Modeling of Very Potent Tacrine−Huperzine A Hybrids as Acetylcholinesterase Inhibitors of Potential Interest for the Treatment of Alzheimer's Disease

“…35 Thus, THA may enhance acetylcholine release besides its AChE inhibitory action. 36 We did not test each of these possibilities to explain the discrepancies between the effects of racemates and enantiomers. However, some preliminary and unpublished data have shown that some of the present compounds bind to M 1 receptors.…”

Tacrine

“…Fast excitatory postsynaptic potentials were augmented by tacrine in rat neuromuscular preparations, and slow inhibitory postsynaptic potentials were blocked (Dutar et al 1990). Tacrine increased miniature endplate potential amplitude (Braga et al 1991;Thesleff et al 1990) and frequency (Provan & Miyamoto 1991) and prolonged the decay phase (Braga et al 1991) in various isolated neuromuscular preparations.…”