The acetylcholinesterase inhibitor, donepezil, is also a high affinity sigma(1) receptor agonist.
We examined the involvement of sigma(1) receptors in its anti-amnesic and neuroprotective properties against amyloid beta(25-35) peptide-induced toxicity in mice. EXPERIMENTAL
Mice were given an intracerebroventricular (i.c.v.) injection of Abeta(25-35) peptide (9 nmol) 7-9 days before being tested for spontaneous alternation and passive avoidance.
Hippocampal lipid peroxidation was measured 7 days after Abeta(25-35) injection to evaluate oxidative stress. Donepezil, the sigma(1) agonist PRE-084 or the cholinesterase (ChE) inhibitors tacrine, rivastigmine and galantamine were administered either 20 min before behavioural sessions to check their anti-amnesic effects, or 20 min before Abeta(25-35) injection, or 24 h after Abeta(25-35) injection and then once daily before behavioural sessions, to check their pre- and post-i.c.v. neuroprotective activity, respectively. KEY
All the drugs tested were anti-amnesic, but only the effects of PRE-084 and donepezil were prevented by the sigma(1) antagonist BD1047. Only PRE-084 and donepezil showed neuroprotection when administered pre i.c.v.; they blocked lipid peroxidation and learning deficits, effects inhibited by BD1047. Post i.c.v., PRE-084 and donepezil showed complete neuroprotection whereas the other ChE inhibitors showed partial effects. BD1047 blocked these effects of PRE-084, attenuated those of donepezil, but did not affect the partial effects of the other ChE inhibitors. CONCLUSIONS AND
The potent anti-amnesic and neuroprotective effects of donepezil against Abeta(25-35)-induced toxicity involve both its cholinergic and sigma(1) agonistic properties.
This dual action may explain its sustained activity compared to other ChE inhibitors.
JournalBritish journal of pharmacology
Br J Pharmacol (0007-1188)
British journal of pharmacology
INSERM U. 710, Montpellier, France.
Br J Pharmacol. 2006 Dec;149(8):998-1012
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