Loading…

A positive allosteric modulator of alpha 7 nAChRs augments neuroprotective effects of endogenous nicotinic agonists in cerebral ischaemia

Background and Purpose Activation of alpha 7 nicotinic acetylcholine receptors (nAChRs) can be neuroprotective. However, endogenous choline and ACh have not been regarded as potent neuroprotective agents because physiological levels of choline/ACh do not produce neuroprotective levels of alpha 7 act...

Full description

Saved in:
Bibliographic Details
Published in:British journal of pharmacology 2013-08, Vol.169 (8), p.1862-1878
Main Authors: Kalappa, Bopanna I, Sun, Fen, Johnson, Stephen R, Jin, Kunlin, Uteshev, Victor V
Format: Article
Language:English
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Background and Purpose Activation of alpha 7 nicotinic acetylcholine receptors (nAChRs) can be neuroprotective. However, endogenous choline and ACh have not been regarded as potent neuroprotective agents because physiological levels of choline/ACh do not produce neuroprotective levels of alpha 7 activation. This limitation may be overcome by the use of type-II positive allosteric modulators (PAMs-II) of alpha 7 nAChRs, such as 1-(5-chloro-2,4-dimethoxyphenyl)-3-(5-methylisoxazol-3-yl)-urea (PNU-120596). This proof-of-concept study presents a novel neuroprotective paradigm that converts endogenous choline/ACh into potent neuroprotective agents in cerebral ischaemia by inhibiting alpha 7 nAChR desensitization using PNU-120596. Experimental Approach An electrophysiological ex vivo cell injury assay (to quantify the susceptibility of hippocampal neurons to acute injury by complete oxygen and glucose deprivation; COGD) and an in vivo middle cerebral artery occlusion model of ischaemia were used in rats. Key Results Choline (20-200 mu M) in the presence, but not absence of 1 mu M PNU-120596 significantly delayed anoxic depolarization/injury of hippocampal CA1 pyramidal neurons, but not CA1 stratum radiatum interneurons, subjected to COGD in acute hippocampal slices and these effects were blocked by 20nM methyllycaconitine, a selective alpha 7 antagonist, thus, activation of alpha 7 nAChRs was required. PNU-120596 alone was ineffective ex vivo. In in vivo experiments, both pre- and post-ischaemia treatments with PNU-120596 (30mg.kg super(-1), s.c. and 1mg.kg super(-1), i.v., respectively) significantly reduced the cortical/subcortical infarct volume caused by transient focal cerebral ischaemia. PNU-120596 (1mg.kg super(-1), i.v., 30min post-ischaemia) remained neuroprotective in rats subjected to a choline-deficient diet for 14days prior to experiments. Conclusions and Implications PNU-120596 and possibly other PAMs-II significantly improved neuronal survival in cerebral ischaemia by augmenting neuroprotective effects of endogenous choline/ACh.
ISSN:0007-1188
1476-5381
DOI:10.1111/bph.12247