A Type-II Positive Allosteric Modulator of α7 nAChRs Reduces Brain Injury and Improves Neurological Function after Focal Cerebral Ischemia in Rats
Open Access
- 9 August 2013
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLOS ONE
- Vol. 8 (8), e73581
- https://doi.org/10.1371/journal.pone.0073581
Abstract
In the absence of clinically-efficacious therapies for ischemic stroke there is a critical need for development of new therapeutic concepts and approaches for prevention of brain injury secondary to cerebral ischemia. This study tests the hypothesis that administration of PNU-120596, a type-II positive allosteric modulator (PAM-II) of α7 nicotinic acetylcholine receptors (nAChRs), as long as 6 hours after the onset of focal cerebral ischemia significantly reduces brain injury and neurological deficits in an animal model of ischemic stroke. Focal cerebral ischemia was induced by a transient (90 min) middle cerebral artery occlusion (MCAO). Animals were then subdivided into two groups and injected intravenously (i.v.) 6 hours post-MCAO with either 1 mg/kg PNU-120596 (treated group) or vehicle only (untreated group). Measurements of cerebral infarct volumes and neurological behavioral tests were performed 24 hrs post-MCAO. PNU-120596 significantly reduced cerebral infarct volume and improved neurological function as evidenced by the results of Bederson, rolling cylinder and ladder rung walking tests. These results forecast a high therapeutic potential for PAMs-II as effective recruiters and activators of endogenous α7 nAChR-dependent cholinergic pathways to reduce brain injury and improve neurological function after cerebral ischemic stroke.This publication has 114 references indexed in Scilit:
- α7 Nicotinic ACh Receptors as a Ligand-Gated Source of Ca2+ Ions: The Search for a Ca2+ OptimumAdvances in Experimental Medicine and Biology, 2012
- Research Review: Cholinergic mechanisms, early brain development, and risk for schizophreniaJournal of Child Psychology and Psychiatry, 2010
- Metabolic and transmitter changes in core and penumbra after middle cerebral artery occlusion in miceBrain Research, 2010
- Physiological Concentrations of Choline Activate Native α7-Containing Nicotinic Acetylcholine Receptors in the Presence of PNU-120596 [1-(5-Chloro-2,4-dimethoxyphenyl)-3-(5-methylisoxazol-3-yl)-urea]The Journal of pharmacology and experimental therapeutics, 2009
- Multiple roles for nicotine in Parkinson's diseaseBiochemical Pharmacology, 2009
- Dietary Choline Supplementation Improves Behavioral, Histological, and Neurochemical Outcomes in a Rat Model of Traumatic Brain InjuryJournal of Neurotrauma, 2008
- The Dichotomy of NMDA Receptor SignalingThe Neuroscientist, 2007
- Treating schizophrenia symptoms with an α7 nicotinic agonist, from mice to menBiochemical Pharmacology, 2007
- CaMKII and CaMKIV mediate distinct prosurvival signaling pathways in response to depolarization in neuronsMolecular and Cellular Neuroscience, 2007
- Nicotinic acetylcholine receptor α7 subunit is an essential regulator of inflammationNature, 2002