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.
Highlights
Clinical management of neuronal damage resulting from ischemic stroke generally involves only palliative treatments
In the last two decades substantial efforts have been invested in developing anti-ischemic medicine, these efforts have not resulted in clinically-efficacious therapies for ischemic stroke [5]
This study evaluates neurological benefits of enhanced activation of α7 nicotinic acetylcholine receptors by endogenous nicotinic agonists 6 hours after ischemic insult induced by middle cerebral artery occlusion (MCAO) in young adult rats
Summary
Clinical management of neuronal damage resulting from ischemic stroke generally involves only palliative treatments. The only FDA-approved drug therapy for ischemic stroke involves the intravenous use of tissue plasminogen activator (tPA) to dissolve clots [1] This strategy appears to be effective in ischemic stroke, but only within the first 3 hours after the onset of ischemic stroke [2,3]. Effective post-stroke treatments with broad therapeutic windows are likely to be the most valuable because of the unexpected nature of stroke In this search, treatments that are based on recruiting and activating endogenous pathways receive special attention as these approaches are expected to be highly efficacious and cause fewer adverse effects than approaches that utilize exogenous agents [6,7,8]. This study evaluates neurological benefits of enhanced activation of α7 nicotinic acetylcholine receptors (nAChRs) by endogenous nicotinic agonists 6 hours after ischemic insult induced by middle cerebral artery occlusion (MCAO) in young adult rats
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