Positive allosteric modulation of alpha7 nicotinic acetylcholine receptors as a novel approach to treatment of ischemic stroke

Abstract

Ischemic cerebral stroke is a leading cause of disability and death worldwide. Despite substantial investments in developing anti-stroke medicines, clinically effective pharmacological treatments remain inadequate. Clinical utility of tissue plasminogen activator (tPA, Alteplase), the only FDA-approved drug treatment is limited ([less than]10%) because of the short therapeutic window and increased risk of hemorrhage. Cytoprotection is a promising stroke therapy compatible with endovascular interventions, neurogenesis and rehabilitation therapies (e.g., targeted plasticity). In this fully randomized blinded study, an effective cytoprotection strategy for ischemic stroke is proposed. In this approach, prototypical and novel Type II positive allosteric modulators (ɑ7 PAMs) of ɑ7 nicotinic acetylcholine receptors (nAChRs) were tested using a transient 90 min suture middle cerebral artery occlusion (MCAO) model of ischemic stroke. Acute ([less than]24 h) and sub-chronic ([greater than]72 h) intravenous (i.v.) or subcutaneous (s.c.) administration of ɑ7 PAMs significantly reduced brain injury and neurological deficits after MCAO. The therapeutic efficacy of ɑ7 PAMs after stroke may arise from activation of multiple converging ɑ7-dependent therapeutic pathways including direct cytoprotection and central/peripheral anti-inflammatory mechanisms and may hold significant translational potential. Our results may become a starting point for developing clinically efficacious therapies utilizing ɑ7 agents and may enable health-care providers to overcome limitations linked to the lack of effective treatments after stroke.