Abstract W P259: Selective Intra-arterial Administration of Verapamil is Neuroprotective in Acute Ischemic Stroke

Abstract

Despite the urgent need for better stroke therapies, experimental stroke treatments have largely failed to translate to stroke patients. In an effort to bridge this translational gap, we have concentrated our efforts on drugs that are already FDA approved and associated with treating stroke-associated pathophysiology, such as cerebral artery vasospasm, with the goal of repurposing them to protect brain tissue from ischemic injury. Verapamil, a calcium channel blocker, is one such drug that is often infused intra-arterially by neurosurgeons treating vasospasm that results in ischemia. In demonstrating a reliable and reproducible stroke mouse model ( transient middle cerebral artery occlusion, MCAo) with the addition of a retro-engineered IA drug delivery model mimicking the human condition, we were able to optimize the injection volume and flow rate for pharmacotherapy administration of verapamil. Through this direct route of administration we have shown a significant decrease (P<0.001) in infarct volume and trending towards significance an increase in behavioral outcome when comparing treated animals versus control. Perfusion studies did not show significant differences in perfusion to account for vasomotor changes as the likely mechanism for ischemia reduction. To further explore this, after 1 hour MCAo in three month old C57/Bl6 mice, we examined the potential neuroprotective effects of verapamil on post stroke day 3. Whole brains were harvested and flash frozen for cryostat sectioning and cellular staining to compare apoptosis, appearance of mature neurons, astrocyte activation and synaptic stability. Results suggest that IA administration of verapamil, more specifically than reducing infarct volume, is directly neuroprotective on brain parenchymal tissue at risk.