Abstract TP140: Intra-Arterial Mesenchymal Stem Cell Therapy Modulates Expression of NLRP1 Inflammasome in Animal Model of Ischemic Stroke

Abstract

Background: Stroke is one of the leading causes of long-term disability worldwide. Ischemia, followed by acidosis, worsens the pathology by activating the acid sensing ion channel 1a (ASIC1a). This activated ASIC1a increases the expression of NLRP1 inflammasome in a pH dependent manner that further activates the inflammatory cascade. ASIC1a once activated triggers the influx of Ca 2+ ions and its overload contributes to neuronal injury and death in ischemic stroke. Cell based therapy with mesenchymal stem cells (MSCs) is promising for clinical translation and reported to improve neurological outcome in rodent model. We aim to test if intra-arterial (IA) MSCs can inhibit the production of inflammasome by attenuating ASIC1a expression to render neuroprotection. Methods: Middle-aged Sprague Dawley rodents were infused with IA MSCs at 6 hours post middle cerebral artery occlusion (MCAo) followed by 24 hours of reperfusion. Rats were evaluated for neurodeficit and motor functions. Brains were harvested for infarct size estimation, biochemical analysis and western blot experiments. Results: IA MSCs when given at a dose of 1x10 5 cells at 6 hours following ischemia confer neuroprotection as evident by reduction in infarct volume, improvement in neurodeficit scores and motor function. Increase in GSH levels and reduction in elevated nitrite and MDA levels were observed in the IA MSCs treated animals. IA MSCs infusion also attenuated the expression of ASIC1a, NLRP1, NLRP3, ASC1, IL1β and caspase-1 in the cortical brain regions following ischemia. Conclusion: IA MSCs confers neuroprotection by attenuating acidosis by modulating NLRP1 mediated ASIC1a expression. Keywords: Ischemic Stroke, Mesenchymal stem cell, Inflammasome, Interleukin-1β, Peri-infarct area