Abstract DP326: Capsinoids, Non-pungent TRPV1 Agonists, Induce A Neuroprotective Mild Hypothermia That Improves Short- and Long-term Outcomes After Experimental Stroke

Intro: Mild hypothermia has been shown to be neuroprotective in experimental stroke models. However, hypothermia protocols in awake subjects are hampered by inconsistent temperature management due to incomplete suppression of cold defense mechanisms (e.g. shiver response). To address a need for better strategies for cooling conscious subjects, we previously showed that pharmacological activation of the heat defense mechanism with classical TRPV1 agonists promotes mild hypothermia and neuroprotection following stroke. In this study, we examine the capacity of non-pungent TRPV1 agonists (capsinoids) to induce a similar neuroprotective mild hypothermia following stroke. We hypothesized that 6 hours of capsinoid-induced mild hypothermia in the post-stroke period can reduce stroke infarct volume and improve short- and long-term stroke outcomes. Methods: Aged C57BL6 mice of both sexes underwent permanent distal middle cerebral artery (MCA) occlusion. At 2 hours after occlusion, mice were given repeated intraperitoneal injections of either mixed capsinoids (capsiate and dihydrocapsiate) or vehicle control over 6 hours. Core body temperature (Tb) was measured by wireless transponder following drug administration. The first cohort (short term outcome) were euthanized at post stroke day (PSD) 3 for infarct analysis by TTC and a second cohort (long term outcome) underwent behavior testing at PSD7 and PSD30. Results: Capsinoid administration induced mild hypothermia over the 6-hour treatment period (Tb=34.0±0.1°C) versus vehicle (Tb=36.1±0.2°C), which returned to baseline upon stopping capsinoid treatment. At PSD3, capsinoid-induced hypothermia mice showed a 48% reduced infarct volume (capsinoid: 11.4±1.3mm 3 vs vehicle: 21.8±2.2mm 3 , p=0.0007). Capsinoid treated mice displayed a more symmetrical gait at PSD7 (1.00±0.01 vs 0.95±0.02, p=0.0302), improved grip strength recovery at PSD7 (capsinoid: 91±4% of baseline, vehicle: 73±6%, p=0.0288) and PSD30 (capsinoid: 96±5% of baseline, vehicle: 65±5%, p=0.0011), and fewer contralateral foot faults at PSD7 (capsinoid: 6.6±0.5% of all steps vs vehicle: 8.8±0.3%, p=0.0030). Conclusion: Intraperitoneal delivery of capsinoids, when administered in the post-stroke period, can effectively induce prolonged and reversible mild hypothermia in aged mice of both sexes. Additionally, capsinoid-mediated hypothermia provides significant neuroprotection and improved functional outcome when initiated 2 hours after stroke induction.