Abstract TMP111: Selective Activation of Peritoneal TRPV1-Containing Vagal Afferents Promotes Sustained Mild Hypothermia and Neuroprotection Following Stroke

Abstract

Intro: Mild hypothermia has been clinically effective at improving outcomes in cardiac arrest patients for decades. Similarly, mild hypothermia has been shown to neuroprotective in experimental stroke models. Unfortunately, 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 sought to promote mild hypothermia by pharmacological activation of heat-sensing nerve fibers in the thermoregulatory system. We hypothesize that selective activation of TRPV1-containing vagal afferents in the peritoneal cavity can promote sustained hypothermia and protection following stroke. Methods: Aged (18-20 mo) and young (11 weeks) C57BL6 mice of both sexes were given a capsinoid mixture consisting of capsiate and dihydrocapsiate. Mice from both the aged and young cohorts underwent permanent distal middle cerebral artery occlusion (pdMCAO) or sham before recovering for 2hrs in warming cages to maintain normal body temperatures during post-stroke recovery. At 2 hours after stroke, mice were given capsinoids or vehicle (4 IP injections, 90 min interval) to produce 6 hours of mild hypothermia (or normothermic control). After 3 days brains were collected for histological analysis. Results: Capsinoids are particularly suited for region selective activation of TRPV1 targets, as they are degraded by ubiquitous esterases, and thus limited in biodistribution to distant targets. This regionally restricted activation was demonstrated through induction of mild hypothermia with IP capsinoid administration, but not with oral or subcutaneous delivery. We demonstrated that the hypothermic effect is TRPV1 dependent and that IP capsinoid delivery increases activity of the cervical vagus (hook electrode). We applied this capsinoid-mediated hypothermia approach to the pdMCAO model and demonstrated a significant reduction of brain infarct at 3 days post-stroke in both young and aged mice of both sexes. Conclusion: Selective activation of TRPV1-containing peritoneal vagal afferents is sufficient to promote sustained mild hypothermia and protection following ischemic stroke.