Capsinoids (non-pungent TRPV1 agonists) promote mild hypothermia and improved outcome following stroke in aged mice

Background and PurposeMild hypothermia provides potent neuroprotection in experimental ischemic stroke, however, its implementation in awake stroke patients is hampered by the induction of intense shivering and inconsistent body temperature control. Pharmacological activation of peripheral/peritoneal TRPV1 channels with non-pungent capsinoids offers a means to induce hypothermia while minimizing TRPV1 activation in the injury region. We tested whether capsinoid-mediated mild hypothermia, initiated within the post-stroke period, reduces brain injury and improves functional outcomes in aged mice. MethodsAged (18-20 months) male and female C57BL/6 mice underwent either permanent distal middle cerebral artery (MCA) occlusion (pdMCAO) or 60-minute MCA occlusion/reperfusion (MCAO/R). At 2 or 4 hours after stroke, mice received intraperitoneal injections of vehicle or capsinoids (>97% purity; 40 mg/kg) every 90 minutes to induce mild hypothermia for 4.5-6 hours. Core temperature was monitored by wireless probe. After pdMCAO, infarct volume was quantified at post-stroke day 3 (PSD3) by TTC and brain atrophy at PSD30 by iodine-enhanced microCT; sensorimotor function (DigiGait, forelimb grip strength, foot fault) was assessed at PSD7 and PSD30. Survival was the primary measured outcome for MCAO/R. ResultsCapsinoids induced a rapid and sustained reduction in core temperature of 2-4{degrees}C, independent of sex. In the pdMCAO model, capsinoid-induced hypothermia reduced infarct volume by 48% at PSD3 and decreased chronic cortical tissue loss by 44% at PSD30. Capsinoid-treated mice showed significant improvements in gait, grip strength, and contralateral foot fault performance at PSD7 and PSD30. In the MCAO/R model, survival was significantly higher in capsinoid-treated mice (80%) versus vehicle controls (33%) through PSD3. ConclusionsIntraperitoneal capsinoid administration after stroke induces mild hypothermia in aged mice and confers robust acute neuroprotection and improved chronic functional outcome and survival. These preclinical findings add support for the use of capsinoids as a means to target peripheral thermoeffectors for promoting neuroprotective hypothermia in conscious stroke subjects.