Pharmacological hypothermia by Trpv1 agonism provides neuroprotection following ischemic stroke (877.13)

Abstract

Stroke is the leading cause of death and major cause of long‐term disability. Current therapeutic hypothermia by physical cooling shows the potential for neuroprotection in animal ischemic stroke, but causes complications and often requires sedation and muscle paralysis. The limitations restrict the translational application in clinic. Our previous studies show agonism of transient receptor potential vanilloid 1 (TRPV1) by dihydrocapsaicin (DHC) induces reliable and reversible pharmacological hypothermia (PH). We hypothesize that DHC induced hypothermia provides neuroprotection in ischemic stroke mice.Acute response of HR, BP and cerebral perfusion to the therapeutic dose of DHC were measured. C57BL/6 WT and TRPV1 KO mice were treated with therapeutic doses (1.25, 1.25 mg/kg) and high doses (30, 15 mg/kg) at two consecutive days. After one month recovery, the temperature change response of DHC (1.25 mg/kg) was applied to evaluate the potential TRPV1 desensitization. Focal cerebral I/R (one hour ischemia + 24 hours reperfusion) was induced by distal middle cerebral artery plus common carotid artery transient occlusion in conscious WT and TRPV1 KO mice. PH (8 hours) was initiated 90 minutes after start of reperfusion by DHC infusion (osmotic pump). Neurofunction (by behavioral tests) and infarct volume (by TTC staining) were measured at 24 hours.DHC (1.25 mg/kg) had no measurable effect on HR and cerebral perfusion, did not desensitize TRPV1 channels, but produced a slight transient drop in BP (<6mmHg). In I/R mice, DHC infusion produced mild hypothermia, decreased infarct volume by 87%, and improved neurofunctional score. The hypothermic and neuroprotective effects were absent in TRPV1 KO mice or mice maintained normothermic with heat support.TRPV1 agonism provides an effective and well‐tolerated PH for acute cerebral I/R neuroprotection. Hypothermic and neuroprotective effects are specifically through TRPV1 agonism.Grant Funding Source: Supported by NIH R21 NS077413, R01 HL088435 (SPM) and AHA Pre Doctoral fellowship 16900006 (ZJC).