Abstract TP113: Beneficial Effect of Faster Cooling Elicited by Combination of TRPV1 Agonist (Dihydrocapsaicin) and Mild Physical Hypothermia in Ischemia/Reperfusion Injury

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Abstract

Introduction: Pharmacologically induced hypothermia (PH) in stroke has been investigated. Achieving faster cooling after stroke would be important in the successful rescue of neurons and improve outcomes. However, drawbacks of PH and physical cooling are the time and large doses required to achieve neuroprotective hypothermia. The induced toxicity and possible drug complications largely limited PH translation in the clinics. Transient Receptor Potential Vanilloid (TRPV) 1 receptor and its agonist dihydrocapsaicin (DHC) have been reported to exert neuroprotective effects in animal stroke models by inducing hypothermia. It is proposed that TRPV1 agonism plays a central thermoregulatory role in possibly reducing thermoregulatory set-point. The combination therapy of physical cooling and PH may achieve faster cooling rates by increasing heat loss and decreasing heat generation. To this end, we assessed the hypothesis that combination of DHC and physical cooling leads to faster cooling and better neuroprotection.

Methods: Sprague Dawley rats were subjected to 2 h middle cerebral artery occlusion (MCAO) and followed by 24 h of reperfusion. Ischemic rats in each group (n=8) received either: no treatment, mild hypothermia, low DHC (0.5 mg/kg), high DHC (1.5 mg/kg) or combination (low DHC plus hypothermia). Treatments lasted for 3 h. Rate to target hypothermia (31 °C) onset was measured. Infarct volume was determined using triphenyl tetrazolium chloride (TTC) staining.

Results: Temperature decrease rate at which groups was determined as 0.1°C/min for hypothermia, 0.06°C/min for low DHC, 0.07°C/min for high DHC and 0.2°C/min for combination. The combination treatment was 3 times faster (p<0.05) than low and high DHC groups, while 2 times faster (p<0.05) than mild hypothermia. Infarct volume was largely and significantly reduced by combination therapy (19.2%), as compared to no treatment (49.5%), mild hypothermia only (50.0%), low DHC (36.6%), and high DHC (39.9%) groups.

Conclusion: Combination of physical hypothermia and DHC elicited a faster reduction of body temperature and strong neuroprotection as compared to single treatments. This novel therapy may provide better opportunity for ischemic brain to reach therapeutic hypothermia temperature.

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