Abstract
Therapeutic hypothermia is a promising new strategy for neuroprotection. However, the methods for safe and effective hypothermia induction in conscious patients are lacking. The current study explored the Transient Receptor Potential Vanilloid 3 (TRPV3) channel activation by the agonist carvacrol as a potential hypothermic strategy. It was found that carvacrol lowers core temperature after intraperitoneal and intravenous administration in mice and rats. However, the hypothermic effect at safe doses was modest, while higher intravenous doses of carvacrol induced a pronounced drop in blood pressure and substantial toxicity. Experiments on the mechanism of the hypothermic effect in mice revealed that it was associated with a decrease in whole-body heat generation, but not with a change in cold-seeking behaviors. In addition, the hypothermic effect was lost at cold ambient temperature. Our findings suggest that although TRPV3 agonism induces hypothermia in rodents, it may have a limited potential as a novel pharmacological method for induction of hypothermia in conscious patients due to suboptimal effectiveness and high toxicity.
Highlights
Therapeutic hypothermia (TH), defined as an intentional mild lowering of the patient’s core temperature, is emerging as a remarkably effective method of neuroprotection from ischemia [1]
Intraperitoneal injection of carvacrol at 10 and 31.6 mg/ kg produced a larger drop in core temperature than vehicle injection did, while the effect of carvacrol injection at 100 mg/kg was not different from the vehicle effect (10 mg/kg: -3.2±0.5°C; 31.6 mg/kg: -3.1±0.7°C.; 100 mg/kg: -2.3±0.7°C; p
To confirm that the hypothermic effect of carvacrol is replicated with a different route of systemic administration and in a different mouse strain, core temperature was measured in adult male CD-1 mice after intravenous injection of carvacrol at 6, 12.5, 25, and 50 mg/kg
Summary
Therapeutic hypothermia (TH), defined as an intentional mild lowering of the patient’s core temperature, is emerging as a remarkably effective method of neuroprotection from ischemia [1]. It has demonstrated a benefit for survival and functional outcome in clinical trials in anesthetized patients resuscitated after out-of-hospital cardiac arrest [2,3] and is being explored for the treatment of stroke, traumatic brain injury and other diseases [4,5,6,7]. Because of the requirements for complicated equipment, procedures and intensive monitoring, the application of hypothermia is limited only to the PLOS ONE | DOI:10.1371/journal.pone.0141994 November 3, 2015
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