Ischemic neuroprotection by TRPV1 receptor-induced hypothermia

Abstract

Although treatment of stroke patients with mild hypothermia is a promising therapeutic approach, chemicals inducing prompt and safe reduction of body temperature are an unmet need. We measured the effects of the transient receptor potential vanilloid-1 (TRPV1) agonist rinvanil on thermoregulation and ischemic brain injury in mice. Intraperitoneal or intracerebroventricular injection of rinvanil induces mild hypothermia that is prevented by the receptor antagonist capsazepine. Both intraischemic and postischemic treatments provide permanent neuroprotection in animals subjected to transient middle cerebral artery occlusion (MCAo), an effect lost in mice artificially kept normothermic. Data indicate that TRPV1 receptor agonists are promising candidates for hypothermic treatment of stroke.

Figure 1

Effect of rinvanil on thermoregulation. Effect of intraperitoneal (A) or intracerebroventricular (B) injection of different doses of rinvanil on body temperature (Tb) of uninjured mice. (C) The transient receptor potential vanilloid-1 (TRPV1) receptor antagonist capsazepine inhibits the hypothermic effect of rinvanil. (D) The effect of capsazepine is competitive. Effect of rinvanil (25 mg/kg) on O₂ consumption during a 20-minute recording (expressed both on time scale (E,a) or as total consumption (E,b)) and skin temperature (F) in mice. Each point/column represents the mean±s.e.m. of three (A–C) or two (E, F) experiments with five animals per group. ^*P<0.05, ^**P<0.01 versus Vehicle. Student's t-test.

Figure 2

Effects of rinvanil on ischemic brain injury in mice. (A) The effect of rinvanil (25 mg/kg intraperitoneally) on body temperature (Tb) of mice subjected to 1 hour middle cerebral artery occlusion (MCAo) is more prolonged than in sham-operated animals. (B, C) Effect of rinvanil (25 mg/kg) on infarct areas and volumes of mice subjected to 1 hour MCAo/24 hours reperfusion. Neuroprotection is lost in animals kept at a Tb of 37°C. (D) Effect of rinvanil (25 mg/kg) on infarct volumes of mice subjected to 1.5 hours MCAo/48 hours reperfusion. Effect of multiple, postischemic injections of rinvanil (25 mg/kg) on Tb (E), infarct areas (F), and volumes (G) of mice subjected to 1 hour MCAo/24 hours reperfusion. (H, I) Effect of 50 mg/kg of rinvanil on infarct areas and volumes of mice subjected to 1 hour MCAo/24 hours reperfusion. Effect of 24 hours hypothermia obtained by multiple (13) injections of rinvanil (25 mg/kg) on infarct areas (J) and volumes (K) of mice subjected to 1 hour MCAo/7 days reperfusion. Each point/column represents the mean±s.e.m. (n=8 per group). ^*P<0.05, ^**P<0.01, ^***P<0.001 versus Vehicle. Analysis of variance plus Tukey's post hoc test.