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Systemic Administration of the TRPV3 Ion Channel Agonist Carvacrol Induces Hypothermia in Conscious Rodents.

Feketa VV, Marrelli SP - PLoS ONE (2015)

Bottom Line: However, the methods for safe and effective hypothermia induction in conscious patients are lacking.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.In addition, the hypothermic effect was lost at cold ambient temperature.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Physiology and Biophysics Graduate Program, Cardiovascular Sciences Track, Baylor College of Medicine, Houston, Texas, United States of America.

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.

No MeSH data available.


Related in: MedlinePlus

Intraperitoneal and intravenous administration of the TRPV3 agonist carvacrol decreases core temperature in conscious mice and rats.(A) Adult male C57Bl/6 mice were injected intraperitoneally with vehicle or carvacrol at 10, 31.6, and 100 mg/kg at time 0. Core temperature was measured by wireless temperature transmitters every 15 min for 2 hours. (B) The drop in core temperature between 0 min pre-injection and 30 min post-injection calculated from the experiment shown in panel A. n = 4 mice per group in a within-subject design. * P<0.05, 1-way ANOVA followed by Student-Neuman-Keuls post-hoc test. (C) Adult male CD-1 mice were injected intravenously with vehicle or carvacrol at 6, 12.5, 25, and 50 mg/kg at time 0. Core temperature was measured by wireless temperature transmitters every 15 min for 1 hour. (D) The drop in core temperature between 0 min pre-injection and 30 min post-injection was calculated from the experiment shown in panel A. n = 4–5 mice per group. * P<0.05, 1-way ANOVA followed by Student-Neuman-Keuls post-hoc test. (E) Adult male Sprague-Dawley rats were injected with vehicle of carvacrol at 25 mg/kg intravenously or 100 mg/kg intraperitoneally at time 0. Core temperature was measured by wireless temperature transmitters every 15 min for 1 hour. (F) The drop in core temperature between 0 min pre-injection and 60 min post-injection calculated from the experiment shown in panel A. n = 6–7 rats per group. * P<0.05, 1-way ANOVA followed by Student-Neuman-Keuls post-hoc test.
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pone.0141994.g001: Intraperitoneal and intravenous administration of the TRPV3 agonist carvacrol decreases core temperature in conscious mice and rats.(A) Adult male C57Bl/6 mice were injected intraperitoneally with vehicle or carvacrol at 10, 31.6, and 100 mg/kg at time 0. Core temperature was measured by wireless temperature transmitters every 15 min for 2 hours. (B) The drop in core temperature between 0 min pre-injection and 30 min post-injection calculated from the experiment shown in panel A. n = 4 mice per group in a within-subject design. * P<0.05, 1-way ANOVA followed by Student-Neuman-Keuls post-hoc test. (C) Adult male CD-1 mice were injected intravenously with vehicle or carvacrol at 6, 12.5, 25, and 50 mg/kg at time 0. Core temperature was measured by wireless temperature transmitters every 15 min for 1 hour. (D) The drop in core temperature between 0 min pre-injection and 30 min post-injection was calculated from the experiment shown in panel A. n = 4–5 mice per group. * P<0.05, 1-way ANOVA followed by Student-Neuman-Keuls post-hoc test. (E) Adult male Sprague-Dawley rats were injected with vehicle of carvacrol at 25 mg/kg intravenously or 100 mg/kg intraperitoneally at time 0. Core temperature was measured by wireless temperature transmitters every 15 min for 1 hour. (F) The drop in core temperature between 0 min pre-injection and 60 min post-injection calculated from the experiment shown in panel A. n = 6–7 rats per group. * P<0.05, 1-way ANOVA followed by Student-Neuman-Keuls post-hoc test.

Mentions: To test the hypothesis that systemic TRPV3 activation induces hypothermia, core temperature was measured by wireless transmitters in adult male C57Bl/6 mice before and after intraperitoneal injection with vehicle or carvacrol at different doses. Core temperature was measured every 15 min for 2 hours. Intraperitoneal injection of vehicle led to ~0.7±0.2°C drop in core temperature at 30 min after injection. 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<0.05 for 10 and 31.6 mg/kg, 1-way ANOVA followed by Student-Neuman-Keuls post-hoc test; n = 4 mice per group in a within-subject design; Fig 1A and 1B).


Systemic Administration of the TRPV3 Ion Channel Agonist Carvacrol Induces Hypothermia in Conscious Rodents.

Feketa VV, Marrelli SP - PLoS ONE (2015)

Intraperitoneal and intravenous administration of the TRPV3 agonist carvacrol decreases core temperature in conscious mice and rats.(A) Adult male C57Bl/6 mice were injected intraperitoneally with vehicle or carvacrol at 10, 31.6, and 100 mg/kg at time 0. Core temperature was measured by wireless temperature transmitters every 15 min for 2 hours. (B) The drop in core temperature between 0 min pre-injection and 30 min post-injection calculated from the experiment shown in panel A. n = 4 mice per group in a within-subject design. * P<0.05, 1-way ANOVA followed by Student-Neuman-Keuls post-hoc test. (C) Adult male CD-1 mice were injected intravenously with vehicle or carvacrol at 6, 12.5, 25, and 50 mg/kg at time 0. Core temperature was measured by wireless temperature transmitters every 15 min for 1 hour. (D) The drop in core temperature between 0 min pre-injection and 30 min post-injection was calculated from the experiment shown in panel A. n = 4–5 mice per group. * P<0.05, 1-way ANOVA followed by Student-Neuman-Keuls post-hoc test. (E) Adult male Sprague-Dawley rats were injected with vehicle of carvacrol at 25 mg/kg intravenously or 100 mg/kg intraperitoneally at time 0. Core temperature was measured by wireless temperature transmitters every 15 min for 1 hour. (F) The drop in core temperature between 0 min pre-injection and 60 min post-injection calculated from the experiment shown in panel A. n = 6–7 rats per group. * P<0.05, 1-way ANOVA followed by Student-Neuman-Keuls post-hoc test.
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pone.0141994.g001: Intraperitoneal and intravenous administration of the TRPV3 agonist carvacrol decreases core temperature in conscious mice and rats.(A) Adult male C57Bl/6 mice were injected intraperitoneally with vehicle or carvacrol at 10, 31.6, and 100 mg/kg at time 0. Core temperature was measured by wireless temperature transmitters every 15 min for 2 hours. (B) The drop in core temperature between 0 min pre-injection and 30 min post-injection calculated from the experiment shown in panel A. n = 4 mice per group in a within-subject design. * P<0.05, 1-way ANOVA followed by Student-Neuman-Keuls post-hoc test. (C) Adult male CD-1 mice were injected intravenously with vehicle or carvacrol at 6, 12.5, 25, and 50 mg/kg at time 0. Core temperature was measured by wireless temperature transmitters every 15 min for 1 hour. (D) The drop in core temperature between 0 min pre-injection and 30 min post-injection was calculated from the experiment shown in panel A. n = 4–5 mice per group. * P<0.05, 1-way ANOVA followed by Student-Neuman-Keuls post-hoc test. (E) Adult male Sprague-Dawley rats were injected with vehicle of carvacrol at 25 mg/kg intravenously or 100 mg/kg intraperitoneally at time 0. Core temperature was measured by wireless temperature transmitters every 15 min for 1 hour. (F) The drop in core temperature between 0 min pre-injection and 60 min post-injection calculated from the experiment shown in panel A. n = 6–7 rats per group. * P<0.05, 1-way ANOVA followed by Student-Neuman-Keuls post-hoc test.
Mentions: To test the hypothesis that systemic TRPV3 activation induces hypothermia, core temperature was measured by wireless transmitters in adult male C57Bl/6 mice before and after intraperitoneal injection with vehicle or carvacrol at different doses. Core temperature was measured every 15 min for 2 hours. Intraperitoneal injection of vehicle led to ~0.7±0.2°C drop in core temperature at 30 min after injection. 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<0.05 for 10 and 31.6 mg/kg, 1-way ANOVA followed by Student-Neuman-Keuls post-hoc test; n = 4 mice per group in a within-subject design; Fig 1A and 1B).

Bottom Line: However, the methods for safe and effective hypothermia induction in conscious patients are lacking.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.In addition, the hypothermic effect was lost at cold ambient temperature.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Physiology and Biophysics Graduate Program, Cardiovascular Sciences Track, Baylor College of Medicine, Houston, Texas, United States of America.

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.

No MeSH data available.


Related in: MedlinePlus