ABSTRACT
Preliminary research in our laboratory found that compound YZG-330 can reduce mouse body temperature, which could be blocked by adenosine A1 receptor (A1R) antagonist DPCPX. Based on the downstream signaling pathway of the A1R, the mechanism by which YZG-330 lowers body temperature was further studied. The pharmacodynamics of YZG-330 was evaluated by measuring the rectal temperature; expression of the transient receptor potential (TRP) ion channel, the P38 protein and its phosphorylated form in mouse hypothalamic homogenate were detected by Western blotting. A Ca2+ fluorescent probe, Fluo-3AM, was added to cells to detect the effect of YZG-330 on the Ca2+ content of mouse hypothalamic cells. YZG-330 dose-dependently reduced the body temperature in mice, and the selective P38 inhibitor SB-203580 (20 mg·kg-1, i.p.) significantly inhibited the hypothermic effect of YZG-330. A TRPM8 antagonist 2 (0.1 μg per mouse, i.c.v.) markedly attenuated the hypothermic effect of YZG-330 (0.25 or 1 mg·kg-1, i.p.). YZG-330 (2 mg·kg-1, i.p.) significantly increased the phosphorylation of P38, an effect that could be attenuated by the A1R antagonist DPCPX (5 mg·kg-1, i.g.) in mouse hypothalamus. In addition, YZG-330 also prominently enhanced the expression of TRPM8, which could be blocked by SB-203580; YZG-330 (0.1-10 μmol·L-1) increased intracellular Ca2+ concetration in mouse hypothalamic cells in a dose-dependent manner, and was inhibited by the A1R inhibitor DPCPX (0.5 and 1 μmol·L-1) and TRPM8 antagonist 2 (1 μmol·L-1). In conclusion, YZG-330 exerts its hypothermic effect by activating the A1R to promote the phosphorylation of P38 protein and thereby up-regulating the expression and activity of the TRPM8 ion channel, resulting in increased intracellular Ca2+ concentration to stimulate mouse hypothalamus cells to down-regulate body temperature. All animal experiments were approved by the Ethics Committee of the Institute of Materia Medica, Chinese Academy of Medical Sciences.
ABSTRACT
Torpor refers to a state in which the metabolic activity in the body of the living animal is greatly reduced during the period of reduced food supply, which is manifested as a substantial decrease in body temperature, metabolic level, and exercise level. Mammals have a strict body temperature regulation system to maintain a constant body temperature. When the energy supply is insufficient for a long time, some mammals will enter a hibernation state. Torpor is very similar to the hibernation state. The research on the mechanism of torpor state is of great significance in aerospace, military medicine and other fields. This review summarizes the specific mechanisms regulating the occurrence of torpor from four aspects: adenylate cyclase activating polypeptide (adcyap) neurons, leptin, pyroglutamylated RFamide peptide (QRFP) neurons, and sympathetic nervous system, aiming to provide ideas for further research on the mechanism of torpor.