Pharmacology Research Lab, University Institute of Pharmaceutical Sciences (UIPS), Panjab University, Chandigarh 160014, India.
Food and Nutritional Biotechnology Division, National Agri-Food Biotechnology Institute (NABI), SAS Nagar, Punjab 140306, India.
Toxicol Appl Pharmacol. 2020 Sep 1;402:115124. doi: 10.1016/j.taap.2020.115124. Epub 2020 Jul 9.
Atypical antipsychotics (AAPs) have the tendency of inducing severe metabolic alterations like obesity, diabetes mellitus, insulin resistance, dyslipidemia and cardiovascular complications. These alterations have been attributed to altered hypothalamic appetite regulation, energy sensing, insulin/leptin signaling, inflammatory reactions and active reward anticipation. Line of evidence suggests that transient receptor potential vanilloid type 1 and 3 (TRPV1 and TRPV3) channels are emerging targets in treatment of obesity, diabetes mellitus and could modulate feed intake. The present study was aimed to investigate the putative role TRPV1/TRPV3 in olanzapine-induced metabolic alterations in mice. Female BALB/c mice were treated with olanzapine for six weeks to induce metabolic alterations. Non-selective TRPV1/TRPV3 antagonist (ruthenium red) and selective TRPV1 (capsazepine) and TRPV3 antagonists (2,2-diphenyltetrahydrofuran or DPTHF) were used to investigate the involvement of TRPV1/TRPV3 in chronic olanzapine-induced metabolic alterations. These metabolic alterations were differentially reversed by ruthenium red and capsazepine, while DPTHF didn't show any significant effect. Olanzapine treatment also altered the mRNA expression of hypothalamic appetite-regulating and nutrient-sensing factors, inflammatory genes and TRPV1/TRPV3, which were reversed with ruthenium red and capsazepine treatment. Furthermore, olanzapine treatment also increased expression of TRPV1/TRPV3 in nucleus accumbens (NAc), TRPV3 expression in ventral tegmental area (VTA), which were reversed by the respective antagonists. However, DPTHF treatment showed reduced feed intake in olanzapine treated mice, which might be due to TRPV3 specific antagonism and reduced hedonic feed intake. In conclusion, our results suggested the putative role TRPV1 in hypothalamic dysregulations and TRPV3 in the mesolimbic pathway; both regulate feeding in olanzapine treated mice.
非典型抗精神病药物（AAPs）有诱导严重代谢改变的倾向，如肥胖、糖尿病、胰岛素抵抗、血脂异常和心血管并发症。这些改变归因于下丘脑食欲调节、能量感应、胰岛素/瘦素信号、炎症反应和积极的奖励预期的改变。有证据表明，瞬时受体电位香草酸型 1 和 3（TRPV1 和 TRPV3）通道是治疗肥胖症、糖尿病的新兴靶点，并可调节摄食。本研究旨在探讨 TRPV1/TRPV3 在奥氮平诱导的小鼠代谢改变中的潜在作用。雌性 BALB/c 小鼠用奥氮平治疗 6 周以诱导代谢改变。非选择性 TRPV1/TRPV3 拮抗剂（钌红）和选择性 TRPV1（辣椒素）和 TRPV3 拮抗剂（2,2-二苯基四氢呋喃或 DPTHF）用于研究 TRPV1/TRPV3 在慢性奥氮平诱导的代谢改变中的作用。这些代谢改变被钌红和辣椒素不同程度地逆转，而 DPTHF 没有显示出任何显著的效果。奥氮平治疗还改变了下丘脑食欲调节和营养感应因子、炎症基因和 TRPV1/TRPV3 的 mRNA 表达，这些表达被钌红和辣椒素治疗逆转。此外，奥氮平治疗还增加了伏隔核（NAc）中 TRPV1/TRPV3 的表达，腹侧被盖区（VTA）中 TRPV3 的表达，这些表达被各自的拮抗剂逆转。然而，DPTHF 治疗显示出减少奥氮平治疗小鼠的摄食量，这可能是由于 TRPV3 特异性拮抗作用和减少享乐性摄食。总之，我们的结果表明 TRPV1 在下丘脑失调中的潜在作用和 TRPV3 在中边缘通路中的作用；两者都调节奥氮平治疗小鼠的摄食。
