Pharmacology Research Laboratory, University Institute of Pharmaceutical Sciences, Panjab University, Sector 14, Chandigarh, India.
Schizophrenia Division, Centre for Addiction and Mental Health (CAMH), Toronto, ON, Canada.
Eur J Pharmacol. 2024 Nov 15;983:177010. doi: 10.1016/j.ejphar.2024.177010. Epub 2024 Sep 18.
Metabolic comorbidities such as obesity type 2 diabetes, insulin resistance, glucose intolerance, dyslipidemia are the major contributors for lower life expectancy and reduced patient compliance during antipsychotic therapy in patients with severe mental illnesses such as schizophrenia, bipolar disorder, and depression. TRPM8 activation by menthol is also reported to alleviate high fat diet-induced obesity in mice. Additionally, this TRPM8 activation leads to increase in gene expression of thermogenic genes in white adipocytes and dietary menthol was found to increase browning of WAT along with improved glucose utilization. Therefore, we aimed to evaluate the plausible role of TRPM8 channels in olanzapine-induced metabolic alterations in female balb/c mice.
6 weeks olanzapine (6 mg kg, per oral) model was used in female balb/c mice. Pharmacological manipulation of TRPM8 channel was done using menthol and N-(3-aminopropyl)-2-[(3-methylphenyl)methoxy]-N-(2-thienylmethyl)-benzamide (AMTB), the agonist and antagonist respectively.
Menthol co-treatment for six weeks prevented olanzapine-induced metabolic alterations such as weight gain, increased food intake, decreased energy expenditure, adiposity, liver lipid accumulation, systemic inflammation and insulin resistance. Although no significant change in TRPM8 mRNA expression was found in the hypothalamus, however, some of the protective effects of menthol were absent in presence of AMTB indicating possible involvement of TRPM8 channels.
Our results suggest possible therapeutic implications of menthol in the management of antipsychotic-induced weight gain and other metabolic alterations.
肥胖症 2 型糖尿病、胰岛素抵抗、葡萄糖耐受不良、血脂异常等代谢合并症是导致严重精神疾病（如精神分裂症、双相情感障碍和抑郁症）患者预期寿命降低和抗精神病药物治疗依从性降低的主要因素。薄荷醇对 TRPM8 的激活作用也被报道可以减轻高脂肪饮食诱导的肥胖小鼠的肥胖。此外，这种 TRPM8 的激活导致白色脂肪组织中产热基因的表达增加，饮食中的薄荷醇被发现可以增加 WAT 的褐色化，并改善葡萄糖利用。因此，我们旨在评估 TRPM8 通道在奥氮平诱导的雌性 balb/c 小鼠代谢改变中的可能作用。
使用 6 周龄奥氮平（6mg/kg，口服）模型进行雌性 balb/c 小鼠。使用薄荷醇和 N-(3-氨基丙基）-2-[(3-甲基苯基）甲氧基]-N-(2-噻吩基甲基）-苯甲酰胺（AMTB）对 TRPM8 通道进行药理学操作，分别作为激动剂和拮抗剂。
薄荷醇共处理 6 周可预防奥氮平引起的代谢改变，如体重增加、食物摄入增加、能量消耗减少、肥胖、肝脂质堆积、全身炎症和胰岛素抵抗。尽管在下丘脑中未发现 TRPM8 mRNA 表达的显著变化，但在 AMTB 存在的情况下，薄荷醇的一些保护作用消失，表明 TRPM8 通道可能参与其中。
我们的结果表明，薄荷醇在管理抗精神病药引起的体重增加和其他代谢改变方面可能具有治疗意义。
