Wilhelms Daniel B, Dock Hua, Brito Haissa O, Pettersson Emma, Stojakovic Andrea, Zajdel Joanna, Engblom David, Theodorsson Elvar, Hammar Mats L, Spetz Holm Anna-Clara E
Division of Drug Research, Department of Medical and Health Sciences, Linköping University, Linköping, Sweden.
Department of Emergency Medicine, Local Health Care Services in Central Östergötland, Linköping, Sweden.
Front Pharmacol. 2019 Jan 4;9:1452. doi: 10.3389/fphar.2018.01452. eCollection 2018.
Hot flushes are common and troublesome symptoms of menopause. The neuropeptide calcitonin gene-related peptide (CGRP) is increased in plasma during hot flushes but it has not been clear if CGRP is causally involved in the mechanism underpinning the flushes. Here, we examined the effect of interventions with CGRP in a mouse model of hot flushes based on flush-like temperature increases triggered by forced physical activity in ovariectomized mice. Compared to normal mice, ovariectomized mice reacted with an exaggerated, flush-like, temperature increase after physical exercise. This increase was completely blocked by the non-peptide CGRP-antagonist MK-8825 (-0.41 degrees Celsius, 95% CI: -0,83 to 0,012, < 0.0001) at a dose that had no obvious effects on locomotor activity (50 mg/kg). Further, the flush-like temperature increases were strongly attenuated in ovariectomized mice lacking αCGRP due to a genetic modification. Collectively, our findings suggest that CGRP is an important mediator of experimentally induced hot flushes and they identify CGRP antagonists as promising treatment candidates for women and possibly also men with hot flushes.
潮热是更年期常见且令人困扰的症状。在潮热期间，血浆中的神经肽降钙素基因相关肽（CGRP）会增加，但CGRP是否因果性地参与潮热发生的机制尚不清楚。在此，我们基于去卵巢小鼠因强迫性体力活动引发的类似潮热的体温升高，在潮热小鼠模型中研究了CGRP干预的效果。与正常小鼠相比，去卵巢小鼠在体育锻炼后会出现夸张的、类似潮热的体温升高。非肽类CGRP拮抗剂MK - 8825（-0.41摄氏度，95%置信区间：-0.83至0.012，<0.0001）在对运动活动无明显影响的剂量（50毫克/千克）下，完全阻断了这种体温升高。此外，由于基因改造而缺乏αCGRP的去卵巢小鼠中，类似潮热的体温升高得到了显著减弱。总体而言，我们的研究结果表明，CGRP是实验诱导潮热的重要介质，并且确定CGRP拮抗剂是有望用于治疗女性以及可能患有潮热的男性的候选药物。
