Manning Jennifer, Kulbida Rebecca, Rai Prerana, Jensen Lindsay, Bouma Judith, Singh Sanjay P, O'Malley Dervla, Yilmazer-Hanke Deniz
Department of Physiology, University College Cork, Cork, Ireland Department of Anatomy & Neuroscience, University College Cork, Cork, Ireland.
Department of Anatomy & Neuroscience, University College Cork, Cork, Ireland.
Exp Physiol. 2014 Oct;99(10):1370-86. doi: 10.1113/expphysiol.2014.079475. Epub 2014 Jun 27.
Mutations in the structural protein dystrophin underlie muscular dystrophies characterized by progressive deterioration of muscle function. Dystrophin-deficient mdx mice are considered a model for Duchenne muscular dystrophy (DMD). Individuals with DMD are also susceptible to mood disorders, such as depression and anxiety. Therefore, the study objectives were to investigate the effects of the tricyclic antidepressant amitriptyline on mood, learning, central cytokine expression and skeletal muscle inflammation in mdx mice. Amitriptyline-induced effects (10 mg kg(-1) daily s.c. injections, 25 days) on the behaviour of mdx mice were investigated using the open field arena and tail suspension tests. The effects of chronic amitriptyline treatment on inflammatory markers were studied in the muscle and plasma of mdx mice, and mood-associated monoamine and cytokine concentrations were measured in the amygdala, hippocampus, prefrontal cortex, striatum, hypothalamus and midbrain. The mdx mice exhibited increased levels of anxiety and depressive-like behaviour compared with wild-type mice. Amitriptyline treatment had anxiolytic and antidepressant effects in mdx mice associated with elevations in serotonin levels in the amygdala and hippocampus. Inflammation in mdx skeletal muscle tissue was also reduced following amitriptyline treatment as indicated by decreased immune cell infiltration of muscle and lower levels of the pro-inflammatory cytokines tumour necrosis factor-α and interleukin-6 in the forelimb flexors. Interleukin-6 mRNA expression was remarkably reduced in the amygdala of mdx mice by chronic amitriptyline treatment. Positive effects of amitriptyline on mood, in addition to its anti-inflammatory effects in skeletal muscle, may make it an attractive therapeutic option for individuals with DMD.
结构蛋白抗肌萎缩蛋白的突变是导致以肌肉功能进行性恶化为特征的肌营养不良症的根本原因。抗肌萎缩蛋白缺陷的mdx小鼠被认为是杜氏肌营养不良症（DMD）的模型。患有DMD的个体也易患情绪障碍，如抑郁症和焦虑症。因此，本研究的目的是调查三环类抗抑郁药阿米替林对mdx小鼠情绪、学习、中枢细胞因子表达和骨骼肌炎症的影响。使用旷场试验和悬尾试验研究了阿米替林（每天皮下注射10 mg kg(-1)，共25天）对mdx小鼠行为的影响。在mdx小鼠的肌肉和血浆中研究了慢性阿米替林治疗对炎症标志物的影响，并测量了杏仁核、海马体、前额叶皮质、纹状体、下丘脑和中脑中心情相关的单胺和细胞因子浓度。与野生型小鼠相比，mdx小鼠表现出更高水平的焦虑和抑郁样行为。阿米替林治疗对mdx小鼠具有抗焦虑和抗抑郁作用，这与杏仁核和海马体中血清素水平的升高有关。阿米替林治疗后，mdx骨骼肌组织中的炎症也有所减轻，表现为肌肉免疫细胞浸润减少以及前肢屈肌中促炎细胞因子肿瘤坏死因子-α和白细胞介素-6水平降低。慢性阿米替林治疗可使mdx小鼠杏仁核中的白细胞介素-6 mRNA表达显著降低。除了对骨骼肌具有抗炎作用外，阿米替林对情绪的积极影响可能使其成为DMD患者有吸引力的治疗选择。
