Amitriptyline is efficacious in ameliorating muscle inflammation and depressive symptoms in the mdx mouse model of Duchenne muscular dystrophy

Abstract

New Findings r What is the central question of this study?Individuals suffering from Duchenne muscular dystrophy show progressive deterioration of muscle function associated with muscle inflammation and are susceptible to anxiety and depression. The central question in this study is whether the tricyclic antidepressant amitriptyline can alleviate symptoms of anxiety and depression, and at the same time has anti-inflammatory effects in mdx mice, which are a model of Duchenne muscular dystrophy. r What is the main finding and its importance?Amitriptyline reduced inflammation and cytokines in mdx skeletal muscle, and had anxiolytic and antidepressant effects in mdx mice. Moreover, amitriptyline elevated the level of serotonin but reduced the expression of the cytokine interleukin-6 in the amygdala of mdx mice.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

Cognitive flexibility deficits in a mouse model for the absence of full‐length dystrophin

“…In addition, mice were tested in the OF after the DLB. Increased anxiety-related behavior was observed in an OF (Manning et al 2014), but mdx mice did not show higher levels of anxiety in the elevated plus maze (Sekiguchi et al 2009), nor was anxiety increased in the DLB experiment (Vaillend et al 1995). The mdx mice tended to respond stronger to the bright LS in the automated home-cage than WT mice, in particular during the first 15 min by spending less time outside of their shelter, suggestive of more anxiety-related behavior as bright light is generally considered anxiogenic in mice (Crawley & Goodwin 1980).…”

“…Previous reports are not conclusive about an anxiety phenotype in mdx mice. Increased anxiety-related behavior was observed in an OF (Manning et al 2014), but mdx mice did not show higher levels of anxiety in the elevated plus maze (Sekiguchi et al 2009), nor was anxiety increased in the DLB experiment (Vaillend et al 1995). In contrast to these previous studies that used male mdx mice, we used females.…”

In vivo neutralization of IL‐6 receptors ameliorates gastrointestinal dysfunction in dystrophin‐deficient mdx mice

“…Stress‐related behaviors such as anxiety and depression are common in DMD patients and are also recapitulated in mdx mice . The effect of stress on GI function is accepted, with evidence that the key stress hormone, corticotropin‐releasing factor (CRF), stimulates colonic propulsive motor function and mediates visceral hypersensitivity via its receptors.…”

“…Stress-related behaviors such as anxiety and depression are common in DMD patients 12 and are also recapitulated in mdx mice. 13 The effect of stress on GI function is accepted, with evidence that the key stress hormone, corticotropin-releasing factor (CRF), stimulates colonic propulsive motor function and mediates visceral hypersensitivity 14 via its receptors. CRF receptor 1 and 2 (CRFR1 and CRFR2) are expressed throughout the GI tract, 15,16 where CRFR1 stimulates colonic motility 17 and visceral hypersensitivity 18,19 in contrast to CRFR2 which inhibits GI motility, delaying gastric emptying and ameliorating visceral pain sensitivity in rodents.…”

Evaluation of central and peripheral analgesic activity of amitriptyline in mice

“…33 Manning J et al, reported that reduced inflammation and cytokines in mdx mice model of Duchenne muscular dystrophy. 34 Another study by Hajhashemi V et al, reported the antiinflammatory effect of amitriptyline in carrageenan induced paw edema in rats. 35 In present study authors found that acetic acid induced writhes were decreased in amitriptyline group, which signifies the peripheral analgesic action of amitriptyline.…”