Nio Yasunori, Tanaka Masayuki, Hirozane Yoshihiko, Muraki Yo, Okawara Mitsugi, Hazama Masatoshi, Matsuo Takanori
Extra Value Generation and General Medicine Drug Discovery Unit, Takeda Pharmaceutical Company Limited, Fujisawa, Japan;
Inflammation Drug Discovery Unit, Takeda Pharmaceutical Company Limited, Fujisawa, Japan; and.
FASEB J. 2017 Dec;31(12):5307-5320. doi: 10.1096/fj.201700249R. Epub 2017 Aug 10.
Duchenne muscular dystrophy (DMD) is the most common inherited muscular dystrophy. Patients experience DMD in their 20s from cardiac or respiratory failure related to progressive muscle wasting. Currently, the only treatments for the symptoms of DMD are available. Muscle fibrosis, a DMD feature, leads to reduced muscle function and muscle mass, and hampers pharmaceutical therapeutic efficacy. Although antifibrotic agents may be useful, none is currently approved. Phosphodiesterase 4 (PDE4) inhibitors have exhibited antifibrotic effects in human and animal models. In this study, we showed beneficial effects of the PDE4 inhibitor piclamilast in the DMD mdx mouse. Piclamilast reduced the mRNA level of profibrotic genes, including collagen 1A1, in the gastrocnemius and diaphragm, in the mdx mouse, and significantly reduced the Sirius red staining area. The PDE5 inhibitors sildenafil and tadalafil ameliorated functional muscle ischemia in boys with DMD, and sildenafil reversed cardiac dysfunction in the mdx mouse. Single-treatment piclamilast or sildenafil showed similar antifibrotic effects on the gastrocnemius; combination therapy showed a potent antifibrotic effect, and piclamilast and combination therapy increased peroxisome proliferator-activated receptor γ coactivator-1α mRNA in mouse gastrocnemius. In summary, we confirmed that piclamilast has significant antifibrotic effects in mdx mouse muscle and is a potential treatment for muscle fibrosis in DMD.-Nio, Y., Tanaka, M., Hirozane, Y., Muraki, Y., Okawara, M., Hazama, M., Matsuo, T. Phosphodiesterase 4 inhibitor and phosphodiesterase 5 inhibitor combination therapy has antifibrotic and anti-inflammatory effects in mdx mice with Duchenne muscular dystrophy.
杜氏肌营养不良症（DMD）是最常见的遗传性肌营养不良症。患者在20多岁时会因进行性肌肉萎缩导致的心脏或呼吸衰竭而患上DMD。目前，针对DMD症状的唯一治疗方法已经存在。肌肉纤维化是DMD的一个特征，会导致肌肉功能和肌肉质量下降，并阻碍药物治疗效果。尽管抗纤维化药物可能有用，但目前尚无一种获得批准。磷酸二酯酶4（PDE4）抑制剂在人和动物模型中已显示出抗纤维化作用。在本研究中，我们展示了PDE4抑制剂咯利普兰在DMD模型小鼠中的有益作用。咯利普兰降低了mdx小鼠腓肠肌和膈肌中包括胶原蛋白1A1在内的促纤维化基因的mRNA水平，并显著减少了天狼星红染色面积。PDE5抑制剂西地那非和他达拉非改善了DMD男孩的功能性肌肉缺血，西地那非逆转了mdx小鼠的心脏功能障碍。单药使用咯利普兰或西地那非对腓肠肌显示出相似的抗纤维化作用；联合治疗显示出强大的抗纤维化作用，咯利普兰和联合治疗增加了小鼠腓肠肌中过氧化物酶体增殖物激活受体γ共激活因子-1α的mRNA水平。总之，我们证实咯利普兰在mdx小鼠肌肉中具有显著的抗纤维化作用，是DMD肌肉纤维化的一种潜在治疗方法。-Nio, Y., Tanaka, M., Hirozane, Y., Muraki, Y., Okawara, M., Hazama, M., Matsuo, T. 磷酸二酯酶4抑制剂和磷酸二酯酶5抑制剂联合治疗对杜氏肌营养不良症mdx小鼠具有抗纤维化和抗炎作用
