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School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, Brisbane, QLD 4072, Australia.
Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia.
Life (Basel). 2021 Sep 21;11(9):994. doi: 10.3390/life11090994.
Duchenne muscular dystrophy (DMD) is characterized by progressive muscle weakness and wasting due to the lack of dystrophin protein. The acute phase of DMD is characterized by muscle necrosis and increased levels of the pro-inflammatory mediator, prostaglandin D2 (PGD2). Inhibiting the production of PGD2 by inhibiting hematopoietic prostaglandin D synthase (HPGDS) may alleviate inflammation and decrease muscle necrosis. We tested our novel HPGDS inhibitor, PK007, in the mouse model of DMD. Our results show that hindlimb grip strength was two-fold greater in the PK007-treated group, compared to untreated mice, and displayed similar muscle strength to strain control mice (C57BL/10ScSn). Histological analyses showed a decreased percentage of regenerating muscle fibers (~20% less) in tibialis anterior (TA) and gastrocnemius muscles and reduced fibrosis in the TA muscle in PK007-treated mice. Lastly, we confirmed that the DMD blood biomarker, muscle creatine kinase activity, was also reduced by ~50% in PK007-treated mice. We conclude that our HPGDS inhibitor, PK007, has effectively reduced muscle inflammation and fibrosis in a DMD mouse model.
杜氏肌营养不良症（DMD）的特征是由于缺乏抗肌萎缩蛋白而导致进行性肌肉无力和萎缩。DMD的急性期以肌肉坏死和促炎介质前列腺素D2（PGD2）水平升高为特征。通过抑制造血前列腺素D合酶（HPGDS）来抑制PGD2的产生可能会减轻炎症并减少肌肉坏死。我们在DMD小鼠模型中测试了我们新型的HPGDS抑制剂PK007。我们的结果表明，与未治疗的小鼠相比，PK007治疗组的后肢握力增加了两倍，并且显示出与品系对照小鼠（C57BL/10ScSn）相似的肌肉力量。组织学分析显示，PK007治疗的小鼠胫前肌（TA）和腓肠肌中再生肌纤维的百分比降低（约减少20%），且TA肌中的纤维化减少。最后，我们证实PK007治疗的小鼠中DMD血液生物标志物肌肉肌酸激酶活性也降低了约50%。我们得出结论，我们的HPGDS抑制剂PK007在DMD小鼠模型中有效减轻了肌肉炎症和纤维化。
