Molecular Medicine Laboratory, School of Pharmacy and Biomedical Sciences, University of Portsmouth, Portsmouth, UK.
Present Address: Biotechnology Department, Faculty of Science, University of Baghdad, Baghdad, Iraq.
Acta Neuropathol Commun. 2018 Apr 11;6(1):27. doi: 10.1186/s40478-018-0530-4.
Duchenne muscular dystrophy (DMD) is the most common inherited muscle disorder that causes severe disability and death of young men. This disease is characterized by progressive muscle degeneration aggravated by sterile inflammation and is also associated with cognitive impairment and low bone density. Given that no current treatment can improve the long-term outcome, approaches with a strong translational potential are urgently needed. Duchenne muscular dystrophy (DMD) alters P2RX7 signaling in both muscle and inflammatory cells and inhibition of this receptor resulted in a significant attenuation of muscle and non-muscle symptoms in DMD mouse model. As P2RX7 is an attractive target in a range of human diseases, specific antagonists have been developed. Yet, these will require lengthy safety testing in the pediatric population of Duchenne muscular dystrophy (DMD) patients. In contrast, Nucleoside Reverse Transcriptase Inhibitors (NRTIs) can act as P2RX7 antagonists and are drugs with an established safety record, including in children. We demonstrate here that AZT (Zidovudine) inhibits P2RX7 functions acting via the same allosteric site as other antagonists. Moreover, short-term AZT treatment at the peak of disease in DMD mice attenuated the phenotype without any detectable side effects. Recovery was evident in the key parameters such as reduced sarcolemma permeability confirmed by lower serum creatine kinase levels and IgG influx into myofibres, decreased inflammatory cell numbers and inflammation markers in leg and heart muscles of treated mice. Moreover, this short-term therapy had some positive impact on muscle strength in vivo and no detrimental effect on mitochondria, which is the main side-effect of Nucleoside Reverse Transcriptase Inhibitors (NRTIs). Given these results, we postulate that AZT could be quickly re-purposed for the treatment of this highly debilitating and lethal disease. This approach is not constrained by causative DMD mutations and may be effective in alleviating both muscle and non-muscle abnormalities.
杜氏肌营养不良症（DMD）是最常见的遗传性肌肉疾病，可导致年轻男性严重残疾和死亡。这种疾病的特征是肌肉进行性退化，伴有非感染性炎症，还与认知障碍和低骨密度有关。鉴于目前尚无治疗方法可以改善长期预后，因此迫切需要具有强大转化潜力的方法。DMD 改变了肌肉和炎症细胞中的 P2RX7 信号，该受体的抑制可显著减轻 DMD 小鼠模型的肌肉和非肌肉症状。由于 P2RX7 是一系列人类疾病的有吸引力的靶点，因此已经开发出了特定的拮抗剂。然而，这些药物需要在杜氏肌营养不良症（DMD）患儿中进行漫长的安全性测试。相比之下，核苷逆转录酶抑制剂（NRTIs）可以作为 P2RX7 的拮抗剂，并且是具有既定安全性记录的药物，包括在儿童中。我们在这里证明，AZT（齐多夫定）通过与其他拮抗剂相同的变构位点作用来抑制 P2RX7 的功能。此外，在 DMD 小鼠疾病高峰期进行短期 AZT 治疗可减轻表型，而没有任何可检测到的副作用。在治疗小鼠的腿部和心脏肌肉中，关键参数（如肌细胞膜通透性降低，血清肌酸激酶水平降低，IgG 流入肌纤维）得到了恢复，炎症细胞数量和炎症标志物减少，这表明恢复了。此外，这种短期治疗对体内肌肉力量有一定的积极影响，对线粒体没有不利影响，而线粒体是核苷逆转录酶抑制剂（NRTIs）的主要副作用。鉴于这些结果，我们推测 AZT 可以迅速重新用于治疗这种高度衰弱和致命的疾病。这种方法不受导致 DMD 的突变的限制，可能对缓解肌肉和非肌肉异常都有效。
