Zidovudine ameliorates pathology in the mouse model of Duchenne muscular dystrophy via P2RX7 purinoceptor antagonism


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 den-sity. Given that no current treatment can improve the long-term outcome, approaches with a strong translational potential are urgently needed. DMD alters P2RX7 signaling in both muscle and inflamma-tory cells and inhibition of this receptor resulted in a significant attenuation of muscle and non-muscle symptoms in DMDmdx 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 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 DMDmdx mice attenu-ated 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 therapy had some positive impact on muscle strength in vivo and no detrimental effect on mitochondria, which is the main side-effect of 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.


The file attached to this record is the author's final peer reviewed version.


AZT, Duchenne muscular dystrophy, eATP, mdx, Purinergic Receptors, P2RX7


Al-Khalidi, R., Górecki, DC., Young, CNJ., Panicucci, C., Cox, P., Róg, J., Chira, N., McGeehan, R. E., Ambati, K., Ambati, J. , Zabłocki, K., Gazzerro, E., Arkle, S., Bruno, C. (2018) Zidovudine ameliorates pathology in the mouse model of Duchenne muscular dystrophy via P2RX7 purinoceptor antagonism. Acta Neuropathologica Communications, 6 (27)


Research Institute

Leicester Institute for Pharmaceutical Innovation - From Molecules to Practice (LIPI)