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dc.contributor.authorAl-Khalidi, Rashaen
dc.contributor.authorGórecki, Dariusz C.en
dc.contributor.authorYoung, Christopher N. J.en
dc.contributor.authorPanicucci, C.en
dc.contributor.authorCox, P.en
dc.contributor.authorRóg, J.en
dc.contributor.authorChira, Nataliaen
dc.contributor.authorMcGeehan, R. E.en
dc.contributor.authorAmbati, K.en
dc.contributor.authorAmbati, J.en
dc.contributor.authorZabłocki, Krzysztofen
dc.contributor.authorGazzerro, E.en
dc.contributor.authorArkle, Stephenen
dc.contributor.authorBruno, C.en
dc.date.accessioned2018-04-10T10:37:54Z
dc.date.available2018-04-10T10:37:54Z
dc.date.issued2018-04-11
dc.identifier.citationAl-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)en
dc.identifier.issn2051-5960
dc.identifier.urihttp://hdl.handle.net/2086/15868
dc.descriptionThe file attached to this record is the author's final peer reviewed version.en
dc.description.abstractDuchenne 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.en
dc.language.isoenen
dc.publisherBMCen
dc.subjectAZTen
dc.subjectDuchenne muscular dystrophyen
dc.subjecteATPen
dc.subjectmdxen
dc.subjectPurinergic Receptorsen
dc.subjectP2RX7en
dc.titleZidovudine ameliorates pathology in the mouse model of Duchenne muscular dystrophy via P2RX7 purinoceptor antagonismen
dc.typeArticleen
dc.identifier.doihttps://dx.doi.org/10.1186/s40478-018-0530-4
dc.researchgroupPharmacology and Neuroscience Research Groupen
dc.peerreviewedYesen
dc.funderRA-K was supported by the Higher Committee for Education Development in Iraq (HCED). This research was supported in parts by the National Science Centre, Poland according to the decision number DEC-2013/11/B/NZ3/01573 (KZ, JR, DCG) and the COST Action BM1406. J.A. was supported by NIH grants (DP1GM114862, R01EY022238 and R01EY024068), the John Templeton Foundation and through a DuPont Guerry, III Professorship.en
dc.projectidDEC-2013/11/B/NZ3/01573, BM1406, DP1GM114862, R01EY022238 and R01EY024068en
dc.cclicenceCC-BY-NCen
dc.date.acceptance2018-03-28en
dc.exception.reasonThe output was published as gold open accessen
dc.researchinstituteLeicester Institute for Pharmaceutical Innovation - From Molecules to Practice (LIPI)en


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