Zidovudine ameliorates pathology in the mouse model of Duchenne muscular dystrophy via P2RX7 purinoceptor antagonism
Tóm tắt
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 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 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 DMDmdx 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.
Tài liệu tham khảo
Adinolfi E, Raffaghello L, Giuliani AL, Cavazzini L, Capece M, Chiozzi P, Bianchi G, Kroemer G, Pistoia V, Di Virgilio F (2012) Expression of P2X7 receptor increases in vivo tumor growth. Cancer Res 72(12):2957–2969
Altamirano F, Valladares D, Henriquez-Olguin C, Casas M, Lopez JR, Allen PD, Jaimovich E (2013) Nifedipine treatment reduces resting calcium concentration, oxidative and apoptotic gene expression, and improves muscle function in dystrophic mdx mice. PLoS One 8(12):e81222
Banihani R, Smile S, Yoon G, Dupuis A, Mosleh M, Snider A, McAdam L (2015) Cognitive and neurobehavioral profile in boys with Duchenne muscular dystrophy. J Child Neurol 30(11):1472–1482
Barka T, Anderson PJ (1962) Histochemical methods for acid phosphatase using hexazonium pararosanalin as coupler. J Histochem Cytochem 10:741–753
Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, Shindyalov IN, Bourne PE (2000) The protein data bank. Nucleic Acids Res 28(1):235–242
Blümer RM, van Vonderen MG, Sutinen J, Hassink E, Ackermans M, van Agtmael MA, Yki-Jarvinen H, Danner SA, Reiss P, Sauerwein HP (2008) Zidovudine/lamivudine contributes to insulin resistance within 3 months of starting combination antiretroviral therapy. AIDS 22(2):227–236
Bowles EJ, Lee JH, Alberio R, Lloyd RE, Stekel D, Campbell KH, St John JC (2007) Contrasting effects of in vitro fertilization and nuclear transfer on the expression of mtDNA replication factors. Genetics 176(3):1511–1526
Buvinic S, Almarza G, Bustamante M, Casas M, López J, Riquelme M, Sáez JC, Huidobro-Toro JP, Jaimovich E (2009) ATP released by electrical stimuli elicits calcium transients and gene expression in skeletal muscle. J Biol Chem 284(50):34490–34505
Caseley EA, Muench SP, Fishwick CW, Jiang LH (2016) Structure-based identification and characterisation of structurally novel human P2X7 receptor antagonists. Biochem Pharmacol 116:130–139
Chessell IP, Hatcher JP, Bountra C, Michel AD, Hughes JP, Green P, Egerton J, Murfin M, Richardson J, Peck WL, Grahames CB, Casula MA, Yiangou Y, Birch R, Anand P, Buell GN (2005) Disruption of the P2X7 purinoceptor gene abolishes chronic inflammatory and neuropathic pain. Pain 114(3):386–396
D’Amario D, Amodeo A, Adorisio R, Tiziano FD, Leone AM, Perri G, Bruno P, Massetti M, Ferlini A, Pane M, Niccoli G, Porto I, D'Angelo GA, Borovac JA, Mercuri E, Crea F (2017) A current approach to heart failure in Duchenne muscular dystrophy. Heart 103:1770–1779
Daluge SM, Purifoy DJ, Savina PM, St Clair MH, Parry NR, Dev IK, Novak P, Ayers KM, Reardon JE, Roberts GB (1994) 5-Chloro-2′,3′-dideoxy-3′-fluorouridine (935U83), a selective anti-human immunodeficiency virus agent with an improved metabolic and toxicological profile. Antimicrob Agents Chemother 38(7):1590–1603
De Luca A, Nico B, Liantonio A, Didonna MP, Fraysse B, Pierno S, Burdi R, Mangieri D, Rolland JF, Camerino C, Zallone A, Confalonieri P, Andreetta F, Arnoldi E, Courdier-Fruh I, Magyar JP, Frigeri A, Pisoni M, Svelto M, Conte Camerino D (2005) A multidisciplinary evaluation of the effectiveness of cyclosporine a in dystrophic mdx mice. Am J Pathol 166(2):477–489
Di Virgilio F (2007) Purinergic signalling in the immune system. A brief update. Purinergic Signal 3(1–2):1–3
Di Virgilio F (2015a) P2X receptors and inflammation. Curr Med Chem 22(7):866–877
Di Virgilio F (2015b) P2RX7: a receptor with a split personality in inflammation and cancer. Mol Cell Oncol 3(2):e1010937
Di Virgilio F, Dal Ben D, Sarti AC, Giuliani AL, Falzoni S (2017) The P2X7 receptor in infection and inflammation. Immunity 47(1):15–31
Di Virgilio F, Ferrari D, Adinolfi E (2009) P2X(7): a growth-promoting receptor-implications for cancer. Purinergic Signal 5(2):251–256
Dumont NA, Wang YX, von Maltzahn J, Pasut A, Bentzinger CF, Brun CE, Rudnicki MA (2015) Dystrophin expression in muscle stem cells regulates their polarity and asymmetric division. Nat Med 21(12):1455–1463
Ermolova NV, Martinez L, Vetrone SA, Jordan MC, Roos KP, Sweeney HL, Spencer MJ (2014) Long-term administration of the TNF blocking drug Remicade (cV1q) to mdx mice reduces skeletal and cardiac muscle fibrosis, but negatively impacts cardiac function. Neuromuscul Disord 24(7):583–595
Eser A, Colombel JF, Rutgeerts P, Vermeire S, Vogelsang H, Braddock M, Persson T, Reinisch W (2015) Safety and efficacy of an oral inhibitor of the purinergic receptor P2X7 in adult patients with moderately to severely active Crohn’s disease: a randomized placebo-controlled, double-blind, phase IIa study. Inflamm Bowel Dis 21(10):2247–2253
Fowler BJ, Gelfand BD, Kim Y, Kerur N, Tarallo V, Hirano Y, Amarnath S, Fowler DH, Radwan M, Young MT, Pittman K, Kubes P, Agarwal HK, Parang K, Hinton DR, Bastos-Carvalho A, Li S, Yasuma T, Mizutani T, Yasuma R, Wright C, Ambati J (2014) Nucleoside reverse transcriptase inhibitors possess intrinsic anti-inflammatory activity. Science 346(6212):1000–1003
Gao RY, Mukhopadhyay P, Mohanraj R, Wang H, Horváth B, Yin S, Pacher P (2011) Resveratrol attenuates azidothymidine-induced cardiotoxicity by decreasing mitochondrial reactive oxygen species generation in human cardiomyocytes. Mol Med Rep 4(1):151–155
Gazzerro E, Baldassari S, Assereto S, Fruscione F, Pistorio A, Panicucci C, Volpi S, Perruzza L, Fiorillo C, Minetti C, Traggiai E, Grassi F, Bruno C (2015) Enhancement of muscle T regulatory cells and improvement of muscular dystrophic process in mdx mice by blockade of extracellular ATP/P2X Axis. Am J Pathol 185(12):3349–3360
Grounds MD, Torrisi J (2004) Anti-TNFalpha (Remicade) therapy protects dystrophic skeletal muscle from necrosis. FASEB J 18(6):676–682
Grynkiewicz G, Poenie M, Tsien RY (1985) A new generation of Ca2+ indicators with greatly improved fluorescent properties. J Biol Chem 260:3440–3450
Guile SD, Alcaraz L, Birkinshaw TN, Bowers KC, Ebden MR, Furber M, Stocks MJ (2009) Antagonists of the P2X(7) receptor. From lead identification to drug development. J Med Chem 52(10):3123–3141
Wehling M, Spencer MJ, Tidball JG (2001) A nitric oxide synthase transgene ameliorates muscular dystrophy in mdx mice. J Cell Biol 155:123–31.
Hodgetts S, Radley H, Davies M, Grounds MD (2006) Reduced necrosis of dystrophic muscle by depletion of host neutrophils, or blocking TNFalpha function with Etanercept in mdx mice. Neuromuscul Disord 16(9–10):591–602
Idzko M, Ferrari D, Eltzschig HK (2014) Nucleotide signalling during inflammation. Nature 509(7500):310–317
Karasawa A, Kawate T (2016) Structural basis for subtype-specific inhibition of the P2X7 receptor. elife 5:e22153
Karmakar M, Katsnelson MA, Dubyak GR, Pearlman E (2016) Neutrophil P2X7 receptors mediate NLRP3 inflammasome-dependent IL-1ß secretion in response to ATP. Nat Commun 7:10555
Kawamura H, Kawamura T, Kanda Y, Kobayashi T, Abo T (2012) Extracellular ATP-stimulated macrophages produce macrophage inflammatory protein-2 which is important for neutrophil migration. Immunology 136(4):448–458
Keystone EC, Wang MM, Layton M, Hollis S, McInnes IB, D1520C00001 Study Team (2012) Clinical evaluation of the efficacy of the P2X7 purinergic receptor antagonist AZD9056 on the signs and symptoms of rheumatoid arthritis in patients with active disease despite treatment with methotrexate or sulphasalazine. Ann Rheum Dis 71(10):1630–1635
Kuno A, Horio Y (2016) SIRT1: a novel target for the treatment of muscular dystrophies. Oxidative Med Cell Longev 2016:6714686
Kuswanto W, Burzyn D, Panduro M, Wang KK, Jang YC, Wagers AJ, Benoist C, Mathis D (2016) Poor repair of skeletal muscle in aging mice reflects a defect in local, Interleukin-33-dependent accumulation of regulatory T cells. Immunity 44(2):355–367
Lambertucci C, Dal Ben D, Buccioni M, Marucci G, Thomas A, Volpini R (2015) Medicinal chemistry of P2X receptors: agonists and orthosteric antagonists. Curr Med Chem 22(7):915–928
McNally EM (2007) New approaches in the therapy of cardiomyopathy in muscular dystrophy. Annu Rev Med 58:75–88
Mizuno H, Nakamura A, Aoki Y, Ito N, Kishi S, Yamamoto K, Sekiguchi M, Takeda S, Hashido K (2011) Identification of muscle-specific microRNAs in serum of muscular dystrophy animal models: promising novel blood-based markers for muscular dystrophy. PLoS One 6(3):e18388
Mizutani T, Fowler BJ, Kim Y, Yasuma R, Krueger LA, Gelfand BD, Ambati J (2015) Nucleoside reverse transcriptase inhibitors suppress laser-induced choroidal neovascularization in mice. Invest Ophthalmol Vis Sci 56(12):7122–7129
Mohamad NS, Sinadinos A, Górecki DC, Zioupos P, Tong J (2016) Impact of P2RX7 ablation on the morphological, mechanical and tissue properties of bones in a murine model of duchenne muscular dystrophy. J Biomech 49(14):3444–3451
Molecular Operating Environment (MOE). 2013.08; Chemical Computing Group ULC, Montreal, 2017. https://www.chemcomp.com/Research-Citing_MOE.htm.
North RA, Jarvis MF (2013) P2X receptors as drug targets. Mol Pharmacol 83(4):759–769
Ambati J, Fowler B, Ambati K (2016) Compositions and methods for treating retinal degradation. Patent Application No. PCT/US2016/019852
Pelosi L, Berardinelli MG, De Pasquale L, Nicoletti C, D'Amico A, Carvello F, Moneta GM, Catizone A, Bertini E, De Benedetti F, Musarò A (2015) Functional and morphological improvement of dystrophic muscle by interleukin 6 receptor blockade. EBioMedicine 2(4):285–293
Percival JM, Whitehead NP, Adams ME, Adamo CM, Beavo JA, Froehner SC (2012) Sildenafil reduces respiratory muscle weakness and fibrosis in the mdx mouse model of Duchenne muscular dystrophy. J Pathol 228(1):77–87
Pigozzo SR, Da Re L, Romualdi C, Mazzara PG, Galletta E, Fletcher S, Wilton SD, Vitiello L (2013) Revertant fibers in the mdx murine model of Duchenne muscular dystrophy: an age- and muscle-related reappraisal. PLoS One 8:e72147
Pizzirani C, Ferrari D, Chiozzi P, Adinolfi E, Sandonà D, Savaglio E, Di Virgilio F (2007) Stimulation of P2 receptors causes release of IL-1beta-loaded microvesicles from human dendritic cells. Blood 109(9):3856–3864
Ponchel F, Toomes C, Bransfield K, Leong FT, Douglas SH, Field SL, Bell SM, Combaret V, Puisieux A, Mighell AJ, Robinson PA, Inglehearn CF, Isaacs JD, Markham AF (2003) Real-time PCR based on SYBR-Green I fluorescence: an alternative to the TaqMan assay for a relative quantification of gene rearrangements, gene amplifications and micro gene deletions. BMC Biotechnol 3:18
Pryce C, Pierre RB, Steel-Duncan J, Evans-Gilbert T, Palmer P, Moore J, Rodriguez B, Christie CD (2008) Safety of antiretroviral drug therapy in Jamaican children with HIV/AIDS. West Indian Med J 57(3):238–245
Radley-Crabb H, Terrill J, Shavlakadze T, Tonkin J, Arthur P, Grounds M (2012) A single 30 min treadmill exercise session is suitable for ‘proof-of concept studies’ in adult mdx mice: a comparison of the early consequences of two different treadmill protocols. Neuromuscul Disord 22(2):170–182
Rando TA (2001a) The dystrophin-glycoprotein complex, cellular signaling, and the regulation of cell survival in muscular dystrophies. Muscle Nerve 24:1575e1594
Rando TA (2001b) Role of nitric oxide in the pathogenesis of muscular dystrophies: a “two hit” hypothesis of the cause of muscle necrosis. Microsc Res Tech 55(4):223–235 Review
Rawat R, Cohen TV, Ampong B, Francia D, Henriques-Pons A, Hoffman EP, Nagaraju K (2010) Inflammasome up-regulation and activation in dysferlin-deficient skeletal muscle. Am J Pathol 176(6):2891–2900
Rufo A, Del Fattore A, Capulli M, Carvello F, De Pasquale L, Ferrari S, Pierroz D, Morandi L, De Simone M, Rucci N, Bertini E, Bianchi ML, De Benedetti F, Teti A (2011) Mechanisms inducing low bone density in Duchenne muscular dystrophy in mice and humans. J Bone Miner Res 26(8):1891–1903
Sacco A, Mourkioti F, Tran R, Choi J, Llewellyn M, Kraft P, Shkreli M, Delp S, Pomerantz JH, Artandi SE, Blau HM (2010) Short telomeres and stem cell exhaustion model Duchenne muscular dystrophy in mdx/mTR mice. Cell 143:1059–1071
Sch mittgen TD, Livak KJ (2008) Analyzing real-time PCR data by the comparative CT method. Nat Protoc 3(6):1101–1108
Sinadinos A, Young CN, Al-Khalidi R, Teti A, Kalinski P, Mohamad S, Floriot L, Henry T, Tozzi G, Jiang T, Wurtz O, Lefebvre A, Shugay M, Tong J, Vaudry D, Arkle S, doRego JC, Górecki DC (2015) sP2RX7 purinoceptor: a therapeutic target for ameliorating the symptoms of duchenne muscular dystrophy. PLoS Med 12(10):e1001888
Snow WM, Anderson JE, Jakobson LS (2013) Neuropsychological and neurobehavioral functioning in Duchenne muscular dystrophy: a review. Neurosci Biobehav Rev 37(5):743–752
Spencer MJ, Montecino-Rodriguez E, Dorshkind K, Tidball JG (2001) Helper (CD4(+)) and cytotoxic (CD8(+)) T cells promote the pathology of dystrophin-deficient muscle. Clin Immunol 98(2):235–243
Sperlágh B, Illes P (2014) P2X7 receptor: an emerging target in central nervous system diseases. Trends Pharmacol Sci 35(10):537–547
Stock TC, Bloom BJ, Wei N, Ishaq S, Park W, Wang X, Gupta P, Mebus CA (2012) Efficacy and safety of CE-224,535, an antagonist of P2X7 receptor, in treatment of patients with rheumatoid arthritis inadequately controlled by methotrexate. J Rheumatol 39(4):720–727
Subramanyam C, Duplantier AJ, Dombroski MA, Chang SP, Gabel CA, Whitney-Pickett C, Perregaux DG, Labasi JM, Yoon K, Shepard RM, Fisher M (2011) Discovery, synthesis and SAR of azinyl- and azolylbenzamides antagonists of the P2X7 receptor. Bioorg Med Chem Lett 21(18):5475–5479
Sugiyama T, Lee SY, Horie T, Oku H, Takai S, Tanioka H, Kuriki Y, Kojima S, Ikeda T (2013) P2X7 receptor activation may be involved in neuronal loss in the retinal ganglion cell layer after acute elevation of intraocular pressure in rats. Mol Vis 19:2080–2091
The European Pregnancy and Paediatric HIV Cohort Collaboration (EPPICC) study group in EuroCoord (2017) Safety of zidovudine/lamivudine scored tablets in children with HIV infection in Europe and Thailand. Eur J Clin Pharmacol 73(4):463–468
Vergani A, Tezza S, D'Addio F, Fotino C, Liu K, Niewczas M, Bassi R, Molano RD, Kleffel S, Petrelli A, Soleti A, Ammirati E, Frigerio M, Visner G, Grassi F, Ferrero ME, Corradi D, Abdi R, Ricordi C, Sayegh MH, Pileggi A, Fiorina P (2013) Long-term heart transplant survival by targeting the ionotropic purinergic receptor P2X7. Circulation 127(4):463–475
Vidal B, Ardite E, Suelves M, Ruiz-Bonilla V, Janue A, Flick MJ, Degen JL, Serrano AL, Munoz-Canoves P (2012) Amelioration of Duchenne muscular dystrophy in mdx mice by elimination of matrix-associated fibrin-driven inflammation coupled to the alphaMbeta2 leukocyte integrin receptor. Hum Mol Genet 21(9):1989–2004
Vieira NM, Elvers I, Alexander MS, Moreira YB, Eran A, Gomes JP, Marshall JL, Karlsson EK, Verjovski-Almeida S, Lindblad-Toh K, Kunkel LM, Zatz M (2015) Jagged 1 rescues the Duchenne muscular dystrophy phenotype. Cell 163(5):1204–1213
Wan P, Liu X, Xiong Y, Ren Y, Chen J, Lu N, Guo Y, Bai A (2016) Extracellular ATP mediates inflammatory responses in colitis via P2 × 7 receptor signaling. Sci Rep 6:19108
Wehling-Henricks M, Li Z, Lindsey C, Wang Y, Welc SS, Ramos JN, Khanlou N, Kuro-O M, Tidball JG (2016) Klotho gene silencing promotes pathology in the mdx mouse model of Duchenne muscular dystrophy. Hum Mol Genet 25(12):2465–2482
Wilhelm K, Ganesan J, Müller T, Dürr C, Grimm M, Beilhack A, Krempl CD, Sorichter S, Gerlach UV, Jüttner E, Zerweck A, Gärtner F, Pellegatti P, Di Virgilio F, Ferrari D, Kambham N, Fisch P, Finke J, Idzko M, Zeiser R (2010) Graft-versus-host disease is enhanced by extracellular ATP activating P2X7R. Nat Med 16(12):1434–1438
Xie X, Tsai SY, Tsai MJ (2016) COUP-TFII regulates satellite cell function and muscular dystrophy. J Clin Invest 126(10):3929–3941
Young CN, Brutkowski W, Lien CF, Arkle S, Lochmüller H, Zabłocki K, Górecki DC (2012) P2X7 purinoceptor alterations in dystrophic mdx mouse muscles: relationship to pathology and potential target for treatment. J Cell Mol Med 16(5):1026–1037
Young CN, Chira N, Róg J, Al-Khalidi R, Benard M, Galas L, Chan P, Vaudry D, Zabłocki K, Górecki DC (2017) Sustained activation of P2X7 induces MMP-2-evoked cleavage and functional purinoceptor inhibition. J Mol Cell Biol. https://doi.org/10.1093/jmcb/mjx030. Epub ahead of print.
Young CN, Sinadinos A, Lefebvre A, Chan P, Arkle S, Vaudry D, Gorecki DC (2015) A novel mechanism of autophagic cell death in dystrophic muscle regulated by P2RX7 receptor large-pore formation and HSP90. Autophagy 11(1):113–130