GNX-4728, a novel small molecule drug inhibitor of mitochondrial permeability transition, is therapeutic in a mouse model of amyotrophic lateral sclerosis

Frontiers in Cellular Neuroscience

Volumn 8, Issue DEC, 2014, Pages

  Martin, Lee J ^a   Fancelli, Daniele ^b   Wong, Margaret ^a   Niedzwiecki, Mark ^a   Ballarini, Marco ^b   Plyte, Simon ^b   Chang, Qing ^a  

^a JOHNS HOPKINS UNIVERSITY SCHOOL OF MEDICINE   (United States)

^b Johns Hopkins University School of Medicine ^*  (Italy)

Author keywords

Mitochondria; Mitochondrial calcium uptake; Mitochondrial permeability transition pore; Motoneuron; Motor neuron disease; Neuromuscular junction; Therapeutics

Indexed keywords

CALCIUM ION; COPPER ZINC SUPEROXIDE DISMUTASE; GNX 4728; MITOCHONDRIAL PERMEABILITY TRANSITION PORE; PLACEBO; UNCLASSIFIED DRUG;

ADULT; AMYOTROPHIC LATERAL SCLEROSIS; ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; BLOOD BRAIN BARRIER; CELL SURVIVAL; CONFOCAL MICROSCOPY; CONTROLLED STUDY; IMAGE ANALYSIS; IMMUNOFLUORESCENCE; IMMUNOHISTOCHEMISTRY; IMMUNOREACTIVITY; MALE; MITOCHONDRIAL PERMEABILITY; MOTOR PERFORMANCE; MOUSE; NERVE ENDING; NEUROMUSCULAR SYNAPSE; NEUROPROTECTION; NONHUMAN; RANDOMIZED CONTROLLED TRIAL; SCORING SYSTEM; SPECTROFLUOROMETRY; SPINAL CORD MOTONEURON;

EID: 84919428972     PISSN: 16625102     EISSN: None     Source Type: Journal    
DOI: 10.3389/fncel.2014.00433     Document Type: Article

References (44)

1. Alavian, K. N., Beutner, G., Lazrove, E., Sacchetti, S., Park, H.-A., Licznerski, P., et al. (2014). An uncoupling channel within the c-subunit ring of the F1F0 ATP synthase is the mitochondrial permeability transition pore. Proc. Natl. Acad. Sci. U S A 111, 10580-10585. doi: 10.1073/pnas.1401591111
2. Alavian, K. N., Dworetzky, S. I., Bonanni, L., Zhanga, P., Sacchetti, S., Mariggio, M. A., et al. (2012). Effects of dexpramipexole on brain mitochondrial conductances and cellular bioenergetics efficiency. Brain Res. 1446, 1-11. doi: 10.1016/j.brainres.2012.01.046
3. Barrientos, S. A., Martinez, N. W., Yoo, S., Jara, J. S., Zamorano, S., Hetz, C., et al. (2011). Axonal degeneration is mediated by the mitochondrial permeability transition pore. J. Neurosci. 31, 966-978. doi: 10.1523/jneurosci.4065-10.2011
4. Bartolome, F., Wu, H.-C., Burchell, V. S., Preza, E., Wray, S., Mahoney, C. J., et al. (2013). Pathogenic VCP mutations induce mitochondrial uncoupling and reduced ATP levels. Neuron 78, 57-64. doi: 10.1016/j.neuron.2013.02.028
5. Beal, M. F. (2005). Mitochondria take center stage in aging and neurodegeneration. Ann. Neurol. 58, 495-505. doi: 10.1002/ana.20624
6. Bendotti, C., Calvaresi, N., Chiveri, L., Prelle, A., Moggio, M., Braga, M., et al. (2001). Early vacuolization and mitochondrial damage in motor neurons of FALS mice are not associated with apoptosis or with changes in cytochrome oxidase histochemical reactivity. J. Neurol. Sci. 191, 25-33. doi: 10.1016/s0022-510x(01)00627-x
7. Bensimon, G., Lacomblez, L., Meininger, V., and the ALS/Riluzole Study group. (1994). A controlled trial of riluzule in amyotrophic lateral sclerosis. N. Engl. J. Med. 330, 585-591. doi: 10.1056/NEJM199403033300901
8. Bernardi, P., Krauskopf, A., Basso, E., Petronilli, V., Blalchy-Dyson, E., Di Lisa, F., et al. (2006). The mitochondrial permeability transition from in vitro artifact to disease target. FEBS J. 273, 2077-2099. doi: 10.1111/j.1742-4658.2006.05213.x
9. Bonora, M., Bononi, A., De Marchi, E., Giorgi, C., Lebiedzinska, M., Marchi, S., et al. (2013). Role of the c subunit of the F0 ATP synthase in mitochondrial permeability transition. Cell Cycle 12, 674-683. doi: 10.4161/cc.23599
10. Bordet, T., Berna, P., Abitbol, J.-L., and Pruss, R. M. (2010). Olesoxime (TRO19622): a novel mitochondrial-targeted neuroprotective compound. Pharmaceuticals 3, 345-368. doi: 10.3390/ph3020345
11. Bordet, T., Buisson, B., Michaud, M., Drouot, C., Galéa, P., Delaage, P., et al. (2007). Identification and characterization of cholest-4-en-3-one, oxime (TRO19622), a novel drug candidate for amyotrophic lateral sclerosis. J. Pharmacol. Exp. Ther. 322, 709-720. doi: 10.1124/jpet.107.123000
12. Comerford, P. T., and Fitzgerald, M. J. T. (1986). Motor innervation of rodent diaphragm. J. Anat. 149, 171-175.
13. Cudkowicz, M. E., van den Berg, L. H., Shefner, J. M., Mitsumoto, H., Mora, J. S., Ludolph, A., et al. (2013). Dexpramipexole versus placebo for patients with amyotrophic lateral sclerosis (EMPOWER): a randomized, double-blind, phase 3 trial. Lancet Neurol. 12, 1059-1067. doi: 10.1016/s1474-4422(13)70221-7
14. Dobrowolny, G., Aucello, M., Rizzuto, E., Beccaficao, S., Mammucari, C., Bonconpagni, S., et al. (2008). Skeletal muscle is a primary target of SOD1G93A-mediated toxicity. Cell Metab. 8, 425-436. doi: 10.1016/j.cmet.2008.09.002
15. Dupuis, L., Gonzalez de Aguilar, J. L., Echaniz-Laguna, A., and Loeffler, J. P. (2006). Mitochondrial dysfunction in amyotrophic lateral sclerosis also affects skeletal muscle. Muscle Nerve 34, 253-254. doi: 10.1002/mus.20556
16. Fancelli, D., Abate, A., Amici, R., Bernardi, P., Ballarini, M., Cappa, A., et al. (2014). Cinnamic anilides as new mitochondrial permeability transition pore inhibitors endowed with ischemia-reperfusion injury protective effect in vivo. J. Med. Chem. 57, 5333-5347. doi: 10.1021/jm500547c
17. Gertz, B., Wong, M., and Martin, L. J. (2012). Nuclear localization of human SOD1 and mutant SOD1-specific disruption of survival motor neuron protein complex in transgenic amyotrophic lateral sclerosis mice. J. Neuropathol. Exp. Neurol. 71, 162-177. doi: 10.1097/nen.0b013e318244b635
18. Gurney, M. E., Pu, H., Chiu, A. Y., Dal Canto, M. C., Polchow, C. Y., Alexander, D. D., et al. (1994). Motor neuron degeneration in mice that express a human Cu,Zn superoxide dismutase mutation. Science 264, 1772-1775. doi: 10.1126/science.8209258
19. Halestrap, A. P. (2009). What is the mitochondrial permeability transition pore? J. Mol. Cell. Cardiol. 46, 821-831. doi: 10.1016/j.yjmcc.2009.02.021
20. Jaiswal, M. K., and Keller, B. U. (2009). Cu/Zn superoxide dismutase typical for familial amyotrophic lateral sclerosis increases the vulnerability of mitochondria and perturbs Ca2+ homeostasis in SOD1G93A mice. Mol. Pharmacol. 75, 478-489. doi: 10.1124/mol.108.050831
21. Kriz, J., Gowing, G., and Julien, J.-P. (2003). Efficient three-drug cocktail for disease induced by mutant superoxide dismutase. Ann. Neurol. 53, 429-436. doi: 10.1002/ana.10500
22. Lenglet, T., Lacomblez, L., Abitbol, J. L., Ludolph, A., Mora, J. S., Robberecht, W., et al. (2014). A phase II-III trial of olesoxime in subjects with amyotrophic lateral sclerosis. Eur. J. Neurol. 21, 529-536. doi: 10.1111/ene.12344
23. Luo, G., Yi, J., Ma, C., Xiao, Y., Yi, F., Yu, T., et al. (2013). Defective mitochondrial dynamics is an early event in skeletal muscle of an amyotrophic lateral sclerosis mouse model. PLoS One 8:e82112. doi: 10.1371/journal.pone.0082112
24. Martin, L. J. (1999). Neuronal death in amyotrophic lateral sclerosis is apoptosis: possible contribution of a programmed cell death mechanism. J. Neuropathol. Exp. Neurol. 58, 459-471. doi: 10.1097/00005072-199905000-00005
25. Martin, L. J. (2010a). Mitochondrial and cell death mechanisms in neurodegenerative diseases. Pharmaceuticals (Basel) 3, 839-915. doi: 10.3390/ph3040839
26. Martin, L. J. (2010b). The mitochondrial permeability transition pore: a molecular target for amyotrophic lateral sclerosis. Biochim. Biophys. Acta 1802, 186-197. doi: 10.1016/j.bbadis.2009.07.009
27. Martin, L. J., Adams, N. A., Pan, Y., Price, A., and Wong, M. (2011). The mitochondrial permeability transition pore regulates nitric oxide-mediated apoptosis of neurons induced by target deprivation. J. Neurosci. 31, 359-370. doi: 10.1523/JNEUROSCI.2225-10.2011
28. Martin, L. J., Gertz, B., Pan, Y., Price, A. C., Molkentin, J. D., and Chang, Q. (2009). The mitochondrial permeability transition pore in motor neurons: involvement in the pathobiology of ALS mice. Exp. Neurol. 218, 333-346. doi: 10.1016/j.expneurol.2009.02.015
29. Martin, L. J., and Liu, Z. (2004). Opportunities for neuroprotection in ALS using cell death mechanism rationales.Drug Discov. Today 1, 135-143. doi: 10.1016/j.ddmod.2004.09.004
30. Martin, L. J., and Liu, Z. (2007). Adult olfactory bulb neural precursor cell grafts provide temporary protection from motor neuron degeneration, improve motor function and extend survival in amyotrophic lateral sclerosis mice. J. Neuropathol. Exp. Neurol. 66, 1002-1018. doi: 10.1097/nen.0b013e318158822b
31. Martin, L. J., Liu, Z., Chen, K., Price, A. C., Pan, Y., Swaby, J. A., et al. (2007). Motor neuron degeneration in amyotrophic lateral sclerosis mutant superoxide dismutase-1 transgenic mice: mechanisms of mitochondriopathy and cell death. J. Comp. Neurol. 500, 20-46. doi: 10.1002/cne.21160
32. Miller, R. G., Mitchell, J. D., and Moore, D. H. (2012). Riluzole for amyotrophic lateral sclerosis (ALS)/ motor neuron disease (MND). Cochrane Database Syst. Rev. 3:CD001447. doi: 10.1002/14651858.CD001447.pub3
33. Miller, R. G., Moore, D. H. II, Gelinas, D. F., Dronsky, V., Mendoza, R. T., Barohn, R. J., et al. (2001). Phase III randomized trial of gabapentin in patients with amyotrophic lateral sclerosis. Neurology 56, 843-848. doi: 10.1212/wnl.56.7.843
34. Morais, V. A., and De Strooper, B. (2010). Mitochondrial dysfunction and neurodegenerative disorders: cause or consequence. J. Alzheimers Dis. 20, S255-S263. doi: 10.3233/JAD-2010-100345
35. Muyderman, H., and Chen, T. (2014). Mitochondrial dysfunction in amyotrophic lateral sclerosis - a valid pharmacological target? Br. J. Pharmacol. 171, 2191-2205. doi: 10.1111/bph.12476
36. Nguyen, K. T., Barrett, J. N., García-Chacón, L., David, G., and Barrett, E. F. (2011). Repetitive nerve stimulation transiently opens the mitochondrial permeability transition pore in motor nerve terminals of symptomatic mutant SOD1 mice. Neurobiol. Dis. 42, 381-390. doi: 10.1016/j.nbd.2011.01.031
37. Reddy, P. H., and Reddy, T. P. (2011). Mitochondria as a therapeutic target for aging and neurodegenerative diseases. Curr. Alzheimer Res. 8, 398-409. doi: 10.2174/156720511795745401
38. Rothstein, J. D., Martin, L. J., and Kuncl, R. W. (1992). Decreased glutamate transport by brain and spinal cord in amyotrophic lateral sclerosis. N. Engl. J. Med. 326, 1464-1468. doi: 10.1056/nejm199205283262204
39. Vielhaber, S., Kunz, D., Winkler, K., Wiedemann, F. R., Kirches, E., Feistner, H., et al. (2000). Mitochondrial DNA abnormalities in skeletal muscle of patients with sporadic amyotrophic lateral sclerosis. Brain 123, 1339-1348. doi: 10.1093/brain/123.7.1339
40. Wong, M., Gertz, B., Chestnut, B. A., and Martin, L. J. (2013). Mitochondrial DNMT3A and DNA methylation in skeletal muscle and CNS of transgenic mouse models of ALS. Front. Cell. Neurosci. 7:279. doi: 10.3389/fncel.2013.00279
41. Wong, M., and Martin, L. J. (2010). Skeletal muscle-restricted expression of human SOD1 causes motor neuron degeneration in transgenic mice. Hum. Mol. Genet. 19, 2284-2302. doi: 10.1093/hmg/ddq106
42. Wong, P. C., Pardo, C. A., Borchelt, D. R., Lee, M. K., Copeland, N. G., Jenkins, N. A., et al. (1995). An adverse property of a familial ALS-linked SOD1 mutation causes motor neuron disease characterized by vacuolar degeneration of mitochondria. Neuron 14, 1105-1116. doi: 10.1016/0896-6273(95)90259-7
43. Zhao, Y.-Y., Yan, D.-J., and Chen, Z.-W. (2013). Role of AIF-1 in the regulation of inflammatory activation and diverse disease processes. Cell. Immunol. 284, 75-83. doi: 10.1016/j.cellimm.2013.07.008
44. Zhou, J., Yi, J., Fu, R., Liu, E., Siddique, T., Rios, E., et al. (2010). Hyperactive intracellular calcium signaling associated with localized mitochondrial defects in skeletal muscle of an animal model of amyotrophic lateral sclerosis. J. Biol. Chem. 285, 705-712. doi: 10.1074/jbc.m109.041319