Selective inhibition of the mitochondrial permeability transition pore protects against neurodegeneration in experimental multiple sclerosis

Journal of Biological Chemistry

Volumn 291, Issue 9, 2016, Pages 4356-4373

  Warne, Justin ^a   Pryce, Gareth ^a,b   Hill, Julia M ^c   Shi, Xiao ^a   Lennerås, Felicia ^b   Puentes, Fabiola ^b   Kip, Maarten ^a   Hilditch, Laura ^c   Walker, Paul ^d   Simone, Michela I ^a,f   Chan, A W Edith ^a   Towers, Greg J ^c   Coker, Alun R ^a   Duchen, Michael R ^d   Szabadkai, Gyorgy ^d,e   Baker, David ^b   Selwood, David L ^a  

^a UNIVERSITY COLLEGE LONDON   (United Kingdom)

^b QUEEN MARY UNIVERSITY OF LONDON   (United Kingdom)

^c UNIVERSITY COLLEGE LONDON   (United Kingdom)

^d CYPROTEX DISCOVERY LTD   (United Kingdom)

^e UNIVERSITY OF PADOVA   (Italy)

^f UNIVERSITY OF NEWCASTLE   (Australia)

Author keywords

[No Author keywords available]

Indexed keywords

BIOLOGICAL ORGANS; ENERGY DISPERSIVE X RAY ANALYSIS; TOXICITY; X RAY DIFFRACTION ANALYSIS;

BIOLOGICAL EVALUATION; EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; ISCHEMIA-REPERFUSION INJURY; MITOCHONDRIAL PERMEABILITY TRANSITION PORE; PEPTIDYL-PROLYL ISOMERASE; PERMEABILITY TRANSITION PORES; SELECTIVE INHIBITION; THERAPEUTIC STRATEGY;

NEURODEGENERATIVE DISEASES;

1 (PENT 4 ENYL)QUINOLINIUM; CALCIUM ION; CYCLOPHILIN D; CYCLOSPORIN A; FLUORESCEIN; ISOMERASE INHIBITOR; MITOCHONDRIAL PERMEABILITY TRANSITION PORE; OXAZOLONE; UNCLASSIFIED DRUG; CARRIER PROTEIN; CYCLOPEPTIDE; CYCLOPHILIN; CYCLOSPORIN DERIVATIVE; JW47 COMPOUND; NEUROPROTECTIVE AGENT; QUINOLINE DERIVATIVE; RECOMBINANT PROTEIN;

AMINO ACID SEQUENCE; ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; BINDING AFFINITY; BRAIN CELL; CALCIUM METABOLISM; CALCIUM TRANSPORT; CELL PROLIFERATION; CONTROLLED STUDY; CYTOTOXICITY; DISEASE SEVERITY; DOSE RESPONSE; DRUG ACTIVITY; DRUG BINDING; DRUG BLOOD LEVEL; DRUG BRAIN LEVEL; DRUG DESIGN; DRUG DOSE COMPARISON; DRUG STRUCTURE; DRUG SYNTHESIS; ENZYME BINDING; ENZYME INHIBITION; EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; HEPG2 CELL LINE; LIVER MITOCHONDRION; LIVER TOXICITY; LOW DRUG DOSE; MALE; MEMBRANE PERMEABILITY; MITOCHONDRIAL MEMBRANE POTENTIAL; MOUSE; MULTIPLE SCLEROSIS; NERVE DEGENERATION; NERVE FIBER; NEUROFILAMENT; NEUROPROTECTION; NONHUMAN; OXIDATIVE PHOSPHORYLATION; PRIORITY JOURNAL; PROTEIN EXPRESSION; RAT; SINGLE DRUG DOSE; THERAPEUTIC INDEX; AMINO ACID SUBSTITUTION; ANIMAL; ANTAGONISTS AND INHIBITORS; BRAIN CORTEX; CELL CULTURE; CHEMISTRY; DRUG EFFECTS; GENETICS; HEP-G2 CELL LINE; HUMAN; IMMUNOLOGY; INBRED MOUSE STRAIN; KNOCKOUT MOUSE; LIVER; METABOLISM; MUTATION; NERVE CELL; PATHOLOGY; RANDOMIZATION; SYNTHESIS; T LYMPHOCYTE;

AMINO ACID SUBSTITUTION; ANIMALS; CELL PROLIFERATION; CELLS, CULTURED; CEREBRAL CORTEX; CYCLOPHILINS; CYCLOSPORINS; HEP G2 CELLS; HUMANS; LIVER; MALE; MICE, INBRED STRAINS; MICE, KNOCKOUT; MITOCHONDRIAL MEMBRANE TRANSPORT PROTEINS; MULTIPLE SCLEROSIS; MUTATION; NEURONS; NEUROPROTECTIVE AGENTS; PEPTIDES, CYCLIC; QUINOLINIUM COMPOUNDS; RANDOM ALLOCATION; RECOMBINANT PROTEINS; T-LYMPHOCYTES;

EID: 84964620721     PISSN: 00219258     EISSN: 1083351X     Source Type: Journal    
DOI: 10.1074/jbc.M115.700385     Document Type: Article

References (99)

1. Giorgio, V., von Stockum, S., Antoniel, M., Fabbro, A., Fogolari, F., Forte, M., Glick, G. D., Petronilli, V., Zoratti, M., Szabó, I., Lippe, G., and Bernardi, P. (2013) Dimers of mitochondrial ATP synthase form the permeability transition pore. Proc. Natl. Acad. Sci. U.S.A. 110, 5887-5892
2. O ATP synthase is the mitochondrial permeability transition pore. Proc. Natl. Acad. Sci. U.S.A. 111, 10580-10585
3. O ATP synthase in mitochondrial permeability transition. Cell Cycle 12, 674-683
4. Halestrap, A. P., and Richardson, A. P. (2015) The mitochondrial permeability transition: a current perspective on its identity and role in ischaemia/reperfusion injury. J. Mol. Cell. Cardiol. 78, 129-141
5. 1-ATP synthase by interacting with the lateral stalk of the complex. J. Biol. Chem. 284, 33982-33988
6. 1-ATP synthase activity by cyclophilin D regulates matrix adenine nucleotide levels. FEBS J. 278, 1112-1125
7. Basso, E., Petronilli, V., Forte, M. A., and Bernardi, P. (2008) Phosphate is essential for inhibition of the mitochondrial permeability transition pore by cyclosporin A and by cyclophilin D ablation. J. Biol. Chem. 283, 26307-26311
8. Compston, A., and Coles, A. (2008) Multiple sclerosis. Lancet 372, 1502-1517
9. Marta, M., and Giovannoni, G. (2012) Disease modifying drugsinmultiple sclerosis: mechanisms of action and new drugs in the horizon. CNS Neurol. Disord. Drug Targets 11, 610-623
10. Trapp, B. D., Peterson, J., Ransohoff, R. M., Rudick, R., Mörk, S., and Bö, L. (1998) Axonal transection in the lesions of multiple sclerosis. N. Engl. J. Med. 338, 278-285
11. Kutzelnigg, A., and Lassmann, H. (2014) Pathology of multiple sclerosis and related inflammatory demyelinating diseases. Handbook of clinical neurology 122, 15-58
12. Campbell, G. R., and Worrall, J. T., and Mahad, D. J. (2014) The central role of mitochondria in axonal degeneration in multiple sclerosis. Mult. Scler. 20, 1806-1813
13. Ohno, N., Chiang, H., Mahad, D. J., and Kidd, G. J., Liu, L., Ransohoff, R. M., and Sheng, Z. H., Komuro, H., and Trapp, B. D. (2014) Mitochondrial immobilization mediated by syntaphilin facilitates survival of demyelinated axons. Proc. Natl. Acad. Sci. U.S.A. 111, 9953-9958
14. Al-Izki, S., Pryce, G., and Hankey, D. J., Lidster, K., von Kutzleben, S. M., Browne, L., Clutterbuck, L., Posada, C, Edith Chan, A. W., Amor, S., Perkins, V., Gerritsen, W. H., Ummenthum, K., Peferoen-Baert, R., van der Valk, P., Montoya, A., Joel, S. P., Garthwaite, J., Giovannoni, G., Selwood, D. L., and Baker, D. (2014) Lesional-targeting of neuroprotection to the inflammatory penumbra in experimental multiple sclerosis. Brain 137, 92-108
15. Barrientos, S. A., and Martinez, N. W., Yoo, S., Jara, J. S., Zamorano, S., Hetz, C., Twiss, J. L., Alvarez, J., and Court, F. A. (2011) Axonal degeneration is mediated by the mitochondrial permeability transition pore. J. Neurosci. 31, 966-978
16. Dutta, R., McDonough, J., Yin, X., Peterson, J., Chang, A., Torres, T., Gudz, T., and Macklin, W. B., Lewis, D. A., Fox, R. J., Rudick, R., Mirnics, K., and Trapp, B. D. (2006) Mitochondrial dysfunction as a cause of axonal degeneration in multiple sclerosis patients. Ann. Neurol. 59, 478-489
17. Mahad, D., Ziabreva, I., Lassmann, H., and Turnbull, D. (2008) Mitochondrial defects in acute multiple sclerosis lesions. Brain 131, 1722-1735
18. Kapoor, R., Davies, M., Blaker, P. A., and Hall, S. M., and Smith, K. J. (2003) Blockers of sodium and calcium entry protect axons from nitric oxidemediated degeneration. Ann. Neurol. 53, 174-180
19. Hazelton, J. L., Petrasheuskaya, M., Fiskum, G., and Kristián, T. (2009) Cyclophilin D is expressed predominantly in mitochondria of 7-aminobutyric acidergic interneurons. J. Neurosci. Res. 87, 1250-1259
20. Forte, M., and Gold, B. G., Marracci, G., Chaudhary, P., Basso, E., Johnsen, D., Yu, X., Fowlkes, J., Rahder, M., Stem, K., Bernardi, P., and Bourdette, D. (2007) Cyclophilin D inactivation protects axons in experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis. Proc. Natl. Acad. Sci. U.S.A. 104, 7558-7563
21. Savino, C, Pelicci, P., and Giorgio, M. (2013) The P66Shc/mitochondrial permeability transition pore pathway determines neurodegeneration. Oxid. Med. Cell. Longev. 2013, 719407
22. Mbye, L. H., and Singh, I. N., Sullivan, P. G., Springer, J. E., and Hall, E. D. (2008) Attenuation of acute mitochondrial dysfunction after traumatic brain injury in mice by NIM811, a non-immunosuppressive cyclosporin A analog. Exp. Neurol. 209, 243-253
23. Hånell, A., and Greer, J. E., McGinn, M. J., and Povlishock, J. T. (2015) Traumatic brain injury-induced axonal phenotypes react differently to treatment. Acta Neuropathol. 129, 317-332
24. Guo, L., Du, H., Yan, S., Wu, X., and McKhann, G. M., Chen, J.X., and Yan, S. S. (2013) Cyclophilin D deficiency rescues axonal mitochondrial transport in Alzheimer's neurons. PLoS One 8, e54914
25. Du, H., Guo, L., Zhang, W., Rydzewska, M., and Yan, S. (2011) Cyclophilin D deficiency improves mitochondrial function and learning/memory in aging Alzheimer disease mouse model. Neurobiol. Aging 32, 398-406
26. Martin, L. J., Semenkow, S., Hanaford, A., and Wong, M. (2014) Mitochondrial permeability transition pore regulates Parkinson's disease development in mutant α-synuclein transgenic mice. Neurobiol. Aging 35, 1132-1152
27. 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
28. Quintanilla, R. A., and Jin, Y. N., von Bernhardi, R., and Johnson, G. V. (2013) Mitochondrial permeability transition pore induces mitochondria injury in Huntington disease. Mol. Neurodegener. 8, 45
29. Reddy, P. H., Tripathi, R., Troung, Q., Tirumala, K., and Reddy, T. P., Anekonda, V., Shirendeb, U. P., and Calkins, M. J., Reddy, A. P., Mao, P., and Manczak, M. (2012) Abnormal mitochondrial dynamics and synaptic degeneration as early events in Alzheimer's disease: implications to mitochondria-targeted antioxidant therapeutics. Biochim. Biophys. Acta 1822, 639-649
30. Readnower, R. D., and Pandya, J. D., McEwen, M. L., Pauly, J. R., and Springer, J. E., and Sullivan, P. G. (2011) Post-injury administration of the mitochondrial permeability transition pore inhibitor, NIM811, is neuroprotective and improves cognition after traumatic brain injury in rats. J. Neurotrauma 28, 1845-1853
31. Nakagawa, T., Shimizu, S., Watanabe, T., Yamaguchi, O., Otsu, K., Yamagata, H, Inohara, H., Kubo, T., and Tsujimoto, Y. (2005) Cyclophilin D-dependent mitochondrial permeability transition regulates some necrotic but not apoptotic cell death. Nature 434, 652-658
32. Baines, C. P., and Kaiser, R. A., Purcell, N. H, Blair, N. S., Osinska, H, and Hambleton, M. A., Brunskill, E. W., Sayen, M. R., and Gottlieb, R. A., Dorn, G. W., Robbins, J., and Molkentin, J. D. (2005) Loss of cyclophilin D reveals a critical role for mitochondrial permeability transition in cell death. Nature 434, 658-662
33. Kato, M., Akao, M., Matsumoto-Ida, M., Makiyama, T., Iguchi, M., Takeda, T., Shimizu, S., and Kita, T. (2009) The targeting of cyclophilin D by RNAi as a novel cardioprotective therapy: evidence from two-photon imaging. Cardiovasc. Res. 83, 335-344
34. Wu, N., and Li, W. N., Shu, W. Q., Lv, Y., and Jia, D. L. (2015) Blocking the mitochondrial permeability transition pore with cyclosporine-A can restore cardioprotection of ischemic postconditioning in hypercholesterolemic rat heart. Eur. Rev. Med. Pharmacol. Sci. 19, 446-454
35. Barbarino, J. M., Staatz, C E., Venkataramanan, R., Klein, T. E., and Altman, R. B. (2013) PharmGKB summary: cyclosporine and tacrolimus pathways. Pharmacogenet. Genomics 23, 563-585
36. Malouitre, S., Dube, H, Selwood, D., and Crompton, M. (2010) Mitochondrial targeting of cyclosporin A enables selective inhibition of cyclophilin-D and enhanced cytoprotection after glucose and oxygen deprivation. Biochem J. 425, 137-148
37. Davis, T. L., and Walker, J. R., Campagna-Slater, V., Finerty, P. J., Paramanathan, R., Bernstein, G., MacKenzie, F., Tempel, W., Ouyang, H., Lee, W. H., and Eisenmesser, E. Z., and Dhe-Paganon, S. (2010) Structural and biochemical characterization of the human cyclophilin family of peptidylprolyl isomerases. PLoS Biol. 8, e1000439
38. Gogarten, W., Van Aken, H., Moskopp, D., Roos, N., Schleef, J., Marcus, M., and Meyer, J. (1998) A case of severe cerebral trauma in a patient under chronic treatment with cyclosporine A. J. Neurosurg Anesthesiol. 10, 101-105
39. Scheinberg, L. C. (1990) Efficacy and toxicity of cyclosporine in chronic progressive multiple sclerosis: a randomized, double-blinded, placebocontrolled clinical trial: the Multiple Sclerosis Study Group. Ann. Neurol. 27, 591-605
40. Hecking, M., Kainz, A., Schillinger, M., Posch, C, Birsan, T., Rasoul-Rockenschaub, S., Bohmig, G. A., Schmaldienst, S., Watschinger, B., Hörl, W. H., Mühlbacher, F., and Säemann, M. D. (2008) Analysis of liver function in renal transplant recipients undergoing C2-monitoring for cyclosporine. Transpl. Int. 21, 223-233
41. Ross, M. F., and Kelso, G. F., Blaikie, F. H, James, A. M., Cochemé, H. M., Filipovska, A., Da Ros, T., Hurd, T. R., Smith, R. A., and Murphy, M. P. (2005) Lipophilic triphenylphosphonium cations as tools in mitochondrial bioenergetics and free radical biology. Biochemistry 70, 222-230
42. Gane, E. J., Weilert, F., Orr, D. W., and Keogh, G. F., Gibson, M., Lockhart, M. M., and Frampton, C. M., Taylor, K. M., Smith, R. A., and Murphy, M. P. (2010) The mitochondria-targeted anti-oxidant mitoquinone decreases liver damage in a phase II study of hepatitis C patients. Liver Int. 30, 1019-1026
43. Millard, M., Pathania, D., Shabaik, Y., Taheri, L., Deng, J., and Neamati, N. (2010) Preclinical evaluation of novel triphenylphosphonium salts with broad-spectrum activity. PLoS One 5, e13131
44. 2+ efflux from the organelle. Ann. N.Y. Acad. Sci. 1147, 264-274
45. Reily, C, Mitchell, T., Chacko, B. K., Benavides, G., and Murphy, M. P., and Darley-Usmar, V. (2013) Mitochondrially targeted compounds and their impact on cellular bioenergetics. Redox Biol. 1, 86-93
46. Porteous, C. M., and Menon, D. K., Aigbirhio, F. I., Smith, R. A., and Murphy M. P. (2013) P-glycoprotein (Mdr1a/1b) and breast cancer resistance protein (Bcrp) decrease the uptake of hydrophobic alkyl triphenylphosphonium cations by the brain. Biochim. Biophys. Acta 1830, 3458-3465
47. Dube, H., Selwood, D., Malouitre, S., Capano, M., and Simone, M. I., and Crompton, M. (2012) A mitochondrial-targeted cyclosporin A with high binding affinity for cyclophilin D yields improved cytoprotection of cardiomyocytes. Biochem. J. 441, 901-907
48. Schlatter, D., Thoma, R., Küng, E., Stihle, M., Müller, F., Borroni, E., Cesura, A., and Hennig, M. (2005) Crystal engineering yields crystals of cyclophilin D diffracting to 1.7 Å resolution. Acta Crystallogr. D Biol. Crystallogr. 61, 513-519
49. Valasani, K. R., and Carlson, E. A., Battaile, K. P., Bisson, A., Wang, C., Lovell, S., and ShiDu Yan, S. (2014) High-resolution crystal structures of two crystal forms of human cyclophilin Din complex with PEG 400 molecules. Acta Crystallogr. F Struct. Biol. Commun. 70, 717-722
50. Kajitani, K., Fujihashi, M., Kobayashi, Y., Shimizu, S., Tsujimoto, Y., and Miki, K. (2008) Crystal structure of human cyclophilin D in complex with its inhibitor, cyclosporin A at 0.96-Å resolution. Proteins 70, 1635-1639
51. McCoy, A. J., Grosse-Kunstleve, R. W., Adams, P. D., Winn, M. D., Storoni, L. C., and Read, R. J. (2007) Phaser crystallographic software. J. Appl. Crystallogr. 40, 658-674
52. Winn, M. D., and Ballard, C. C., Cowtan, K. D., Dodson, E. J., Emsley, P., and Evans, P. R., Keegan, R. M., Krissinel, E. B., and Leslie, A. G., McCoy, A., McNicholas, S. J., and Murshudov, G. N., Pannu, N. S., Potterton, E. A., and Powell, H. R., Read, R. J., Vagin, A., and Wilson, K. S. (2011) Overview of the CCP4 suite and current developments. Acta Crystallogr. D Biol. Crystallogr. 67, 235-242
53. Murshudov, G. N., and Vagin, A. A., and Dodson, E. J. (1997) Refinement of macromolecular structures by the maximum-likelihood method. Acta Crystallogr. D Biol. Crystallogr. 53, 240-255
54. Vagin, A. A., and Steiner, R. A., Lebedev, A. A., Potterton, L., McNicholas, S., Long, F., and Murshudov, G. N. (2004) REFMAC5 dictionary: organization of prior chemical knowledge and guidelines for its use. Acta Crystallogr. D Biol. Crystallogr. 60, 2184-2195
55. Emsley, P., and Cowtan, K. (2004) Coot: model-building tools for molecular graphics. Acta Crystallogr. D Biol. Crystallogr. 60, 2126-2132
56. Schüttelkopf, A. W., and van Aalten, D. M. (2004) PRODRG: a tool for high-throughput crystallography of protein-ligand complexes. Acta Crystallogr. D Biol. Crystallogr. 60, 1355-1363
57. Laskowski, R. A., and MacArthur, M. W., Moss, D. S., and Thornton, J. M. (1993) PROCHECK: a program to check the stereochemical quality of protein structures. J. Appl. Cryst. 26, 283-291
58. Davis, I. W., Leaver-Fay, A., Chen, V. B., and Block, J. N., Kapral, G. J., Wang, X., Murray, L. W., and Arendall, W. B., 3rd, Snoeyink, J., Richardson, J. S., and Richardson, D. C. (2007) MolProbity: all-atom contacts and structure validation for proteins and nucleic acids. Nucleic Acids Res. 35, W375-W383
59. Gaali, S., Kozany, C., Hoogeland, B., Klein, M., and Hausch, F. (2010) Facile synthesis of a fluorescent cyclosporin a analogue to study cyclophilin 40 and cyclophilin 18 ligands. ACS Med. Chem. Lett. 1, 536-539
60. Liu, Y., Jiang, J., Richardson, P. L., and Reddy, R. D., Johnson, D. D., and Kati, W. M. (2006) A fluorescence polarization-based assay for peptidyl prolyl cis/trans isomerase cyclophilin A. Anal. Biochem. 356, 100-107
61. Nikolovska-Coleska, Z., Wang, R., Fang, X., Pan, H., Tomita, Y., Li, P., Roller, P. P., Krajewski, K., and Saito, N. G., Stuckey, J. A., and Wang, S. (2004) Development and optimization of a binding assay for the XIAP BIR3 domain using fluorescence polarization. Anal. Biochem. 332, 261-273
62. Astin, R., Bentham, R., Djafarzadeh, S., Horscroft, J. A., and Kuc, R. E., Leung, P. S., Skipworth, J. R., and Vicencio, J. M., Davenport, A. P., Murray, A. J., Takala, J., and Jakob, S. M., Montgomery, H., and Szabadkai, G. (2013) No evidence for a local renin-angiotensin system in liver mitochondria. Sci. Rep. 3, 2467
63. Lim, S. Y., and Hausenloy, D. J., Arjun, S., Price, A. N., and Davidson, S. M., Lythgoe, M. F., and Yellon, D. M. (2011) Mitochondrial cyclophilin-D as a potential therapeutic target for post-myocardial infarction heart failure. J. Cell. Mol. Med. 15, 2443-2451
64. Naldini, L., Blömer, U., Gallay, P., Ory, D., Mulligan, R., Gage, F. H., and Verma, I. M., and Trono, D. (1996) In vivo gene delivery and stable transduction of nondividing cells by a lentiviral vector. Science 272, 263-267
65. Zufferey, R., Nagy, D., Mandel, R. J., Naldini, L., and Trono, D. (1997) Multiply attenuated lentiviral vector achieves efficient gene delivery in vivo. Nat. Biotechnol. 15, 871-875
66. Bainbridge, J. W., Stephens, C., Parsley, K., Demaison, C., Halfyard, A., Thrasher, A. J., and Ali, R. R. (2001) In vivo gene transfer to the mouse eye using an HIV-based lentiviral vector: efficient long-term transduction of corneal endothelium and retinal pigment epithelium. Gene Ther. 8, 1665-1668
67. Ylinen, L. M., and Price, A. J., Rasaiyaah, J., Hué, S., Rose, N. J., Marzetta, F., and James, L. C., and Towers, G. J. (2010) Conformational adaptation of Asian macaque TRIMCyp directs lineage specific antiviral activity. PLoS Pathog. 6, e1001062
68. McEwan, W. A., Schaller, T., Ylinen, L. M., and Hosie, M. J., Towers, G. J., and Willett, B. J. (2009) Truncation of TRIM5 in the Feliformia explains the absence of retroviral restriction in cells of the domestic cat. J. Virol. 83, 8270-8275
69. Amor, S., Groome, N., Linington, C., Morris, M. M., Dornmair, K., and Gardinier, M. V., Matthieu, J. M., and Baker, D. (1994) Identification of epitopes of myelin oligodendrocyte glycoprotein for the induction of experimental allergic encephalomyelitis in SJL and Biozzi AB/H mice. J. Immunol. 153, 4349-4356
70. O'Neill, J. K., Baker, D., Davison, A. N., and Maggon, K. K., Jaffee, B. D., and Turk, J. L. (1992) Therapy of chronic relapsing experimental allergic encephalomyelitis and the role of the blood-brain barrier: elucidation by the action of Brequinar sodium. J. Neuroimmunol. 38, 53-62
71. Al-Izki, S., Pryce, G., O'Neill, J. K., Butter, C., Giovannoni, G., Amor, S., and Baker, D. (2012) Practical guide to the induction of relapsing progressive experimental autoimmune encephalomyelitis in the Biozzi ABH mouse. Mult. Scler. Relat. Disord. 1, 29-38
72. Jackson, S. J., Pryce, G., Diemel, L. T., and Cuzner, M. L., and Baker, D. (2005) Cannabinoid-receptor 1 null mice are susceptible to neurofilament damage and caspase 3 activation. Neuroscience 134, 261-268
73. Macarrón, R., and Luengo, J. I. (2011) Yin and Yang in medicinal chemistry: what does drug-likeness mean? Future Med. Chem. 3, 505-507
74. Sharma, P., and Varma, M. V., Chawla, H. P., and Panchagnula, R. (2005) Relationship between lipophilicity of BCS class III and IV drugs and the functional activity of peroral absorption enhancers. Farmaco 60, 870-873
75. Hogan, P. G., Chen, L., Nardone, J., and Rao, A. (2003) Transcriptional regulation by calcium, calcineurin, and NFAT. Genes Dev. 17, 2205-2232
76. Rasaiyaah, J., and Tan, C. P., Fletcher, A. J., Price, A. J., Blondeau, C., Hilditch, L., Jacques, D. A., and Selwood, D. L., James, L. C., Noursadeghi, M., and Towers, G. J. (2013) HIV-1 evades innate immune recognition through specific cofactor recruitment. Nature 503, 402-405
77. Hoye, A. T., and Davoren, J. E., Wipf, P., Fink, M. P., and Kagan, V. E. (2008) Targeting mitochondria. Acc. Chem. Res. 41, 87-97
78. Rodrigues, J. R., and Gamboa de Domínguez, N. (2007) Plasmodium berghei: in vitro and in vivo activity of dequalinium. Exp. Parasitol. 115, 19-24
79. Schinkel, A. H., Wagenaar, E., van Deemter, L., Mol, C. A., and Borst, P. (1995) Absence of the mdr1a P-glycoprotein in mice affects tissue distribution and pharmacokinetics of dexamethasone, digoxin, and cyclosporin A. J. Clin. Invest. 96, 1698-1705
80. Templeton, I., Eichenbaum, G., Sane, R., and Zhou, J. (2014) Case study 5: deconvoluting hyperbilirubinemia: differentiating between hepatotoxicity and reversible inhibition of UGT1A1, MRP2, or OATP1B1 in drug development. Methods Mol. Biol. 1113, 471-483
81. Hampton, D. W., Serio, A., Pryce, G., Al-Izki, S., Franklin, R. J., Giovannoni, G., Baker, D., and Chandran, S. (2013) Neurodegeneration progresses despite complete elimination of clinical relapses in a mouse model of multiple sclerosis. Acta Neuropathol. Commun. 1, 84
82. Allen, S. J., Baker, D., O'Neill, J. K., Davison, A. N., and Turk, J. L. (1993) Isolation and characterization of cells infiltrating the spinal cord during the course of chronic relapsing experimental allergic encephalomyelitis in the Biozzi AB/H mouse. Cell. Immunol. 146, 335-350
83. Jackson, S. J., Lee, J., Nikodemova, M., Fabry, Z., and Duncan, I. D. (2009) Quantification of myelin and axon pathology during relapsing progressive experimental autoimmune encephalomyelitis in the Biozzi ABH mouse. J. Neuropathol. Exp. Neurol. 68, 616-625
84. Baker, D., Gerritsen, W., Rundle, J., and Amor, S. (2011) Critical appraisal of animal models of multiple sclerosis. Mult. Scler. 17, 647-657
85. Starr, R., Attema, B., DeVries, G. H., and Monteiro, M. J. (1996) Neurofilament phosphorylation is modulated by myelination. J. Neurosci. Res. 44, 328-337
86. Smulik, J. A., and Diver, S. T., Pan, F., and Liu, J. O. (2002) Synthesis of cyclosporin A-derived affinity reagents by olefin metathesis. Org. Lett. 4, 2051-2054
87. Lemasters, J. J., and Ramshesh, V. K. (2007) Imaging of mitochondrial polarization and depolarization with cationic fluorophores. Methods Cell Biol. 80, 283-295
88. Gallay, P. A., and Lin, K. (2013) Profile of alisporivir and its potential in the treatment of hepatitis C. Drug Des. Devel. Ther. 7, 105-115
89. Chung, N. S., and Wasan, K. M. (2004) Potential role of the low-density lipoprotein receptor family as mediators of cellular drug uptake. Adv. Drug Deliv. Rev. 56, 1315-1334
90. Su, K. G., Savino, C., Marracci, G., Chaudhary, P., Yu, X., Morris, B., Galipeau, D., Giorgio, M., Forte, M., and Bourdette, D. (2012) Genetic inactivation of the p66 isoform of ShcA is neuroprotective in a murine model of multiple sclerosis. Eur. J. Neurosci. 35, 562-571
91. Kappos, L., Patzold, U., Dommasch, D., Poser, S., Haas, J., Krauseneck, P., Malin, J. P., Fierz, W., and Graffenried, B. U., and Gugerli, U. S. (1988) Cyclosporine versus azathioprine in the long-term treatment of multiple sclerosis: results of the German multicenter study. Ann. Neurol. 23, 56-63
92. Coles, A. J., and Wing, M. G., Molyneux, P., Paolillo, A., Davie, C. M., Hale, G., Miller, D., Waldmann, H., and Compston, A. (1999) Monoclonal antibody treatment exposes three mechanisms underlying the clinical course of multiple sclerosis. Ann. Neurol. 46, 296-304
93. Raftopoulos, R., Rangarajan, A., Chen, C.-L., Hickman, S., Toosy, A., Wheeler-Kingshott, C. A., Altmann, D., Malik, S., Paling, D., Yiannakas, M., Schmierer, K., Sharrack, B., Sheridan, R., Giovannoni, G., Balcer, L., Miller, D., Ishikawa, H., and Kapoor, R. (2015) Sodium channel blockade with phenytoin has a neuroprotective effect on the ganglion cell complex after acute optic neuritis. Mult. Scler. 21, 273-274
94. Pryce, G., O'Neill, J. K., Croxford, J. L., Amor, S., Hankey, D. J., East, E., Giovannoni, G., and Baker, D. (2005) Autoimmune tolerance eliminates relapses but fails to halt progression in a model of multiple sclerosis. J. Neuroimmunol. 165, 41-52
95. Kageyama, T., Komori, M., Miyamoto, K., Ozaki, A., Suenaga, T., Takahashi, R., Kusunoki, S., Matsumoto, S., and Kondo, T. (2013) Combination of cyclosporine A with corticosteroids is effective for the treatment of neuromyelitis optica. J. Neurol. 260, 627-634
96. Bart, J., and Groen, H. J., Hendrikse, N. H., van der Graaf, W. T., Vaalburg, W., and de Vries, E. G. (2000) The blood-brain barrier and oncology: new insights into function and modulation. Cancer Treat. Rev. 26, 449-462
97. Pryce, G., Visintin, C., Ramagopalan, S. V., Al-Izki, S., De Faveri, L. E., Nuamah, R. A., Mein, C. A., Montpetit, A., Hardcastle, A. J., Kooij, G., de Vries, H. E., Amor, S., Thomas, S. A., Ledent, C., Marsicano, G., Lutz, B., Thompson, A. J., Selwood, D. L., Giovannoni, G., and Baker, D. (2014) Control of spasticity in a multiple sclerosis model using central nervous system-excluded CB1 cannabinoid receptor agonists. FASEB J. 28, 117-130
98. Su, K., Bourdette, D., and Forte, M. (2013) Mitochondrial dysfunction and neurodegeneration in multiple sclerosis. Front. Physiol. 4, 169
99. Makler, M. T. (August 7, 1990) U. S. Patent 4,946,849