FK506 is neuroprotective in a model of antiretroviral toxic neuropathy
Sanjay C. Keswani MBBS, MRCP
Department of Neurology, The Johns Hopkins University, Baltimore, MD
Search for more papers by this authorBani Chander BS
Department of Neurology, The Johns Hopkins University, Baltimore, MD
Search for more papers by this authorChiler Hasan MS
Department of Neurology, The Johns Hopkins University, Baltimore, MD
Search for more papers by this authorJohn W. Griffin MD
Department of Neurology, The Johns Hopkins University, Baltimore, MD
Department of Neuroscience, The Johns Hopkins University, Baltimore, MD
Search for more papers by this authorJustin C. McArthur MBBS, MPH
Department of Neurology, The Johns Hopkins University, Baltimore, MD
Department of Epidemiology, The Johns Hopkins University, Baltimore, MD
Search for more papers by this authorCorresponding Author
Ahmet Hoke MD, PhD
Department of Neurology, The Johns Hopkins University, Baltimore, MD
Department of Neuroscience, The Johns Hopkins University, Baltimore, MD
Department of Neurology, The Johns Hopkins Hospital, Path 509, 600 North Wolfe Street, Baltimore, MD 21287Search for more papers by this authorSanjay C. Keswani MBBS, MRCP
Department of Neurology, The Johns Hopkins University, Baltimore, MD
Search for more papers by this authorBani Chander BS
Department of Neurology, The Johns Hopkins University, Baltimore, MD
Search for more papers by this authorChiler Hasan MS
Department of Neurology, The Johns Hopkins University, Baltimore, MD
Search for more papers by this authorJohn W. Griffin MD
Department of Neurology, The Johns Hopkins University, Baltimore, MD
Department of Neuroscience, The Johns Hopkins University, Baltimore, MD
Search for more papers by this authorJustin C. McArthur MBBS, MPH
Department of Neurology, The Johns Hopkins University, Baltimore, MD
Department of Epidemiology, The Johns Hopkins University, Baltimore, MD
Search for more papers by this authorCorresponding Author
Ahmet Hoke MD, PhD
Department of Neurology, The Johns Hopkins University, Baltimore, MD
Department of Neuroscience, The Johns Hopkins University, Baltimore, MD
Department of Neurology, The Johns Hopkins Hospital, Path 509, 600 North Wolfe Street, Baltimore, MD 21287Search for more papers by this authorAbstract
Antiretroviral toxic neuropathy is the most common neurological complication of human immunodeficiency virus infection. This painful neuropathy not only affects the quality of life of human immunodeficiency virus–infected patients but also severely limits viral suppression strategies. We have developed an in vitro model of this toxic neuropathy to better understand the mechanism of neurotoxicity and to test potential neuroprotective compounds. We show that among the dideoxynucleosides, ddC appears to be the most neurotoxic, followed by ddI and then d4T. This reflects their potency in causing neuropathy. AZT, which does not cause a peripheral neuropathy in patients, does not cause significant neurotoxicity in our model. Furthermore, in this model, we show that the immunophilin ligand FK506 but not cyclosporin A prevents the development of neurotoxicity by ddC, as judged by amelioration of ddC-induced “neuritic pruning,” neuronal mitochondrial depolarization, and neuronal necrotic death. This finding suggests a calcineurin-independent mechanism of neuroprotection. As calcineurin inhibition underlies the immunosuppressive properties of these clinically used immunophilin ligands, this holds promise for the neuroprotective efficacy of nonimmunosuppressive analogs of FK506 in the prevention or treatment of antiretroviral toxic neuropathy. Ann Neurol 2003;53:000–000
References
- 1 Wulff EA, Wang AK, Simpson, DM. HIV-associated peripheral neuropathy: epidemiology, pathophysiology and treatment. Drugs 2000; 59: 1251–1260.
- 2 Chen CH, Vazquez-Padua M, Cheng YC. Effect of anti-human immunodeficiency virus nucleoside analogs on mitochondrial DNA and its implication for delayed toxicity. Mol Pharmacol 1991; 39: 625–628.
- 3 Cui L, Locatelli L, Xie MY, Sommadossi JP. Effect of nucleoside analogs on neurite regeneration and mitochondrial DNA synthesis in PC-12 cells. J Pharmacol Exp Ther 1997; 280: 1228–1234.
- 4 Keilbaugh SA, Prusoff WH, Simpson MV. The PC12 cell as a model for studies of the mechanism of induction of peripheral neuropathy by anti-HIV-1 dideoxynucleoside analogs. Biochem Pharmacol 1991; 42: R5–R8.
- 5 Benbrik E, Chariot P, Bonavaud S, et al. Cellular and mitochondrial toxicity of zidovudine (AZT), didanosine (ddI) and zalcitabine (ddC) on cultured human muscle cells. J Neurol Sci 1997; 149: 19–25.
- 6 Yarchoan R, Pluda JM, Thomas RV, et al. Long-term toxicity/activity profile of 2′,3′-dideoxyinosine in AIDS or AIDS-related complex. Lancet 1990; 336: 526–529.
- 7 Snyder SH, Sabatini DM, Lai MM, et al. Neural actions of immunophilin ligands. Trends Pharmacol Sci 1998; 19: 21–26.
- 8 Gold BG. Neuroimmunophilin ligands: evaluation of their therapeutic potential for the treatment of neurological disorders. Expert Opin Investig Drugs 2000; 9: 2331–2342.
- 9 Dawson TM, Steiner JP, Dawson VL, et al. Immunosuppressant FK506 enhances phosphorylation of nitric oxide synthase and protects against glutamate neurotoxicity. Proc Natl Acad Sci USA 1993; 90: 9808–9812.
- 10 Sezen SF, Hoke A, Burnett AL, Snyder SH. Immunophilin ligand FK506 is neuroprotective for penile innervation. Nat Med 2001; 7: 1073–1074.
- 11 Steiner JP, Connolly MA, Valentine HL, et al. Neurotrophic actions of nonimmunosuppressive analogues of immunosuppressive drugs FK506, rapamycin and cyclosporin A. Nat Med 1997; 3: 421–428.
- 12 Brockes JP, Fields KL, Raff MC. Studies on cultured rat Schwann cells. I. Establishment of purified populations from cultures of peripheral nerve. Brain Res 1979; 165: 105–118.
- 13 Eldridge CF, Bunge MB, Bunge RP, Wood PM. Differentiation of axon-related Schwann cells in vitro. I. Ascorbic acid regulates basal lamina assembly and myelin formation. J Cell Biol 1987; 105: 1023–1034.
- 14 Lazarovici P, Yanai P, Yavin E. Molecular interactions between micellar polysialogangliosides and affinity-purified tetanotoxins in aqueous solution. J Biol Chem 1987; 262: 2645–2651.
- 15 Stockel K, Schwab M, Thoenen H. Comparison between the retrograde axonal transport of nerve growth factor and tetanus toxin in motor, sensory and adrenergic neurons. Brain Res 1975; 99: 1–16.
- 16 Ankarcrona M, Dypbukt JM, Bonfoco E, et al. Glutamate-induced neuronal death: a succession of necrosis or apoptosis depending on mitochondrial function. Neuron 1995; 15: 961–973.
- 17 White RJ, Reynolds IJ. Mitochondrial depolarization in glutamate-stimulated neurons: an early signal specific to excitotoxin exposure. J Neurosci 1996; 16: 5688–5697.
- 18 Fayaz I, Tator CH. Modeling axonal injury in vitro: injury and regeneration following acute neuritic trauma. J Neurosci Methods 2000; 102: 69–79.
- 19 Moore RD, Wong WM, Keruly JC, McArthur JC. Incidence of neuropathy in HIV-infected patients on monotherapy versus those on combination therapy with didanosine, stavudine and hydroxyurea. AIDS 2000; 14: 273–278.
- 20 Moyle GJ, Sadler M. Peripheral neuropathy with nucleoside antiretrovirals: risk factors, incidence and management. Drug Saf 1998; 19: 481–494.
- 21 Cossarizza A, Troiano L, Mussini C. Mitochondria and HIV infection: the first decade. J Biol Regul Homeost Agents 2002; 16: 18–24.
- 22 Lewis W, Dalakas MC. Mitochondrial toxicity of antiviral drugs. Nat Med 1995; 1: 417–422.
- 23 Dalakas MC, Semino-Mora C, Leon-Monzon M. Mitochondrial alterations with mitochondrial DNA depletion in the nerves of AIDS patients with peripheral neuropathy induced by 2′3′-dideoxycytidine (ddC). Lab Invest 2001; 81: 1537–1544.
- 24 Cherry CL, Gahan ME, McArthur JC, et al. Exposure to dideoxynucleosides is reflected in lowered mitochondrial DNA in subcutaneous fat. J AIDS 2002; 30: 271–277.
- 25 Brew B, Tisch S, Law M. Lactate concentrations distinguish between nucleoside neuropathy and HIV distal symmetrical sensory polyneuropathy. Paper presented at: Eighth Conference on Retrovirus and Opportunistic Infections; 2001; Chicago.
- 26 Famularo G, Moretti S, Marcellini S, et al. Acetyl-carnitine deficiency in AIDS patients with neurotoxicity on treatment with antiretroviral nucleoside analogues. AIDS 1997; 11: 185–190.
- 27 Starnes MC, Cheng YC. Cellular metabolism of 2′,3′-dideoxycytidine, a compound active against human immunodeficiency virus in vitro. J Biol Chem 1987; 262: 988–991.
- 28 Lewis LD, Hamzeh FM, Lietman PS. Ultrastructural changes associated with reduced mitochondrial DNA and impaired mitochondrial function in the presence of 2′3′-dideoxycytidine. Antimicrob Agents Chemother 1992; 36: 2061–2065.
- 29 Chen CH, Cheng YC. Delayed cytotoxicity and selective loss of mitochondrial DNA in cells treated with the anti-human immunodeficiency virus compound 2′,3′-dideoxycytidine. J Biol Chem 1989; 264: 11934–11937.
- 30 Jiang S, Cai J, Wallace DC, Jones DP. Cytochrome c-mediated apoptosis in cells lacking mitochondrial DNA. Signaling pathway involving release and caspase 3 activation is conserved. J Biol Chem 1999; 274: 29905–29911.
- 31 Yamaguchi T, Katoh I, Kurata S. Azidothymidine causes functional and structural destruction of mitochondria, glutathione deficiency and HIV-1 promoter sensitization. Eur J Biochem 2002; 269: 2782–2788.
- 32 Modica-Napolitano JS. AZT causes tissue-specific inhibition of mitochondrial bioenergetic function. Biochem Biophys Res Commun 1993; 194: 170–177.
- 33 Barile M, Valenti D, Hobbs GA, et al. Mechanisms of toxicity of 3′-azido-3′-deoxythymidine. Its interaction with adenylate kinase. Biochem Pharmacol 1994; 48: 1405–1412.
- 34 Barile M, Valenti D, Passarella S, Quagliariello E. 3′-Azido-3′-deoxythmidine uptake into isolated rat liver mitochondria and impairment of ADP/ATP translocator. Biochem Pharmacol 1997; 53: 913–920.
- 35 Hobbs GA, Keilbaugh SA, Rief PM, Simpson MV. Cellular targets of 3′-azido-3′-deoxythymidine: an early (non-delayed) effect on oxidative phosphorylation. Biochem Pharmacol 1995; 50: 381–390.
- 36 Skuta G, Fischer GM, Janaky T, et al. Molecular mechanism of the short-term cardiotoxicity caused by 2′,3′-dideoxycytidine (ddC): modulation of reactive oxygen species levels and ADP-ribosylation reactions. Biochem Pharmacol 1999; 58: 1915–1925.
- 37 Petit F, Arnoult D, Lelievre JD, et al. Productive HIV-1 infection of primary CD4+ T cells induces mitochondrial membrane permeabilization leading to a caspase- independent cell death. J Biol Chem 2002; 277: 1477–1487.
- 38 Raidel SM, Haase C, Jansen NR, et al. Targeted myocardial transgenic expression of HIV Tat causes cardiomyopathy and mitochondrial damage. Am J Physiol Heart Circ Physiol 2002; 282: H1672–H1678.
- 39 Ferri KF, Jacotot E, Blanco J, et al. Mitochondrial control of cell death induced by HIV-1-encoded proteins. Ann N Y Acad Sci 2000; 926: 149–164.
- 40 Sharkey J, Butcher SP. Immunophilins mediate the neuroprotective effects of FK506 in focal cerebral ischaemia. Nature 1994; 371: 336–339.
- 41 Toung TJ, Bhardwaj A, Dawson VL, et al. Neuroprotective FK506 does not alter in vivo nitric oxide production during ischemia and early reperfusion in rats. Stroke 1999; 30: 1279–1285.
- 42 Wang HG, Pathan N, Ethell IM, et al. Ca2+-induced apoptosis through calcineurin dephosphorylation of BAD. Science 1999; 284: 339–343.
- 43 Ankarcrona M, Dypbukt JM, Orrenius S, Nicotera P. Calcineurin and mitochondrial function in glutamate-induced neuronal cell death. FEBS Lett 1996; 394: 321–324.
- 44 Crompton M, Virji S, Ward JM. Cyclophilin-D binds strongly to complexes of the voltage-dependent anion channel and the adenine nucleotide translocase to form the permeability transition pore. Eur J Biochem 1998; 258: 729–735.
- 45
Dubinsky JM,
Levi Y.
Calcium-induced activation of the mitochondrial permeability transition in hippocampal neurons.
J Neurosci Res
1998;
53:
728–741.
10.1002/(SICI)1097-4547(19980915)53:6<728::AID-JNR10>3.0.CO;2-U CAS PubMed Web of Science® Google Scholar
- 46 Schweizer M, Schlegel J, Baumgartner D, Richter C. Sensitivity of mitochondrial peptidyl-prolyl cis-trans isomerase, pyridine nucleotide hydrolysis and Ca2+ release to cyclosporine A and related compounds. Biochem Pharmacol 1993; 45: 641–646.
- 47 Kaibori M, Inoue T, Tu W, et al. FK506, but not cyclosporin A, prevents mitochondrial dysfunction during hypoxia in rat hepatocytes. Life Sci 2001; 69: 17–26.
- 48 Dedeoglu A, Ferrante RJ, Andreassen OA, et al. Mice overexpressing 70-kDa heat shock protein show increased resistance to malonate and 3-nitropropionic acid. Exp Neurol 2002; 176: 262–265.
- 49 Costantini LC, Chaturvedi P, Armistead DM, et al. A novel immunophilin ligand: distinct branching effects on dopaminergic neurons in culture and neurotrophic actions after oral administration in an animal model of Parkinson's disease. Neurobiol Dis 1998; 5: 97–106.