Antioxidants halt axonal degeneration in a mouse model of X-adrenoleukodystrophy
Jone López-Erauskin, Stéphane Fourcade, Jorge Galino, Montserrat Ruiz, Agatha Schlüter, Alba Naudi, Mariona Jove, Manuel Portero-Otin, Reinald Pamplona, Isidre Ferrer, Aurora Pujol, Jone López-Erauskin, Stéphane Fourcade, Jorge Galino, Montserrat Ruiz, Agatha Schlüter, Alba Naudi, Mariona Jove, Manuel Portero-Otin, Reinald Pamplona, Isidre Ferrer, Aurora Pujol
Abstract
Objective: Axonal degeneration is a main contributor to disability in progressive neurodegenerative diseases in which oxidative stress is often identified as a pathogenic factor. We aim to demonstrate that antioxidants are able to improve axonal degeneration and locomotor deficits in a mouse model of X-adrenoleukodystrophy (X-ALD).
Methods: X-ALD is a lethal disease caused by loss of function of the ABCD1 peroxisomal transporter of very long chain fatty acids (VLCFA). The mouse model for X-ALD exhibits a late onset neurological phenotype with locomotor disability and axonal degeneration in spinal cord resembling the most common phenotype of the disease, adrenomyeloneuropathy (X-AMN). Recently, we identified oxidative damage as an early event in life, and the excess of VLCFA as a generator of radical oxygen species (ROS) and oxidative damage to proteins in X-ALD.
Results: Here, we prove the capability of the antioxidants N-acetyl-cysteine, α-lipoic acid, and α-tocopherol to scavenge VLCFA-dependent ROS generation in vitro. Furthermore, in a preclinical setting, the cocktail of the 3 compounds reversed: (1) oxidative stress and lesions to proteins, (2) immunohistological signs of axonal degeneration, and (3) locomotor impairment in bar cross and treadmill tests.
Interpretation: We have established a direct link between oxidative stress and axonal damage in a mouse model of neurodegenerative disease. This conceptual proof of oxidative stress as a major disease-driving factor in X-AMN warrants translation into clinical trials for X-AMN, and invites assessment of antioxidant strategies in axonopathies in which oxidative damage might be a contributing factor.
Copyright © 2011 American Neurological Association.
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References
- Lin MT, Beal MF. Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature. 2006;443:787–795.
- Martinez A, Portero-Otin M, Pamplona R, Ferrer I. Protein targets of oxidative damage in human neurodegenerative diseases with abnormal protein aggregates. Brain Pathol. 2010;20:281–297.
- Pratico D. Evidence of oxidative stress in Alzheimer's disease brain and antioxidant therapy: lights and shadows. Ann N Y Acad Sci. 2008;1147:70–78.
- Stack EC, Matson WR, Ferrante RJ. Evidence of oxidant damage in Huntington's disease: translational strategies using antioxidants. Ann N Y Acad Sci. 2008;1147:79–92.
- Zhou C, Huang Y, Przedborski S. Oxidative stress in Parkinson's disease: a mechanism of pathogenic and therapeutic significance. Ann N Y Acad Sci. 2008;1147:93–104.
- Bjartmar C, Trapp BD. Axonal and neuronal degeneration in multiple sclerosis: mechanisms and functional consequences. Curr Opin Neurol. 2001;14:271–278.
- McSharry C. Multiple sclerosis: axonal loss linked to MS disability. Nat Rev Neurol. 2010;6:300.
- Press C, Milbrandt J. Nmnat delays axonal degeneration caused by mitochondrial and oxidative stress. J Neurosci. 2008;28:4861–4871.
- Sherer TB, Betarbet R, Testa CM, et al. Mechanism of toxicity in rotenone models of Parkinson's disease. J Neurosci. 2003;23:10756–10764.
- Testa CM, Sherer TB, Greenamyre JT. Rotenone induces oxidative stress and dopaminergic neuron damage in organotypic substantia nigra cultures. Brain Res Mol Brain Res. 2005;134:109–118.
- Ferrer I, Aubourg P, Pujol A. General aspects and neuropathology of X-linked adrenoleukodystrophy. Brain Pathol. 2010;20:817–830.
- Moser H, Smith KD, Watkins PA, et al. Scriver C. The metabolic and molecular bases of inherited disease. 8th ed. II. New York, NY: McGraw-Hill; 2001. X-linked adrenoleukodystrophy; pp. 3257–3301.
- Powers JM, DeCiero DP, Ito M, et al. Adrenomyeloneuropathy: a neuropathologic review featuring its noninflammatory myelopathy. J Neuropathol Exp Neurol. 2000;59:89–102.
- Hettema EH, van Roermund CW, Distel B, et al. The ABC transporter proteins Pat1 and Pat2 are required for import of long-chain fatty acids into peroxisomes of Saccharomyces cerevisiae. EMBO J. 1996;15:3813–3822.
- van Roermund CW, Visser WF, Ijlst L, et al. The human peroxisomal ABC half transporter ALDP functions as a homodimer and accepts acyl-CoA esters. FASEB J. 2008;22:4201–4208.
- Pujol A, Ferrer I, Camps C, et al. Functional overlap between ABCD1 (ALD) and ABCD2 (ALDR) transporters: a therapeutic target for X-adrenoleukodystrophy. Hum Mol Genet. 2004;13:2997–3006.
- Pujol A, Hindelang C, Callizot N, et al. Late onset neurological phenotype of the X-ALD gene inactivation in mice: a mouse model for adrenomyeloneuropathy. Hum Mol Genet. 2002;11:499–505.
- Gilg AG, Singh AK, Singh I. Inducible nitric oxide synthase in the central nervous system of patients with X-adrenoleukodystrophy. J Neuropathol Exp Neurol. 2000;59:1063–1069.
- Powers JM, Pei Z, Heinzer AK, et al. Adreno-leukodystrophy: oxidative stress of mice and men. J Neuropathol Exp Neurol. 2005;64:1067–1079.
- Fourcade S, Lopez-Erauskin J, Galino J, et al. Early oxidative damage underlying neurodegeneration in X-adrenoleukodystrophy. Hum Mol Genet. 2008;17:1762–1773.
- Fourcade S, Ruiz M, Guilera C, et al. Valproic acid induces antioxidant effects in X-linked adrenoleukodystrophy. Hum Mol Genet. 2010;19:2005–2014.
- Henderson JT, Javaheri M, Kopko S, Roder JC. Reduction of lower motor neuron degeneration in wobbler mice by N-acetyl-L-cysteine. J Neurosci. 1996;16:7574–7582.
- Karunakaran S, Diwakar L, Saeed U, et al. Activation of apoptosis signal regulating kinase 1 (ASK1) and translocation of death-associated protein, Daxx, in substantia nigra pars compacta in a mouse model of Parkinson's disease: protection by alpha-lipoic acid. FASEB J. 2007;21:2226–2236.
- Nakashima H, Ishihara T, Yokota O, et al. Effects of alpha-tocopherol on an animal model of tauopathies. Free Radic Biol Med. 2004;37:176–186.
- Lu JF, Lawler AM, Watkins PA, et al. A mouse model for X-linked adrenoleukodystrophy. Proc Natl Acad Sci U S A. 1997;94:9366–9371.
- Hagen TM, Liu J, Lykkesfeldt J, et al. Feeding acetyl-L-carnitine and lipoic acid to old rats significantly improves metabolic function while decreasing oxidative stress. Proc Natl Acad Sci U S A. 2002;99:1870–1875.
- De Rosa SC, Zaretsky MD, Dubs JG, et al. N-acetylcysteine replenishes glutathione in HIV infection. Eur J Clin Invest. 2000;30:915–929.
- Hurd RW, Wilder BJ, Helveston WR, Uthman BM. Treatment of four siblings with progressive myoclonus epilepsy of the Unverricht-Lundborg type with N-acetylcysteine. Neurology. 1996;47:1264–1268.
- Sano M, Ernesto C, Thomas RG, et al. A controlled trial of selegiline, alpha-tocopherol, or both as treatment for Alzheimer's disease. The Alzheimer's Disease Cooperative Study. N Engl J Med. 1997;336:1216–1222.
- Ziegler D, Ametov A, Barinov A, et al. Oral treatment with alpha-lipoic acid improves symptomatic diabetic polyneuropathy: the SYDNEY 2 trial. Diabetes Care. 2006;29:2365–2370.
- Davison GW, Hughes CM, Bell RA. Exercise and mononuclear cell DNA damage: the effects of antioxidant supplementation. Int J Sport Nutr Exerc Metab. 2005;15:480–492.
- Mantovani G, Madeddu C, Gramignano G, et al. Subcutaneous interleukin-2 in combination with medroxyprogesterone acetate and antioxidants in advanced cancer responders to previous chemotherapy: phase II study evaluating clinical, quality of life, and laboratory parameters. J Exp Ther Oncol. 2003;3:205–219.
- Gibson GE, Zhang H, Sheu KR, Park LC. Differential alterations in antioxidant capacity in cells from Alzheimer patients. Biochim Biophys Acta. 2000;1502:319–329.
- Briganti S, Wlaschek M, Hinrichs C, et al. Small molecular antioxidants effectively protect from PUVA-induced oxidative stress responses underlying fibroblast senescence and photoaging. Free Radic Biol Med. 2008;45:636–644.
- Moreira PI, Harris PL, Zhu X, et al. Lipoic acid and N-acetyl cysteine decrease mitochondrial-related oxidative stress in Alzheimer disease patient fibroblasts. J Alzheimers Dis. 2007;12:195–206.
- Voloboueva LA, Liu J, Suh JH, et al. (R)-alpha-lipoic acid protects retinal pigment epithelial cells from oxidative damage. Invest Ophthalmol Vis Sci. 2005;46:4302–4310.
- Robinson CE, Keshavarzian A, Pasco DS, et al. Determination of protein carbonyl groups by immunoblotting. Anal Biochem. 1999;266:48–57.
- Ferrer I, Kapfhammer JP, Hindelang C, et al. Inactivation of the peroxisomal ABCD2 transporter in the mouse leads to late-onset ataxia involving mitochondria, Golgi and endoplasmic reticulum damage. Hum Mol Genet. 2005;14:3565–3577.
- Martinez de Lagran M, Altafaj X, Gallego X, et al. Motor phenotypic alterations in TgDyrk1a transgenic mice implicate DYRK1A in Down syndrome motor dysfunction. Neurobiol Dis. 2004;15:132–142.
- Halliwell B, Gutteridge JMC. Halliwell B, Gutteridge JMC. Free radicals in biology and medicine. Oxford, UK: Clarendon Press; 1996. Lipid peroxidation: a radical chain reaction; pp. 188–266.
- Harvey BH, Joubert C, du Preez JL, Berk M. Effect of chronic N-acetyl cysteine administration on oxidative status in the presence and absence of induced oxidative stress in rat striatum. Neurochem Res. 2008;33:508–517.
- Arivazhagan P, Panneerselvam C. Effect of DL-alpha-lipoic acid on neural antioxidants in aged rats. Pharmacol Res. 2000;42:219–222.
- Lacraz G, Figeac F, Movassat J, et al. Diabetic beta-cells can achieve self-protection against oxidative stress through an adaptive up-regulation of their antioxidant defenses. PLoS One. 2009;4:e6500.
- Rodriguez MC, MacDonald JR, Mahoney DJ, et al. Beneficial effects of creatine, CoQ10, and lipoic acid in mitochondrial disorders. Muscle Nerve. 2007;35:235–242.
- Tan JS, Wang JJ, Flood V, et al. Dietary antioxidants and the long-term incidence of age-related macular degeneration: the Blue Mountains Eye Study. Ophthalmology. 2008;115:334–341.
- Tarnopolsky MA. The mitochondrial cocktail: rationale for combined nutraceutical therapy in mitochondrial cytopathies. Adv Drug Deliv Rev. 2008;60:1561–1567.
- Bohr VA, Ottersen OP, Tonjum T. Genome instability and DNA repair in brain, ageing and neurological disease. Neuroscience. 2007;145:1183–1186.
- Dizdaroglu M, Jaruga P, Birincioglu M, Rodriguez H. Free radical-induced damage to DNA: mechanisms and measurement. Free Radic Biol Med. 2002;32:1102–1115.
- Mastroeni R, Bensadoun JC, Charvin D, et al. Insulin-like growth factor-1 and neurotrophin-3 gene therapy prevents motor decline in an X-linked adrenoleukodystrophy mouse model. Ann Neurol. 2009;66:117–122.
- Fourcade S, Ruiz M, Camps C, et al. A key role for the peroxisomal ABCD2 transporter in fatty acid homeostasis. Am J Physiol Endocrinol Metab. 2009;296:E211–E221.
- Armstrong JS, Khdour O, Hecht SM. Does oxidative stress contribute to the pathology of Friedreich's ataxia? A radical question. FASEB J. 2010;24:2152–2163.
- Morral JA, Davis AN, Qian J, et al. Pathology and pathogenesis of sensory neuropathy in Friedreich's ataxia. Acta Neuropathol. 2010;120:97–108.
- Pandolfo M. Friedreich ataxia: the clinical picture. J Neurol. 2009;256(suppl 1):3–8.
- Meier T, Buyse G. Idebenone: an emerging therapy for Friedreich ataxia. J Neurol. 2009;256(suppl 1):25–30.
- Schulz JB, Di Prospero NA, Fischbeck K. Clinical experience with high-dose idebenone in Friedreich ataxia. J Neurol. 2009;256(suppl 1):42–45.
- Rinaldi C, Tucci T, et al. Low-dose idebenone treatment in Friedreich's ataxia with and without cardiac hypertrophy. J Neurol. 2009;256:1434–1437.
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