Nature Medicine
2, 1017 - 1021 (1996)
doi:10.1038/nm0996-1017
Inhibition of neuronal nitric oxide synthase prevents MPTP−induced parkinsonism in baboonsPhilippe Hantraye1, Emmanuel Brouillet1, Robert Ferrante2, Stéphane Palfi1, Robert Dolan1, Russell T. Matthews3
& M. Flint Beal3, 4
1Unité de Recherché Associe Commissariat á l'Energie Atomique, Centre National de la Recherche Scientiflque 2210, Service Hospitalier Frederic Joliot, Orsay, France
2Geriatric Research Education Clinical Center, Veterans Affairs Medical Center, Bedford, Massachusetts, USA, and Department of Neurology, Boston University School of Medicine, Boston, Massachusetts 02118, USA
3Neurochemistry Laboratory, Neurology Service, WRN 408, Massachusetts General Hospital, 32 Fruit Street, and Harvard Medical School, Boston, Massachusetts 02114, USA
4Correspondence should be addressed to M.F.B. 1−Methyl−4−phenyl−1,2/3,6−tetrahydropyridine (MPTP) produces clinical, biochemical and neuropathologic changes reminiscent of those which occur in idiopathic Parkinson's disease. 7−Nitroindazole (7−NI) is a relatively selective inhibitor of the neuronal isoform of nitric oxide synthase (NOS) that blocks MPTP neurotoxicity in mice. We now show that 7−NI protects against profound striatal dopamine depletions and loss of tyrosine hydroxylase−positive neurons in the substantia nigra in MPTP−treated baboons. Furthermore, 7−NI protected against MPTP−induced motor and frontal−type cognitive deficits. These results strongly implicate a role of nitric oxide in MPTP neurotoxicity and suggest that inhibitors of neuronal NOS might be useful in treating Parkinson's disease.
REFERENCES
- Burns, R.S. et al. A primate model of parkinsonism: Selective destruction of dopaminergic neurons in the pars compacta of the substantia nigra by N-methyl-4-phenyl-l,2,3,6-tetrahydropyridine. Proc. Nath Acad. Sci. USA 80, 4546−4550 (1983). | ChemPort |
- Bloem, B.R. et al. The MPTP model: Versatile contributions to the treatment of idiopathic Parkinson's disease. J. Neuroh Sci. 97, 273−293 (1990). | Article | ChemPort |
- Langston, J.W., Ballard, P., Tetrud, J.W. & Irwin, I. Chronic parkinsonism in humans due to a product of meperidine-analog synthesis. Science 219, 979−980 (1983). | PubMed | ISI | ChemPort |
- Hantraye, P. et al. Stable parkinsonian syndrome and uneven loss of striatal dopamine fibers following chronic MPTP administration in baboons. Neuroscience 53, 169−178 (1993). | Article | PubMed | ISI | ChemPort |
- Varastet, M., Riche, D., Maziere, M. & Hantraye, P. Chronic MPTP treatment reproduces in baboons the differential vulnerability of mesencephalic dopaminergic neurons observed in Parkinson's disease. Neuroscience 63, 47−56 (1994). | Article | PubMed | ISI | ChemPort |
- Forno, L.S., Langston, J.W., DeLanney, L.E., Irwin, I. & Ricaurte, G.A. Locus ceruleus lesions and eosinophilic inclusions in MPTP-treated monkeys. Ann. Neuroh 20, 449−455 (1986). | ChemPort |
- Tipton, K.F. & Singer, T.P. Advances in our understanding of the mechanisms of the neurotoxicity of MPTP and related compounds. J. Neurochem. 61, 1191−1206 (1993). | PubMed | ISI | ChemPort |
- Beal, M.F., Aging, energy and oxidative stress in neurodegenerative diseases. Ann. Neuroh 38, 357−366 (1995). | ChemPort |
- Dawson, V.L. et al. Nitric oxide mediates glutamate neurotoxicity in primary cortical cultures. Proc. Nath Acad. Sci. USA 88, 6368−6371 (1991). | ChemPort |
- Dawson, V.L. et al. Mechanisms of nitric oxide mediated neurotoxicity in primary brain cultures. J. Neurosci. 13, 2651−2661 (1993). | PubMed | ISI | ChemPort |
- Schulz, J.B., Matthews, R.T., Muqit, M.M.K., Browne, S.E. & Beal, M.F. Inhibition of neuronal nitric oxide synthase by 7-nitroindazole protects against MFTP-induced neurotoxicity in mice. J. Neurochem. 64, 936−939 (1995a) | PubMed | ISI | ChemPort |
- Przedborski, S. et al Role of nitric oxide in MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-induced dopaminergic neurotoxicity. Proc. Nath Acad. Sci. USA 93, 4565−4571 (1996). | Article | ChemPort |
- German, D.C., Dubach, M., Askari, S., Speciale, S.G. & Bowden, D.M. 1-Methyl-4-phenyl-1,2,3,6-tetra-hydropyridine-induced parkinsonian syndrome in Macaca fascicularis: Which midbrain dopaminergic neurons are lost? Neuroscience 24, 161−174 (1988). | Article | PubMed | ISI | ChemPort |
- Schneider, J.S. Behavioral and neuropathological consequences of chronic exposure to low doses of the dopaminergic neurotoxin MPTP. in The Vulnerable Brain and Environmental Risks (eds. Isaacson, R.L. & Jensen, K.F.) 293−308 (Plenum, New York, 1992). | ChemPort |
- Lipton, S.A. et al. A redox-based mechanism for the neuroprotective and neu-rodestructive effects of nitric oxide and related nitroso-compounds. Nature 364, 626−632 (1993). | Article | PubMed | ISI | ChemPort |
- Schulz, J.B. et al. Blockade of neuronal nitric oxide synthase protects against excitotoxicity in vivo. J. Neurosci. 15, 8419−8429 (1995b). | ISI | ChemPort |
- Beckman, J.S. et al. Kinetics of superoxide dismutase- and iron-catalyzed nitration of phenolics by peroxynitrite. Arch. Biochem. Biophys. 298, 438−445 (1992). | PubMed | ISI | ChemPort |
- Ischiropoulos, H. et al. Peroxynitrite-mediated tyrosine nitration catalyzed by superoxide dismutase. Arch. Biochem. Biophys. 298, 431−437 (1992). | PubMed | ISI | ChemPort |
- Wolff, D.J. & BJThe inhibition of the constitutive and inducible nitric oxide synthase isoforms by indazole agents. Arch. Biochem. Biophys. 311, 300−306 (1994). | Article | PubMed | ISI | ChemPort |
- Babbedge, R.C. et al. Inhibition of rat cerebellar nitric oxide synthase by 7-nitroindazole and related substituted indazoles. Br. J. Pharmacol. 110, 225−228 (1993). | PubMed | ISI | ChemPort |
- Przedborski, S. et al. Transgenic mice with increased Cu/Zn-superoxide dismutase activity are resistant to N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neurotoxicity. J. Neurosci. 12, 1658−1667 (1992). | PubMed | ISI | ChemPort |
- Diamond, A. Developmental time course in human infants and infant monkeys, and the neural bases of inhibitory control in reaching. Ann. N.Y. Acad. Sci. 608, 637−669 (1990). | PubMed | ChemPort |
- Palfi, S. et al Chronic 3-nitropropionic acid treatment in baboons replicates the cognitive and motor deficits of Huntington disease. J. Neurosci. (in the press).
- Lin, A.M.-Y., Kao, L.-S. & Chai, C.Y. Involvement of nitric oxide in dopaminergic transmission in rat striatum: An in vivo electrochemical study. J. Neurochem . 65, 2043−2049 (1995). | PubMed | ISI |
- Lonart, G. & Johnson, K.M. Inhibitory effects of nitric oxide on the uptake of [3H]dopamine and [3H]glutamate by striatal synaptosomes. J. Neurochem. 63, 2108−2117 (1994). | PubMed | ISI | ChemPort |
- Silva, M.T. et al. Increased striatal dopamine efflux in vivo following inhibition of cerebral nitric oxide synthase by the novel monosodium salt of 7-nitro indazole. Br. J. Pharmacol. 114, 257−258 (1995). | PubMed | ISI | ChemPort |
- Brouillet, E. et al. Chronic mitochondrial energy impairment produces selective striatal degeneration and abnormal choreiform movements in primates. Proc. Nath Acad. Sci. USA 92, 7105−7109 (1995). | ChemPort |
- Beal, M.F., Kowall, N.W., Swartz, K.J. & Ferrante, R. Homocysteic acid striatal lesions in rats spare somatostatin-neuropeptide Y neurons. Neurosci. Lett. 108, 36−42 (1990). | Article | PubMed | ISI | ChemPort |
- Ferrante, R.J., Kowall, N.W., Cipolloni, P.B., Storey, E. & Beal, M.F. Excitotoxin lesions in primates as a model of Huntington's disease: Histopathologic and neurochemical characterization. Exp. Neuroh 119, 46−71 (1993). | Article | ChemPort |
|
