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Titolo:
THE ROLE OF MITOCHONDRIAL DYSFUNCTION AND NEURONAL NITRIC-OXIDE IN ANIMAL-MODELS OF NEURODEGENERATIVE DISEASES
Autore:
SCHULZ JB; MATTHEWS RT; KLOCKGETHER T; DICHGANS J; BEAL MF;
Indirizzi:
UNIV TUBINGEN,DEPT NEUROL,SCH MED,HOPPE SEYLER STR 3 D-72076 TUBINGENGERMANY MASSACHUSETTS GEN HOSP,NEUROL SERV,NEUROCHEM LAB BOSTON MA 02114 HARVARD UNIV,SCH MED BOSTON MA 02114
Titolo Testata:
Molecular and cellular biochemistry
fascicolo: 1-2, volume: 174, anno: 1997,
pagine: 193 - 197
SICI:
0300-8177(1997)174:1-2<193:TROMDA>2.0.ZU;2-C
Fonte:
ISI
Lingua:
ENG
Soggetto:
MPTP-INDUCED NEUROTOXICITY; EXCITOTOXICITY IN-VIVO; SUPEROXIDE-DISMUTASE; RESPIRATORY-CHAIN; RADICAL FORMATION; 7-NITRO INDAZOLE; SYNTHASE; PEROXYNITRITE; INHIBITION; PROTECTS;
Keywords:
NITRIC OXIDE; MPTP; 3-NITROPROPIONIC ACID; MALONATE; 3-NITROTYROSINE; FREE RADICALS;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Science Citation Index Expanded
Citazioni:
31
Recensione:
Indirizzi per estratti:
Citazione:
J.B. Schulz et al., "THE ROLE OF MITOCHONDRIAL DYSFUNCTION AND NEURONAL NITRIC-OXIDE IN ANIMAL-MODELS OF NEURODEGENERATIVE DISEASES", Molecular and cellular biochemistry, 174(1-2), 1997, pp. 193-197

Abstract

Excitotoxicity, mitochondrial dysfunction and free radical induced oxidative damage have been implicated in the pathogenesis of several different neurodegenerative diseases, such as amyotrophic lateral sclerosis, Parkinson's disease (PD), Alzheimer's disease (AD), and Huntington's disease. Much of the interest in the association of neurodegeneration with mitochondrial dysfunction and oxidative damage emerged from animal studies using mitochondrial toxins. Within mitochondria 1-methyl-4-phenylpyridinium (MPP+), the active metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), acts to inhibit NADH-coenzyme Q reductase (complex I) of the electron transport chain. MPTP produces Parkinsonism in humans, primates, and mice. Similarly, lesions produced bythe reversible inhibitor of succinate dehydrogenase (complex II), malonate, and the irreversible inhibitor, 3-nitropropionic acid (3-NP), closely resemble the histologic, neurochemical and clinical features ofHD in both rats and non-human primates. The interruption of oxidativephosphorylation results in decreased levels of ATP. A consequence is partial neuronal depolarization and secondary activation of voltage-dependent NMDA receptors, which may result in excitotoxic neuronal cell death (secondary excitotoxicity). The increase in intracellular Ca2+ concentration leads to an actiation of Ca2+ dependent enzymes, including the constitutive neuronal nitric oxide synthase (cnNOS) which produces NO .. NO . may react with the superoxide anion to form peroxynitrite. We show that systemic administration of 7-nitroindazole (7-NI), a relatively specific inhibitor of cnNOS in vivo. attenuates lesions produced by striatal malonate injections or systemic treatment with 3-NP or MPTP. Furthermore 7-NI attenuated increases in lactate production and hydroxyl radical and 3-nitrotyrosine generation in vivo, which may be a consequence of peroxynitrite formation. Our results suggest that neuronal nitric oxide synthase inhibitors may be useful in the treatment of neurologic diseases in which excitotoxic mechanisms play a role.

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Documento generato il 03/07/20 alle ore 22:03:48