1‐Methyl‐4‐Phenylpyridinium Produces Excitotoxic Lesions in Rat Striatum as a Result of Impairment of Oxidative Metabolism

Abstract: The effects of 1‐methyl‐4‐phenylpyridinium (MPP+) were studied in rat striatum. Using freeze‐clamp, microwave, and water‐suppressed proton chemical shift magnetic resonance imaging techniques, MPP+ resulted in marked increases in lactate and a depletion of ATP for up to 48 h after the injections. MPP+ produced dose‐dependent depletions of dopamine, serotonin, γ‐aminobutyric acid, and substance P that were partially blocked at 1 week by prior decortication or completely blocked by MK‐801 at 24 h. The lesions showed relative sparing of somatostatin‐neuropeptide Y neurons, consistent with N‐methyl‐D‐aspartate (NMDA) excitotoxicity. MPP+ produces impairment of oxidative phosphorylation in vivo, which may result in membrane depolarization with persistent activation of NMDA receptors and excitotoxic neuronal degeneration. An impairment of energy metabolism may therefore underlie slow excitotoxic neuronal death in neurodegenerative diseases.

[1]  B. Hyman,et al.  Aminooxyacetic Acid Results in Excitotoxin Lesions by a Novel Indirect Mechanism , 1991, Journal of neurochemistry.

[2]  J. Langston,et al.  Rapid ATP Loss Caused by 1‐Methyl‐4‐Phenyl‐1,2,3,6‐Tetrahydropyridine in Mouse Brain , 1991, Journal of neurochemistry.

[3]  M. Beal,et al.  Chronic quinolinic acid lesions in rats closely resemble Huntington's disease , 1991, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[4]  G. Zeevalk,et al.  Mechanisms underlying initiation of excitotoxicity associated with metabolic inhibition. , 1991, The Journal of pharmacology and experimental therapeutics.

[5]  J. Casida,et al.  Interaction of 1‐Methyl‐4‐Phenylpyridinium Ion (MPP+) and Its Analogs with the Rotenone/Piericidin Binding Site of NADH Dehydrogenase , 1991, Journal of neurochemistry.

[6]  P. Löschmann,et al.  Protection of substantia nigra from MPP+ neurotoxicity by N-methyl-D-aspartate antagonists , 1991, Nature.

[7]  M. Beal,et al.  Kynurenine Pathway Measurements in Huntington's Disease Striatum: Evidence for Reduced Formation of Kynurenic Acid , 1990, Journal of neurochemistry.

[8]  Richard J. Miller,et al.  Potassium channel activators abolish excitotoxicity in cultured hippocampal pyramidal neurons , 1990, Neuroscience Letters.

[9]  B. R. Bloem,et al.  The MPTP model: versatile contributions to the treatment of idiopathic Parkinson's disease , 1990, Journal of the Neurological Sciences.

[10]  G. Zeevalk,et al.  Chemically induced hypoglycemia and anoxia: relationship to glutamate receptor-mediated toxicity in retina. , 1990, The Journal of pharmacology and experimental therapeutics.

[11]  W. Whetsell,et al.  Ultrastructural alterations induced by 1-methyl-4-phenylpyridinium (MPP+) in canine substantia nigra and rat mesencephalon in vitro , 1989, Experimental Neurology.

[12]  Edward Byrne,et al.  DECLINE IN SKELETAL MUSCLE MITOCHONDRIAL RESPIRATORY CHAIN FUNCTION: POSSIBLE FACTOR IN AGEING , 1989, The Lancet.

[13]  Joseph B. Martin,et al.  Differential sparing of somatostatin‐neuropeptide y and cholinergic neurons following striatal excitotoxin lesions , 1989, Synapse.

[14]  A. Novelli,et al.  Glutamate becomes neurotoxic via the N-methyl-d-aspartate receptor when intracellular energy levels are reduced , 1988, Brain Research.

[15]  J. Olney,et al.  The role of specific ions in glutamate neurotoxicity , 1986, Neuroscience Letters.

[16]  R. Duvoisin,et al.  Dopaminergic toxicity after the stereotaxic administration of the 1-methyl-4-phenylpyridinium ion (MPP+) to rats , 1985, Neuroscience Letters.

[17]  W. Nicklas,et al.  Inhibition of NADH-linked oxidation in brain mitochondria by 1-methyl-4-phenyl-pyridine, a metabolite of the neurotoxin, 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine. , 1985, Life sciences.

[18]  J. Passonneau,et al.  The enzymatic measurement of adenine nucleotides and P-creatine in picomole amounts. , 1981, Analytical biochemistry.

[19]  R. Schön.  A simple and sensitive enzymic method for determination of L(+)-lactic acid. , 1965, Analytical Biochemistry.