Role for dopamine in malonate-induced damage in vivo in striatum and in vitro in mesencephalic cultures.
Defects in mitochondrial energy metabolism have been implicated in the pathology of several neurodegenerative disorders. In addition, the reactive metabolites generated from the metabolism and oxidation of the neurotransmitter dopamine (DA) are thought to contribute to the damage to neurons of the basal ganglia. We have previously demonstrated that infusions of the metabolic inhibitor malonate into the striata of mice or rats produce degeneration of DA nerve terminals. In the present studies, we demonstrate that an intrastriatal infusion of malonate induces a substantial increase in DA efflux in awake, behaving mice as measured by in vivo microdialysis. Furthermore, pretreatment of mice with tetrabenazine (TBZ) or the TBZ analogue Ro 4-1284 (Ro-4), compounds that reversibly inhibit the vesicular storage of DA, attenuates the malonate-induced DA efflux as well as the damage to DA nerve terminals. Consistent with these findings, the damage to both DA and GABA neurons in mesencephalic cultures by malonate exposure was attenuated by pretreatment with TBZ or Ro-4. Treatment with these compounds did not affect the formation of free radicals or the inhibition of oxidative phosphorylation resulting from malonate exposure alone. Our data suggest that DA plays an important role in the neurotoxicity produced by malonate. These findings provide direct evidence that inhibition of succinate dehydrogenase causes an increase in extracellular DA levels and indicate that bioenergetic defects may contribute to the pathogenesis of chronic neurodegenerative diseases through a mechanism involving DA.
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Department of Neurology, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Piscataway, USA.
Zeevalk
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Sonsalla
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D012369:2H-Benzo(a)quinolizin-2-ol, 2-Ethyl-1,3,4,6,7,11b-hexahydro-3-isobutyl-9,10-dimethoxy- / Q000494:pharmacology; D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology; D000818:Animals; D001692:Biological Transport / Q000187:drug effects / Q000502:physiology; D002250:Carbon Radioisotopes; D002478:Cells, Cultured; D003342:Corpus Striatum / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000493:pharmacokinetics / Q000502:physiology*; D004734:Energy Metabolism / Q000187:drug effects / Q000502:physiology; D005609:Free Radicals / Q000378:metabolism; D019344:Lactic Acid / Q000378:metabolism; D008297:Male; D008314:Malonates / Q000494:pharmacology*; D008562:Membrane Glycoproteins / Q000378:metabolism; D026901:Membrane Transport Proteins; D051379:Mice; D017551:Microdialysis; D009410:Nerve Degeneration / Q000139:chemically induced / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009479:Neuropeptides; D010300:Parkinson Disease / Q000378:metabolism; D017729:Presynaptic Terminals / Q000187:drug effects; D013572:Synaptic Vesicles / Q000378:metabolism; D013747:Tetrabenazine / Q000494:pharmacology; D014316:Tritium; D050492:Vesicular Biogenic Amine Transport Proteins; D005680:gamma-Aminobutyric Acid / Q000378:metabolism / Q000493:pharmacokinetics
D018759:Adrenergic Uptake Inhibitors; D002250:Carbon Radioisotopes; D005609:Free Radicals; D008314:Malonates; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009479:Neuropeptides; D050492:Vesicular Biogenic Amine Transport Proteins; D014316:Tritium; D015102:3,4-Dihydroxyphenylacetic Acid; D012369:2H-Benzo(a)quinolizin-2-ol, 2-Ethyl-1,3,4,6,7,11b-hexahydro-3-isobutyl-9,10-dimethoxy-; D019344:Lactic Acid; D005680:gamma-Aminobutyric Acid; C030290:malonic acid; D004298:Dopamine; D013747:Tetrabenazine