Relative vulnerability of dopamine and GABA neurons in mesencephalic culture to inhibition of succinate dehydrogenase by malonate and 3-nitropropionic acid and protection by NMDA receptor blockade.
The effects of different severities of metabolic stress on dopamine (DA) and gamma-aminobutyric acid (GABA) cell loss were examined in rat mesencephalic culture. Partial metabolic inhibition was induced in 12-day-old cultures by a 24-hr treatment with various concentrations of 3-nitropropionic acid(3-NPA, 0.1-0.5 mM) or malonate (10-50 mM), irreversible and reversible inhibitors of the Krebs cycle enzyme, succinate dehydrogenase. Cell damage to the DA and GABA populations was assessed after a 48-hr recovery period by simultaneous measurement of high affinity uptake for 3H-DA and 14C-GABA. 3-NPA or malonate caused a dose-dependent loss of DA uptake (EC50 0.21 or 42 mM, respectively). 3-NPA treatment was equally detrimental to the GABA population, whereas malonate exposure did not cause any significant loss of GABA uptake. The presence of the NMDA antagonist, MK-801 (1 microM), during 24 hr of 3-NPA or malonate treatment fully protected against DA and GABA loss with 50 mM malonate or 0.25 mM 3-NPA and partially protected versus 0.5 mM 3-NPA. To determine the degree of metabolic stress imposed by 3-NPA and malonate, 12-day-old cultures were treated with 0.5 mM 3-NPA or 50 mM malonate for 3 hr and the rate of lactate formation was measured. lactate was increased nearly 2-fold at 3 hr of treatment with 3-NPA, but was not significantly elevated above basal with malonate treatment. SDH activity was decreased by 48 or 58% after 3 hr of treatment with 0.25 and 0.5 mM 3-NPA, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
Department of Neurology, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Piscataway, USA.
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D000818:Animals; D002478:Cells, Cultured; D004298:Dopamine / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018698:Glutamic Acid / Q000378:metabolism; D008314:Malonates / Q000494:pharmacology*; D008636:Mesencephalon / Q000166:cytology / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D009574:Nitro Compounds; D011422:Propionates / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D013385:Succinate Dehydrogenase / Q000037:antagonists & inhibitors*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D004791:Enzyme Inhibitors; D008314:Malonates; D009574:Nitro Compounds; D011422:Propionates; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; C030290:malonic acid; D013385:Succinate Dehydrogenase; C015392:3-nitropropionic acid; D004298:Dopamine