6-cyano-7-nitroquinoxaline-2-3-dione and 3-nitropropionic-acid

Glutamate antagonists mitigate hypoxic damage upon acute inhibition of energy metabolism. The goal of this study was to investigate their effect on increased hypoxic tolerance induced by preceding chemical inhibition of energy metabolism. While recovery of population spike amplitude (psap) is 30% of onset in slices prepared from control animals (15 min hypoxia, 45 min recovery), recovery exceeds 90% in slices prepared from animals that underwent mild chemical hypoxia in vivo by treatment with 20 mg/kg 3-nitropropionic acid 1 h prior to slice preparation (p-slices). In p-slices perfused for 5 min with D(-)-2-amino-5-phosphonopentanoic acid (APV) (100 microM) 45 min prior to hypoxia, recovery declines to 42 +/- 13% (mean +/- SEM). In contrast, posthypoxic recovery after similar perfusion with 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) (10 microM) is 72 +/- 15% (P < 0.05). We conclude that increased hypoxic tolerance is abolished by N-methyl-D-aspartate (NMDA)-antagonists but not non-NMDA-antagonists.

Topics: 2-Amino-5-phosphonovalerate; 6-Cyano-7-nitroquinoxaline-2,3-dione; Animals; Antihypertensive Agents; Brain Ischemia; Energy Metabolism; Excitatory Amino Acid Antagonists; Hypoxia, Brain; In Vitro Techniques; Male; Nitro Compounds; Oxygen Consumption; Propionates; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate

Exposure of mesencephalic dopamine neurons to an irreversible inhibitor of succinate dehydrogenase (SDH), 3-nitropropionic acid (3-NPA), for 24 h on day 12 in vitro, produced a dose-dependent loss of high-affinity dopamine uptake when measured 48 h following 3-NPA removal. ATP concentrations in the cultures were reduced by 57% after 3 h of treatment with the highest concentration of 3-NPA tested (500 microM). To determine whether glutamate receptors mediated the dopamine toxicity by 3-NPA, cultures were examined for their sensitivity to excitatory amino acid-induced toxicity. Mesencephalic cultures exposed to either 100 microM NMDA or kainate, on day 12 for 24 h, showed complete loss of dopamine uptake following 48 h of recovery. The NMDA and non-NMDA antagonists, MK-801 (1 microM) or 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX; 15 microM), completely prevented the effects of NMDA or kainate, respectively, when present at the time of toxin exposure. In cultures treated with 3-NPA, MK-801, but not CNQX, significantly attenuated the loss of dopamine uptake. Direct measurement of the effect of 3-NPA on SDH activity showed that 3-NPA dose-dependently inhibited SDH in vitro in a manner commensurate with the loss of dopamine uptake by 3-NPA. MK-801 had no effect on basal SDH activity or on 3-NPA inhibition of SDH. These data are consistent with the interpretation that metabolic inhibition in dopamine neurons can trigger a secondary excitotoxicity that is mediated by NMDA receptors.

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Adenosine Triphosphate; Animals; Antihypertensive Agents; Cells, Cultured; Dizocilpine Maleate; Dopamine; Mesencephalon; N-Methylaspartate; Neurons; Nitro Compounds; Propionates; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Succinate Dehydrogenase

Succinic dehydrogenase in mouse cortical explant cultures was inhibited by 3-nitropropionic acid (3-NPA). ATP concentrations declined upon application of 3-NPA. At 4 h, ATP levels of cultures treated with 3-NPA alone were no different from those in cultures treated additionally with MK-801 (20 microM), 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX; 10 microM) or a combination thereof. However, MK-801 and MK-801 plus CNQX mitigated morphological lesions caused by 3-NPA. CNQX alone did not influence the extent of morphological damage. In conclusion, MK-801, at concentrations which were neuroprotective against 3-NPA lesions in cortical explant cultures, did not modify 3-NPA dependent decreases in cellular ATP levels. These data indicate that the neuroprotective effects of glutamate receptor antagonists in this model are probably receptor mediated and do not involve effects on cellular metabolism.

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Adenosine Triphosphate; Animals; Culture Techniques; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Mice; Nerve Degeneration; Neurotoxins; Nitro Compounds; Oxidative Phosphorylation; Plant Extracts; Propionates