The non-NMDA glutamate receptor antagonists 6-cyano-7-nitroquinoxaline-2,3-dione and 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(f)quinoxaline, but not NMDA antagonists, block the intrastriatal neurotoxic effect of MPP+.
Altered glutamatergic neurotransmission appears to be central to the pathophysiology of Parkinson's disease; consequently, considerable effort has been made to elucidate neuroprotective mechanisms against such toxicity. In the present study, the possible neuroprotective effect of glutamate receptor antagonists against MPP+ neurotoxicity on dopaminergic terminals of rat striatum was investigated. Different doses of glutamate receptor antagonists were coinfused with 1.5 microg of MPP+ into the striatum; kynurenic acid, a nonselective antagonist of glutamate receptors (30 and 60 nmol), partially protected dopaminergic terminal degeneration in terms of rescue of dopamine levels and tyrosine hydroxylase immunohistochemistry. Dizocilpine, a channel blocker of the NMDA receptor (1, 4, and 8 nmol), and 7-chlorokynurenic acid, a selective antagonist at the glycine site of the NMDA receptor (1 and 10 nmol), failed to protect dopaminergic terminals from MPP+ toxicity. However, 6-cyano-7-nitroquinoxaline-2,3-dione (0.5 and 1 nmol) and 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(f)quinoxaline (1 nmol), two AMPA-kainate receptor antagonists, protected against MPP toxicity. Our findings suggest that the toxic effects of MPP+ on dopaminergic terminals are not mediated through a direct interaction with the NMDA subtype of glutamate receptor, but with the AMPA-kainate subtype.
Merino
M
M
Departamento de Bioquímica, Bromatología y Toxicología, Facultad de Farmacia, Sevilla, Spain.
Vizuete
M L
ML
Cano
J
J
Machado
A
A
D015655:1-Methyl-4-phenylpyridinium / Q000633:toxicity*; D015102:3,4-Dihydroxyphenylacetic Acid / Q000032:analysis; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology*; D000818:Animals; D003342:Corpus Striatum / Q000737:chemistry / Q000187:drug effects* / Q000201:enzymology; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004298:Dopamine / Q000031:analogs & derivatives / Q000032:analysis / Q000378:metabolism; D015259:Dopamine Agents / Q000633:toxicity*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005260:Female; D006719:Homovanillic Acid / Q000032:analysis; D007736:Kynurenic Acid / Q000494:pharmacology; D008845:Microinjections; D018696:Neuroprotective Agents / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors; D018092:Kainic Acid Receptors / Q000037:antagonists & inhibitors; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D014446:Tyrosine 3-Monooxygenase / Q000032:analysis
D015655:1-Methyl-4-phenylpyridinium; D015102:3,4-Dihydroxyphenylacetic Acid; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D016291:Dizocilpine Maleate; D004298:Dopamine; D015259:Dopamine Agents; D018691:Excitatory Amino Acid Antagonists; D006719:Homovanillic Acid; D007736:Kynurenic Acid; D018696:Neuroprotective Agents; D011810:Quinoxalines; D018091:Receptors, AMPA; D018092:Kainic Acid Receptors; D016194:Receptors, N-Methyl-D-Aspartate; D014446:Tyrosine 3-Monooxygenase; C062865:2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline; C001746:3-methoxytyramine