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+ |
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Authors: | M Merino M L Vizuete J Cano & A Machado |
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Institution: | Departamento de Bioquímica, Bromatología y Toxicología, Facultad de Farmacia, Sevilla, Spain. |
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Abstract: | 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. |
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Keywords: | MPP+ Rat striatum Dopaminergic neuroprotection Kynurenic acid Dizocilpine 6-Cyano-7-nitroquinoxaline-2 3-dione 2 3-Dihydroxy-6-nitro-7-sulfamoylbenzo (f)quinoxaline |
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