In vivo protection of striatum from MPP+ neurotoxicity by N-methyl-D-aspartate antagonists.
The present study was designed to assess by microdialysis whether N-methyl-D-aspartate (NMDA) non-competitive receptor antagonist, MK-801, is able to protect dopaminergic neurons against 1-methyl-4-phenylpyridinium ion (MPP+) neurotoxicity. An intraperitoneal injection of MK-801, 10 mumol/kg, half an hour before striatal MPP+, 10 mM, perfusion did not protect against its neurotoxicity. Afterwards, rats received an intraperitoneal injection of MK-801 every 4 h, during 24 h. Under these conditions, one day after MPP+ perfusion, DA basal extracellular levels were close to the detection limit of our HPLC equipment in both control and MK-801 treated rats. 3,4-Dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) basal output were lower in the former than in the latter rats. A second MPP+ perfusion statistically increased extracellular levels of DA and decreased DOPAC and HVA output in both groups of rats. However, the increase in extracellular DA overflow was higher in MK-801 treated rats than in the control group, indicating a higher number of surviving dopaminergic terminals. These results suggest that MK-801 is not able to protect against the primary direct neurotoxic action of MPP+, but a second MPP+ neurotoxic action mediated by excitatory amino acids could be partially prevented by MK-801.
Santiago
M
M
Departamento de Bioquímica, Bromatología y Toxicología, Facultad de Farmacia, Universidad de Sevilla, Spain.
Venero
J L
JL
Machado
A
A
Cano
J
J
D015655:1-Methyl-4-phenylpyridinium / Q000633:toxicity*; D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D016291:Dizocilpine Maleate / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism*; D006719:Homovanillic Acid / Q000378:metabolism; D007700:Kinetics; D008297:Male; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors*; D009498:Neurotoxins / Q000633:toxicity*; D051381:Rats; D011919:Rats, Inbred Strains; D013997:Time Factors
D009498:Neurotoxins; D015102:3,4-Dihydroxyphenylacetic Acid; D016202:N-Methylaspartate; D016291:Dizocilpine Maleate; D015655:1-Methyl-4-phenylpyridinium; D004298:Dopamine; D006719:Homovanillic Acid