The neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine induces apoptosis in mouse nigrostriatal glia. Relevance to nigral neuronal death and striatal neurochemical changes.
Swiss mice were given 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), 25 mg/kg/day, for 5 consecutive days and killed at different days after MPTP discontinuance. Decreases in striatal tyrosine hydroxylase activity and levels of dopamine and its metabolites were observed 1 day after MPTP discontinuance. Ascorbic acid and glutamate levels had increased, dehydroascorbic acid and GSH decreased, whereas catabolites of high-energy phosphates (inosine, hypoxanthine, xanthine, and uric acid) were unchanged. In addition, gliosis was observed in both striatum and substantia nigra compacta (SNc). Sections of SNc showed some terminal deoxynucleotidyl transferase-mediated 2'-deoxyuridine 5'-triphosphate nick end labeling (TUNEL)-positive cells. Neurochemical parameters of dopaminergic activity showed a trend toward recovery 3 days after MPTP discontinuance. At this time point, TUNEL-positive cells were detected in SNc; some of them showed nuclei with neuronal morphology. A late (days 6-11) increase in striatal dopamine oxidative metabolism, ascorbic acid oxidative status, and catabolites of high-energy phosphates were observed concomitant with nigral neuron and nigrostriatal glial cell apoptotic death, as revealed by TUNEL, acridine orange, and Hoechst staining, and transmission electron microscopy. These data suggest that MPTP-induced activation/apoptotic death of glial cells plays a key role in the sequential linkage of neurochemical and cellular events leading to dopaminergic nigral neuron apoptotic death.
Serra
Pier Andrea
PA
Department of Pharmacology, University of Sassari, Viale San Pietro 43B, 07100 Sassari, Italy. Pharmaco@ssmain.uniss.it
Sciola
Luigi
L
Delogu
Maria Rosaria
MR
Spano
Alessandra
A
Monaco
Gianni
G
Miele
Egidio
E
Rocchitta
Gaia
G
Miele
Maddalena
M
Migheli
Rossana
R
Desole
Maria Speranza
MS
D015102:3,4-Dihydroxyphenylacetic Acid / Q000032:analysis; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D003342:Corpus Striatum / Q000737:chemistry / Q000187:drug effects* / Q000473:pathology; D004298:Dopamine / Q000032:analysis; D005978:Glutathione / Q000032:analysis; D006719:Homovanillic Acid / Q000032:analysis; D020287:In Situ Nick-End Labeling; D020267:MPTP Poisoning / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D009457:Neuroglia / Q000187:drug effects* / Q000473:pathology; D013378:Substantia Nigra / Q000737:chemistry / Q000187:drug effects* / Q000473:pathology; D013997:Time Factors
D015102:3,4-Dihydroxyphenylacetic Acid; D005978:Glutathione; D004298:Dopamine; D006719:Homovanillic Acid