Endogenously released DOPA is a causal factor for glutamate release and resultant delayed neuronal cell death by transient ischemia in rat striata.
Glutamate is implicated in neuronal cell death. Exogenously applied DOPA by itself releases neuronal glutamate and causes neuronal cell death in in vitro striatal systems. Herein, we attempt to clarify whether endogenous DOPA is released by 10 min transient ischemia due to four-vessel occlusion during rat striatal microdialysis and, further, whether DOPA, when released, functions to cause glutamate release and resultant delayed neuronal cell death. Ischemia increased extracellular DOPA, dopamine, and glutamate, and elicited neuronal cell death 96 h after ischemic insult. Inhibition of striatal L-aromatic amino acid decarboxylase 10 min before ischemia increased markedly basal DOPA, tripled glutamate release with a tendency of decrease in dopamine release by ischemia, and exaggerated neuronal cell death. Intrastriatal perfusion of 10-30 nM DOPA cyclohexyl ester, a competitive DOPA antagonist, 10 min before ischemia, concentration-dependently decreased glutamate release without modification of dopamine release by ischemia. At 100 nM, the antagonist elicited a slight ceiling effect on decreases in glutamate release by ischemia and protected neurons from cell death. Glutamate was released concentration-dependently by intrastriatal perfusion of 0.3-1 mM DOPA and stereoselectively by 0.6 mM DOPA. The antagonist elicited no hypothermia during and after ischemia. Endogenously released DOPA is an upstream causal factor for glutamate release and resultant delayed neuronal cell death by brain ischemia in rat striata. DOPA antagonist has a neuroprotective action.
Furukawa
N
N
Department of Pharmacology, Yokohama City University School of Medicine, Yokohama, Japan.
Arai
N
N
Goshima
Y
Y
Miyamae
T
T
Ohshima
E
E
Suzuki
F
F
Fujita
K
K
Misu
Y
Y
D000818:Animals; D016923:Cell Death; D003342:Corpus Striatum / Q000378:metabolism* / Q000473:pathology; D004295:Dihydroxyphenylalanine / Q000494:pharmacology / Q000502:physiology*; D004298:Dopamine / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018698:Glutamic Acid / Q000378:metabolism*; D006834:Hydrazines / Q000494:pharmacology; D002546:Ischemic Attack, Transient / Q000378:metabolism*; D007980:Levodopa / Q000031:analogs & derivatives* / Q000494:pharmacology; D008297:Male; D009474:Neurons / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors
D004791:Enzyme Inhibitors; D006834:Hydrazines; C110321:levodopa cyclohexyl ester; D018698:Glutamic Acid; D007980:Levodopa; D004295:Dihydroxyphenylalanine; C004297:3-hydroxybenzylhydrazine; D004298:Dopamine