A competitive DOPA antagonist, DOPA cyclohexyl ester, inhibits transient aglycemia-induced glutamate release in rat striatal slices

• Published in: Japanese Journal of Pharmacology Vol. 82; no. suppl.2; p. 244
• Main Authors: Hashimoto, Mizuki, Miyamae, Takeaki, Goshima, Yoshio, Yamamoto, Isao, Misu, Yoshimi
• Format: Journal Article
• Language: English; Japanese
• Published: The Japanese Pharmacological Society 2000
• ISSN: 0021-5198
• DOI: 10.1016/S0021-5198(19)48437-0

We have demonstrated neuromodulatory and neurotoxic roles of L-DOPA (DOPA), acting on competitive DOPA antagonists-sensitive sites, in rat striata. Exogenously applied DOPA itself releases a neurotoxic amino acid glutamate and causes neuronal death in cultured fetal striatal neurons. Transient forebrain ischemia releases endogenous DOPA, and DOPA cyclohexyl ester (CHE), a novel competitive antagonist, inhibits both ischemia-induced glutamate release and resultant neuronal death in in vivo striata (JJP 76, Suppl.I, 85P, 1999). To further estimate the role of DOPA as a causal factor for glutamate release, we tried to establish an ischemic model using striatal slice preparations and investigate whether CHE inhibits glutamate release under various conditions. Striatal slices from 5-6-week-old Wistar rats were continuously superfused with Krebs medium at 37 ℃ and the glutamate levels in perfusates were measured every 6 min using HPLC-spectrofluorometer. Glucose deprivation for 18 min increased glutamate release by 4-6 fold of the basal levels with maximal increases 0-6 min after discontinuing the aglycemia. CHE at 0.3 μM slightly and 1 μM significantly suppressed glutamate release induced by the aglycemia. On the other hand, CHE had no effect on the glutamate release evoked by 18 min-deprivation of both glucose and oxygen. These results suggest that CHE is neuroprotective under relatively mild ischemic conditions, being consistent with our previous findings in in vivo striata.