Neuroprotective effects of group II metabotropic glutamate receptor agonist DCG-IV on hippocampal neurons in transient forebrain ischemia.
Activation of group II metabotropic glutamate receptor (mGluR) inhibits the excessive release of glutamate that may be crucial in the pathogenesis of cerebral ischemia. This study investigated the protective effects of the group II mGluR agonist (2S,2'R,3'R)-2-(2',3'-dicarboxycyclopropyl)glycine (DCG-IV), against cerebral ischemia by examining extracellular glutamate concentration ([Glu]e) and neuronal damage in a rat model of transient forebrain ischemia. Cerebral ischemia was induced by 5 min of bilateral carotid artery occlusion and hypotension. DCG-IV (10, 100, or 250 pmol) was administered into the lateral ventricle four times every 12 h from 36 h before the start of ischemia, or administered intraperitoneally (40 micromol/kg) 24 h before ischemia, and the effect of the group II mGluR antagonist (LY341495) was also examined. [Glu]e in the CA1 subfield was measured by microdialysis during the peri-ischemic period, and the survival rate of CA1 neurons was evaluated 5 days after ischemia. [Glu]e increased significantly after cerebral ischemia and reached the maximum at 1 min after reperfusion, then gradually decreased and returned to the preischemic level in the vehicle group. The intraventricular injection of DCG-IV (250 pmol) significantly attenuated the [Glu]e increase and significantly increased the survival rate of CA1 neurons. Co-injection of LY341495 reversed the protective effects of DCG-IV. These results suggest that pretreatment with DCG-IV has neuroprotective effects against ischemic neuronal injuries through the inhibition of the glutamate release via the activation of group II mGluR.
Yoshioka
Hideyuki
H
Department of Neurosurgery, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, 1110 Shimokato, Chuou, Yamanashi 409-3898, Japan.
Sugita
Masao
M
Kinouchi
Hiroyuki
H
D000596:Amino Acids / Q000494:pharmacology; D000818:Animals; D016893:Carotid Stenosis / Q000150:complications; D002560:Cerebrovascular Circulation / Q000187:drug effects; D003521:Cyclopropanes / Q000494:pharmacology / Q000627:therapeutic use*; D005110:Extracellular Space / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D006624:Hippocampus / Q000187:drug effects* / Q000473:pathology; D002546:Ischemic Attack, Transient / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D008297:Male; D017551:Microdialysis; D009474:Neurons / Q000187:drug effects* / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D016548:Prosencephalon / Q000098:blood supply / Q000473:pathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists* / Q000037:antagonists & inhibitors; D014966:Xanthenes / Q000494:pharmacology
D000596:Amino Acids; D003521:Cyclopropanes; C114624:LY 341495; D018696:Neuroprotective Agents; D018094:Receptors, Metabotropic Glutamate; D014966:Xanthenes; C082313:2-(2,3-dicarboxycyclopropyl)glycine; D018698:Glutamic Acid; D005998:Glycine