GIF-0173 protects against cerebral infarction through DP1 receptor activation.
The neuroprotective effects and mechanism of action of GIF-0173, a Delta12-prostaglandin J analogue, were investigated in the early phase of cerebral ischemia. GIF-0173 was administered intravenously immediately following middle cerebral artery occlusion (MCAO) in photochemically induced thrombosis model of rat. Neurological scores and infarct sizes were examined at 24 h after MCAO. Cerebral blood flow (CBF) was monitored by laser-Doppler flowmetry for 1 h after MCAO. In cultured cortical neurons obtained from 1-day-old rats, the effects of GIF-0173 on the excitotoxicity induced by glutamate were examined. Morphological changes, neuronal death, and changes in intracellular calcium concentration ([Ca(2+)](i)) were also examined. GIF-0173 improved neurological scores and reduced the infarct size in a dose-dependent manner following MCAO. But GIF-0173 did not improve CBF after MCAO. GIF-0173 also prevented glutamate-induced neuronal death and acute cellular swelling in primary cultures in a dose-dependent manner, indicating that it inhibited neuronal necrosis. GIF-0173 dose-dependently suppressed the glutamate-induced increase in [Ca(2+)](i), but could not inhibit NMDA-induced calcium influx. The effects of GIF-0173 against glutamate-induced [Ca(2+)](i) increase were reversed by addition of non-specific prostaglandin D (PGD(2)) receptor antagonist and were comparable to the effects of PGD(2) DP1 receptor agonist, which prevented [Ca(2+)](i) increase and neuronal death. We conclude that GIF-0173 reduces cerebral infarction and protects cultured neurons against glutamate-induced excitotoxicity by inhibiting [Ca(2+)](i) increase through DP1 receptor activation.
Thura
Min
M
Department of Pharmacology, Hamamatsu University School of Medicine, Hamamatsu, Japan.
Hokamura
Kazuya
K
Yamamoto
Seiji
S
Maeda
Masahide
M
Furuta
Kyoji
K
Suzuki
Masaaki
M
Ibaraki
Kyoko
K
Umemura
Kazuo
K
D000818:Animals; D020520:Brain Infarction / Q000209:etiology / Q000517:prevention & control*; D002118:Calcium / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex; D002560:Cerebrovascular Circulation / Q000187:drug effects; D003620:Dantrolene / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D018698:Glutamic Acid / Q000633:toxicity; D006827:Hydantoins / Q000494:pharmacology; D020244:Infarction, Middle Cerebral Artery / Q000139:chemically induced / Q000150:complications; D007424:Intracellular Fluid / Q000187:drug effects / Q000378:metabolism; D007783:Lactones / Q000494:pharmacology; D017078:Laser-Doppler Flowmetry / Q000379:methods; D008297:Male; D016202:N-Methylaspartate / Q000633:toxicity; D009474:Neurons / Q000187:drug effects; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D015230:Prostaglandin D2 / Q000031:analogs & derivatives / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D011971:Receptors, Immunologic / Q000378:metabolism*; D011982:Receptors, Prostaglandin / Q000378:metabolism*; D012717:Sesquiterpenes / Q000494:pharmacology; D012720:Severity of Illness Index; D013778:Tetrazolium Salts
D006827:Hydantoins; D007783:Lactones; C424427:NEPP11 compound; D018696:Neuroprotective Agents; D010975:Platelet Aggregation Inhibitors; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin; D012717:Sesquiterpenes; D013778:Tetrazolium Salts; C058848:BW A868C; D018698:Glutamic Acid; D016202:N-Methylaspartate; C046319:thapsigargicin; C030669:BW 245C; C009591:triphenyltetrazolium; D003620:Dantrolene; D015230:Prostaglandin D2; D002118:Calcium; C036293:prostaglandin D2 receptor