GIF-0173 protects against cerebral infarction through DP1 receptor activation

Abstract

The neuroprotective effects and mechanism of action of GIF-0173, a Δ12-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.