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.