Neuroprotection by a central nervous system-type prostacyclin receptor ligand demonstrated in monkeys subjected to middle cerebral artery occlusion and reperfusion: a positron emission tomography study.

Abstract

Recently, we found that a novel subtype of prostacyclin (PGI(2)) receptor clearly distinct from the peripheral subtype in terms of ligand specificity is expressed in the central nervous system (CNS). (15R)-16-m-tolyl-17,18,19,20-tetranorisocarbacyclin (15R-TIC) was synthesized and demonstrated to be a specific ligand for this CNS-type PGI(2) receptor. Previously, we demonstrated 15R-TIC to be neuroprotective in vivo during transient forebrain ischemia in gerbils and permanent middle cerebral artery occlusion (MCAO) in rats. Furthermore, this compound was shown to exert an anti-apoptotic effect on primary cultured hippocampal neurons, indicating its neuroprotective effect against ischemic insults occurs via direct action on CNS-type PGI(2) receptor. Local cerebral hemodynamics and oxygen metabolism were measured simultaneously by using positron emission tomography with the (15)O steady-state method, before and up to 18 hours after 3-hour transient MCAO reperfusion in cynomolgus monkeys. Methyl ester of 15R-TIC (50 microg/kg, n=4) or its vehicle (10% Intralipos, n=4) was injected intravenously within 5 minutes after onset of MCAO and continuously infused for 5 hours (50 microg/kg per hour). Neuropathology showed that 15R-TIC significantly reduced cortical damage after 3-hour MCAO. Positron emission tomography results showed 15R-TIC significantly reduced the volume of "infarct" region of interest and attenuated the decrease in cerebral metabolic rate of oxygen and oxygen extraction fraction, and these protective effects were not attributable to improvement of cerebral circulation. These results suggest that 15R-TIC has a potent neuroprotective effect against focal cerebral ischemia in a monkey MCAO via its direct action on CNS-type PGI(2) receptors.