CNS-specific prostacyclin ligands as neuronal survival-promoting factors in the brain

Prostacyclin (PGI(2)) is a critical regulator of the cardiovascular system, via dilatation of vascular smooth muscle and inhibition of platelet aggreg ation (Moncada, S., 1982, Br. J. Pharmacol., 76, 3). Our previous studies d emonstrated that a novel subtype of PGI(2) receptor, which is clearly disti nct from a peripheral subtype in terms of ligand specificity, is expressed in the rostral region of the brain, e.g. cerebral cortex, hippocampus, thal amus and striatum, and that (15R)-16-m-17,18,19,20-tetranorisocarbacyclin ( 15R-TIC) and 15-deoxy-16-m-17,18,19,20-tetranorisocarbacyclin (15-deoxy-TIC ) specifically bind to the central nervous system (CNS)-specific PGI(2) rec eptor. Here, we report that these CNS-specific PGI(2) receptor ligands, inc luding PGI(2) itself, prevented the neuronal death. They prevented apoptoti c cell death of hippocampal neurons induced by high (50%) oxygen atmosphere , xanthine + xanthine oxidase, and serum deprivation. IC(50)s for neuronal death were similar to 30 and 300 nM for 15-deoxy-TIC and 15R-TIC, respectiv ely, which well correlated with the binding potency for the CNS-specific PG I(2) receptor. 6-Keto-PGF(1 alpha) (a stable metabolite of PGI(2)), periphe ral nervous system-specific PGI(2) ligands and other prostaglandins (PGs) t han PGI(2) did not show such neuroprotective effects. In vivo, 15R-TIC prot ected CA1 pyramidal neurons against ischaemic damage in gerbils. These resu lts indicate that CNS-specific PGI(2) ligands have neuronal survival-promot ing activity both in vitro and in vivo, and may represent a new type of the rapeutic drug for neurodegeneration.