CNS-specific prostacyclin ligands as neuronal survival-promoting factors in the brain.
Prostacyclin (PGI2) is a critical regulator of the cardiovascular system, via dilatation of vascular smooth muscle and inhibition of platelet aggregation (Moncada, S. 1982, Br. J. Pharmacol., 76, 3). Our previous studies demonstrated that a novel subtype of PGI2 receptor, which is clearly distinct from a peripheral subtype in terms of ligand specificity, is expressed in the rostral region of the brain, e.g. cerebral cortex, hippocampus, thalamus 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 PGI2 receptor. Here, we report that these CNS-specific PGI2 receptor ligands, including PGI2 itself, prevented the neuronal death. They prevented apoptotic cell death of hippocampal neurons induced by high (50%) oxygen atmosphere, xanthine + xanthine oxidase, and serum deprivation. IC50s for neuronal death were approximately 30 and 300 nM for 15-deoxy-TIC and 15R-TIC, respectively, which well correlated with the binding potency for the CNS-specific PGI2 receptor. 6-Keto-PGF1alpha (a stable metabolite of PGI2), peripheral nervous system-specific PGI2 ligands and other prostaglandins (PGs) than PGI2 did not show such neuroprotective effects. In vivo, 15R-TIC protected CA1 pyramidal neurons against ischaemic damage in gerbils. These results indicate that CNS-specific PGI2 ligands have neuronal survival-promoting activity both in vitro and in vivo, and may represent a new type of therapeutic drug for neurodegeneration.
Satoh
T
T
Department of Neuroscience, Osaka Bioscience Institute, Furuedai, Suita-shi, Japan.
Ishikawa
Y
Y
Kataoka
Y
Y
Cui
Y
Y
Yanase
H
H
Kato
K
K
Watanabe
Y
Y
Nakadate
K
K
Matsumura
K
K
Hatanaka
H
H
Kataoka
K
K
Noyori
R
R
Suzuki
M
M
Watanabe
Y
Y
D000818:Animals; D001345:Autoradiography; D002545:Brain Ischemia / Q000473:pathology; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology*; D002490:Central Nervous System / Q000166:cytology / Q000502:physiology*; D011464:Epoprostenol / Q000031:analogs & derivatives / Q000494:pharmacology / Q000502:physiology*; D005260:Female; D005849:Gerbillinae; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D018496:Hyperoxia / Q000473:pathology; D008024:Ligands; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D017966:Pyramidal Cells / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D044006:Receptors, Epoprostenol; D011982:Receptors, Prostaglandin / Q000096:biosynthesis; D019820:Xanthine / Q000633:toxicity; D014969:Xanthine Oxidase / Q000633:toxicity
C119304:16-tolyl-17,18,19,20-tetranorisocarbacyclin; D008024:Ligands; D044006:Receptors, Epoprostenol; D011982:Receptors, Prostaglandin; D019820:Xanthine; D011464:Epoprostenol; D014969:Xanthine Oxidase