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CNS‐specific prostacyclin ligands as neuronal survival‐promoting factors in the brain
Author(s) -
Satoh Takumi,
Ishikawa Yasuyuki,
Kataoka Yosky,
Cui Yilong,
Yanase Hisato,
Kato Koichi,
Watanabe Yumiko,
Nakadate Kazuhiko,
Matsumura Kiyoshi,
Hatanaka Hiroshi,
Kataoka Kiyoshi,
Noyori Ryoji,
Suzuki Masaaki,
Watanabe Yasuyoshi
Publication year - 1999
Publication title -
european journal of neuroscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.346
H-Index - 206
eISSN - 1460-9568
pISSN - 0953-816X
DOI - 10.1046/j.1460-9568.1999.00791.x
Subject(s) - prostacyclin , receptor , neuroprotection , hippocampal formation , medicine , in vivo , endocrinology , central nervous system , hippocampus , biology , pharmacology , chemistry , microbiology and biotechnology
Prostacyclin (PGI 2 ) 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 PGI 2 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 (15 r )‐16‐m‐17,18,19,20‐tetranorisocarbacyclin (15 r ‐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 receptor. Here, we report that these CNS‐specific PGI 2 receptor ligands, including PGI 2 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. IC 50 s for neuronal death were ∼ 30 and 300 n m for 15‐deoxy‐TIC and 15 r ‐TIC, respectively, which well correlated with the binding potency for the CNS‐specific PGI 2 receptor. 6‐Keto‐PGF 1α (a stable metabolite of PGI 2 ), peripheral nervous system‐specific PGI 2 ligands and other prostaglandins (PGs) than PGI 2 did not show such neuroprotective effects. In vivo, 15 r ‐TIC protected CA1 pyramidal neurons against ischaemic damage in gerbils. These results indicate that CNS‐specific PGI 2 ligands have neuronal survival‐promoting activity both in vitro and in vivo, and may represent a new type of therapeutic drug for neurodegeneration.