PROTECTIVE EFFECT OF A PROSTAGLANDIN I-2 ANALOG, TEI-7165, ON ISCHEMIC NEURONAL DAMAGE IN GERBILS

TTC-909 (Clinprost), a chemically stable PGI(2) analog, isocarbacyclin methyl ester (TEI-9090 or Clinprost) incorporated in lipid microspher es, when administered intravenously after brain ischemia, prevents isc hemic neuronal damage possibly by modulating cerebral blood flow and p latelet aggregation. However, the possibility exists that TEI-7165, wh ich is the free acid form and a central metabolite of TEI-9090, has di rect neurotrophic action in vivo, since TEI-7165 has been shown to blo ck neuronal voltage-dependent Ca2+ channels in vitro, and a novel pros tacyclin receptor showing high affinity with TEI-7165 has been detecte d in a variety of brain regions including the hippocampus. In the pres ent study, we infused TEI-7165 for 7 days into the lateral ventricle o f gerbils starting 2 h before or just after 3-min forebrain ischemia. TEI-7165 infusion prevented significantly the ischemia-induced shorten ing of response latency time as revealed by a step-down passive avoida nce task. Subsequent light and electron microscopic examinations showe d that pyramidal neurons in the hippocampal CA1 region, as well as syn apses within the strata moleculare, radiatum and oriens of the region, were significantly more numerous in gerbils infused with TEI-7165 tha n in those receiving vehicle infusion. TEI-7165 infusion did not affec t hippocampal blood flow or temperature. These findings, together with the previously depicted accumulation of centrally administered [H-3]T EI-7165 around hippocampal neurons, suggest that TEI-7165 has a direct neuroprotective action in brain ischemia. (C) 1997 Elsevier Science B .V.