TTC-909 (
Clinprost), a chemically stable PGI2 analog,
isocarbacyclin methyl ester (
TEI-9090 or
Clinprost) incorporated in
lipid microspheres, when administered intravenously after
brain ischemia, prevents ischemic neuronal damage possibly by modulating cerebral blood flow and platelet aggregation. However, the possibility exists that
TEI-7165, which is the free
acid form and a central metabolite of
TEI-9090, has direct neurotrophic action in vivo, since
TEI-7165 has been shown to block neuronal voltage-dependent Ca2+ channels in vitro, and a novel
prostacyclin receptor showing high affinity with
TEI-7165 has been detected in a variety of brain regions including the hippocampus. In the present study, we infused
TEI-7165 for 7 days into the lateral ventricle of gerbils starting 2 h before or just after 3-min forebrain
ischemia.
TEI-7165 infusion prevented significantly the
ischemia-induced shortening of response latency time as revealed by a step-down passive avoidance task. Subsequent light and electron microscopic examinations showed that pyramidal neurons in the hippocampal CA1 region, as well as synapses within the strata moleculare, radiatum and oriens of the region, were significantly more numerous in gerbils infused with
TEI-7165 than in those receiving vehicle infusion.
TEI-7165 infusion did not affect hippocampal blood flow or temperature. These findings, together with the previously depicted accumulation of centrally administered [3H]
TEI-7165 around hippocampal neurons, suggest that
TEI-7165 has a direct neuroprotective action in
brain ischemia.