BACTERIAL ALKALOIDS MITIGATE SEIZURE-INDUCED HIPPOCAMPAL DAMAGE AND SPATIAL MEMORY DEFICITS

Studies of human patients with temporal lobe epilepsy and animal model s of epilepsy have established relationships between seizures, excitot oxic hippocampal damage, and memory impairment. We report that bacteri al alkaloids, recently shown to mimic actions of neurotrophic factors in cell culture, attenuate seizure-induced damage to hippocampal neuro ns and memory impairment in adult rats when administered subcutaneousl y, Intrahippocampal administration of convulsant doses of kainic acid (KA) to adult rats resulted in degeneration of neurons in CA3, CA1, an d hilus, Rats administered KA exhibited (24 h later) deficits in perfo rmance on both goal latency and probe trial tasks in Morris water maze (MWM) tests of visuospatial memory. Seizure-induced damage to hippoca mpal neurons was significantly reduced, to varying extents, in rats ad ministered the bacterial alkaloids K252a, K252b, or staurosporine (dai ly injections of 4 mu g/kg body weight) prior to KA administration. Th e KA-induced deficits in MWM goal latency performance were abrogated i n rats administered K252a or K252b, and K252a and staurosporine comple tely prevented seizure-induced impairment on the MWM probe trial, The alkaloids did not suppress electroencephalographic seizure activity, s uggesting a dissociation between synchronization of activity and synap tically mediated excitotoxic injury to hippocampal neurons, Each alkal oid caused an increase in levels of protein tyrosine phosphorylation a s determined by Western blot analysis of-hippocampal tissue. Our data indicate that these bacterial alkaloids have potent antiexcitotoxic ac tivities which may have clinical utility in epilepsy and other disorde rs that involve excitotoxic damage. (C) 1996 Academic Press, Inc.