Bacterial alkaloids mitigate seizure-induced hippocampal damage and spatial memory deficits

Virginia L. Smith-Swintosky, Philipp J. Kraemer, Annadora J. Bruce, Nicole McCants, Andrew Maki, Russell W. Brown, Mona Alcala, Yadong Goodman, John T. Slevin, Mark P. Mattson

Research output: Contribution to journalArticlepeer-review

Abstract

Studies of human patients with temporal lobe epilepsy and animal models of epilepsy have established relationships between seizures, excitotoxic hippocampal damage, and memory impairment. We report that bacterial alkaloids, recently shown to mimic actions of neurotrophic factors in cell culture, attenuate seizure-induced damage to hippocampal neurons and memory impairment in adult rats when administered subcutaneously. Intrahippocampal administration of convulsant doses of kainic acid (KA) to adult rats resulted in degeneration of neurons in CA3, CA1, and hilus. Rats administered KA exhibited (24 h later) deficits in performance on both goal latency and probe trial tasks in Morris water maze (MWM) tests of visuospatial memory. Seizure-induced damage to hippocampal neurons was significantly reduced, to varying extents, in rats administered the bacterial alkaloids K252a, K252b, or staurosporine (daily injections of 4 μg/kg body weight) prior to KA administration. The KA-induced deficits in MWM goal latency performance were abrogated in rats administered K252a or K252b, and K252a and staurosporine completely prevented seizure-induced impairment on the MWM probe trial. The alkaloids did not suppress electroencephalographic seizure activity, suggesting a dissociation between synchronization of activity and synaptically mediated excitotoxic injury to hippocampal neurons. Each alkaloid caused an increase in levels of protein tyrosine phosphorylation as determined by Western blot analysis of hippocampal tissue. Our data indicate that these bacterial alkaloids have potent antiexcitotoxic activities which may have clinical utility in epilepsy and other disorders that involve excitotoxic damage.

Original languageEnglish (US)
Pages (from-to)287-296
Number of pages10
JournalExperimental Neurology
Volume141
Issue number2
DOIs
StatePublished - 1996
Externally publishedYes

ASJC Scopus subject areas

  • Neurology
  • Neuroscience(all)

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