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Journal of Neuroscience, Vol 12, 4173-4187, Copyright © 1992 by Society for Neuroscience
Alteration of long-lasting structural and functional effects of kainic acid in the hippocampus by brief treatment with phenobarbital
T Sutula, J Cavazos and G Golarai
Neuroscience Training Program, University of Wisconsin, Madison 53792.
Kainic acid, an analog of the excitatory amino acid L-glutamate, induces
acute hyperexcitability and permanent structural alterations in the
hippocampal formation of the adult rat. Administration of kainic acid is
followed by acute seizures in hippocampal pathways, neuronal loss in CA3
and the hilus of the dentate gyrus, and reorganization of the synaptic
connections of the mossy fiber pathway. Rats with these hippocampal
structural alterations have increased susceptibility to kindling. To
evaluate the role of the acute seizures and associated hippocampal
structural alterations in the development of this long- lasting
susceptibility, rats that received intraventricular kainic acid were
cotreated with phenobarbital (60 mg/kg, s.c., once daily). Treatment with
this dose for 5 d after administration of kainic acid suppressed acute
seizure activity, protected against excitotoxic damage in the dentate
gyrus, reduced mossy fiber sprouting, and completely abolished the
increased susceptibility to kindling associated with kainic acid. Brief
treatment with phenobarbital modified the pattern of damage and synaptic
reorganization in the dentate gyrus in response to seizure-induced injury,
and altered the long-lasting functional effects associated with hippocampal
damage. As phenobarbital treatment did not protect against neuronal damage
in CA3 or other regions of the hippocampus, the circuitry of the dentate
gyrus was implicated as a locus of cellular alterations that influenced the
development of kindling. These observations are evidence that
pharmacological intervention can prevent the development of epilepsy in
association with acquired structural lesions, and suggest that
pharmacological modification of cellular responses to injury can favorably
alter long- term functional effects of CNS damage.
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