Systemic administration of kainic acid induces selective time dependent decrease in [125I]insulin-like growth factor I, [125I]insulin-like growth factor II and [125I]insulin receptor binding sites in adult rat hippocampal formation.
Administration of kainic acid evokes acute seizure in hippocampal pathways that results in a complex sequence of functional and structural alterations resembling human temporal lobe epilepsy. The structural alterations induced by kainic acid include selective loss of neurones in CA1-CA3 subfields and the hilar region of the dentate gyrus followed by sprouting and permanent reorganization of the synaptic connections of the mossy fibre pathways. Although the neuronal degeneration and process of reactive synaptogenesis have been extensively studied, at present little is known about means to prevent pathological conditions leading to kainate-induced cell death. In the present study, to address the role of insulin-like growth factors I and II, and insulin in neuronal survival as well as synaptic reorganization following kainate-induced seizure, the time course alterations of the corresponding receptors were evaluated. Additionally, using histological preparations, the temporal profile of neuronal degeneration and hypertrophy of resident astroglial cells were also studied. [125I]Insulin-like growth factor I binding was found to be decreased transiently in almost all regions of the hippocampal formation at 12 h following treatment with kainic acid. The dentate hilar region however, exhibited protracted decreases in [125I]insulin-like growth factor I receptor sites throughout (i.e. 30 days) the study. [125I]Insulin-like growth factor II receptor binding sites in the hippocampal formation were found to be differentially altered following systemic administration of kainic acid. A significant decrease in [125I]insulin-like growth factor II receptor sites was observed in CA1 subfield and the pyramidal cell layer of the Ammon's horn at all time points studied whereas the hilar region and the stratum radiatum did not exhibit alteration at any time. A kainate-induced decrease in [125I]insulin receptor binding was noted at all time points in the molecular layer of the dentate gyrus whereas binding in CA1-CA3 subfields and discrete layers of the Ammon's horn was found to be affected only after 12 h of treatment. These results, when analysed with reference to the observed histological changes and established neurotrophic/protective roles of insulin-like growth factors and insulin, suggest possible involvement of these growth factors in the cascade of neurotrophic events that is associated with the reorganization of the hippocampal formation observed following kainate-induced seizures.
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Douglas Hospital Research Center, Department of Psychiatry, McGill University, Montreal, Quebec, Canada.
Seto
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Doré
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Chabot
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Quirion
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D000818:Animals; D001345:Autoradiography; D001665:Binding Sites; D002470:Cell Survival; D018891:Dentate Gyrus / Q000378:metabolism / Q000473:pathology; D015536:Down-Regulation; D004833:Epilepsy, Temporal Lobe / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007328:Insulin / Q000031:analogs & derivatives / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D007335:Insulin-Like Growth Factor II / Q000378:metabolism; D007457:Iodine Radioisotopes; D007608:Kainic Acid / Q000633:toxicity*; D008297:Male; D009410:Nerve Degeneration; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D017966:Pyramidal Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017526:Receptor, IGF Type 1 / Q000032:analysis / Q000096:biosynthesis*; D017527:Receptor, IGF Type 2 / Q000032:analysis / Q000096:biosynthesis*; D011972:Receptor, Insulin / Q000032:analysis / Q000096:biosynthesis*; D013997:Time Factors
D007328:Insulin; D007457:Iodine Radioisotopes; D017527:Receptor, IGF Type 2; C008147:insulin, iodo-; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin; D007608:Kainic Acid