title: Temporal progression of kainic acid induced neuronal and myelin degeneration in the rat forebrain.
abstract: The excitatory amino acid glutamate has been implicated in the neurodegeneration associated with several different central nervous system diseases. Treatment with kainic acid (KA), a glutamate analog known to activate the AMPA/KA subtype of glutamate receptor, has been widely used as a model of epilepsy. Long term temporal studies of its neuropathological effects, however, are lacking. In this study, two techniques were used to directly visualize and characterize the neuropathology that occurred over a 2-month period following KA-induced status epilepticus in adult female Sprague-Dawley rats. Post-injection survival was 2, 4, 8 h, 2 days, 2 weeks, or 2 months. Labeling with Fluoro-Jade B (FJB), a fluorescent green dye that labels the cell body, dendrites, axons and axon terminals of degenerating neurons, was observed within the cortex, hippocampus, thalamus, basal ganglia, and amygdala by 4 h post-treatment. The highest level of labeling was seen in the piriform cortex, hippocampus, and thalamus. Myelin changes in the rat forebrain following KA treatment were also examined using the myelin-specific Black-Gold (BG) stain. Varicose myelinated fibers were observed in the same regions as FJB positive neurons, although these changes were evident by the 2-h survival time-point. Both stains showed a temporal progression of brain damage throughout the affected areas. By 2 months post-treatment, few degenerating neurons could be detected and abnormal myelin was absent in most regions. As myelin changes can be seen prior to neuronal degeneration, and oligodendrocytes express functional AMPA/kainate-type glutamate receptors, the neurodegeneration and myelin pathologies may occur as independent events. Thus, researchers should consider the temporal and multiple effects of kainic acid to optimize conditions for their endpoint of interest when designing experiments.
authors.affiliation: Division of Neurotoxicology, National Center for Toxicological Research, Food and Drug Administration, 3900 NCTR Road, Jefferson, AR, USA. khopkins@nctr.fda.gov
authors.forename: K J
authors.initials: KJ
authors.lastname: Hopkins
authors.forename: G
authors.initials: G
authors.lastname: Wang
authors.forename: L C
authors.initials: LC
authors.lastname: Schmued
mesh_terms: D000679:Amygdala / Q000473:pathology / Q000503:physiopathology; D000818:Animals; D001479:Basal Ganglia / Q000473:pathology / Q000503:physiopathology; D004396:Coloring Agents; D003714:Denervation / Q000009:adverse effects*; D004195:Disease Models, Animal; D004827:Epilepsy / Q000473:pathology / Q000503:physiopathology; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity*; D005260:Female; D005456:Fluorescent Dyes; D018698:Glutamic Acid / Q000378:metabolism; D006624:Hippocampus / Q000473:pathology / Q000503:physiopathology; D007031:Hypothalamus / Q000473:pathology / Q000503:physiopathology; D007608:Kainic Acid / Q000633:toxicity*; D009186:Myelin Sheath / Q000187:drug effects* / Q000473:pathology*; D009410:Nerve Degeneration / Q000139:chemically induced* / Q000473:pathology* / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects* / Q000473:pathology*; D009498:Neurotoxins / Q000378:metabolism; D009833:Olfactory Pathways / Q000473:pathology / Q000503:physiopathology; D010296:Parietal Lobe / Q000473:pathology / Q000503:physiopathology; D010710:Phosphates; D016548:Prosencephalon / Q000187:drug effects* / Q000473:pathology* / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000187:drug effects / Q000378:metabolism; D018092:Kainic Acid Receptors / Q000187:drug effects / Q000378:metabolism; D013226:Status Epilepticus / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology; D013788:Thalamus / Q000473:pathology / Q000503:physiopathology; D013997:Time Factors
chemical_list: D004396:Coloring Agents; D018690:Excitatory Amino Acid Agonists; D005456:Fluorescent Dyes; D018698:Glutamic Acid; D007608:Kainic Acid; D009498:Neurotoxins; D010710:Phosphates; D018091:Receptors, AMPA; D018092:Kainic Acid Receptors; C121848:Black-Gold