title: Increased levels and activity of cathepsins B and D in kainate-induced toxicity.
abstract: Administration of kainic acid induces acute seizures that result in the loss of neurons, gliosis and reorganization of mossy fiber pathways in the hippocampus resembling those observed in human temporal lobe epilepsy. Although these structural changes have been well characterized, the mechanisms underlying the degeneration of neurons following administration of kainic acid remain unclear. Since the lysosomal enzymes, cathepsins B and D, are known to be involved in the loss of neurons and clearance of degenerative materials in a variety of experimental conditions, we evaluated their potential roles in kainic acid-treated rats. In parallel, we also measured the levels and expression of insulin-like growth factor-II/mannose 6-phosphate (IGF-II/M6P) receptors, which mediate the intracellular trafficking of these enzymes, in kainic acid-treated rats. Our results showed that systemic administration of kainic acid evoked severe loss of neurons along with hypertrophy of astrocytes and microglia in the hippocampus of the adult rat brain. The levels and activity of cathepsins B and D increased with time in the hippocampus of kainic acid-treated rats compared to the saline-injected control animals. The expression of both cathepsins B and D, as evident by immunolabeling studies, was also markedly increased in activated astrocytes and microglia of the kainic acid-treated rats. Additionally, cytosolic levels of the cathepsins were enhanced along with cytochrome c and to some extent Bax in the hippocampus in kainic acid-treated rats. These changes were accompanied by appearance of cleaved caspase-3-positive neurons in the hippocampus of kainic acid-treated animals. The levels of IGF-II/M6P receptors, on the other hand, were not significantly altered, but these receptors were found to be present in a subset of reactive astrocytes following administration of kainic acid. These results, taken together, suggest that enhanced levels/expression and activity of lysosomal enzymes may have a role in the loss of neurons and/or clearance of degenerative materials observed in kainic acid-treated rats.
authors.affiliation: Centre for Prions and Protein Folding Diseases, Department of Medicine (Neurology), University of Alberta, Edmonton, Alberta T6G 2M8, Canada.
authors.forename: M
authors.initials: M
authors.lastname: Banerjee
authors.affiliation: Centre for Prions and Protein Folding Diseases, Department of Medicine (Neurology), University of Alberta, Edmonton, Alberta T6G 2M8, Canada; Department of Psychiatry, University of Alberta, Edmonton, Alberta T6G 2M8, Canada.
authors.forename: V A
authors.initials: VA
authors.lastname: Sasse
authors.affiliation: Centre for Prions and Protein Folding Diseases, Department of Medicine (Neurology), University of Alberta, Edmonton, Alberta T6G 2M8, Canada; Department of Psychiatry, University of Alberta, Edmonton, Alberta T6G 2M8, Canada.
authors.forename: Y
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Centre for Prions and Protein Folding Diseases, Department of Medicine (Neurology), University of Alberta, Edmonton, Alberta T6G 2M8, Canada; Centre for Neuroscience, University of Alberta, Edmonton, Alberta T6G 2M8, Canada.
authors.forename: M
authors.initials: M
authors.lastname: Maulik
authors.affiliation: Centre for Prions and Protein Folding Diseases, Department of Medicine (Neurology), University of Alberta, Edmonton, Alberta T6G 2M8, Canada; Department of Psychiatry, University of Alberta, Edmonton, Alberta T6G 2M8, Canada; Centre for Neuroscience, University of Alberta, Edmonton, Alberta T6G 2M8, Canada. Electronic address: skar@ualberta.ca.
authors.forename: S
authors.initials: S
authors.lastname: Kar
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D053148:Caspase 3 / Q000378:metabolism; D002401:Cathepsin B / Q000378:metabolism*; D002402:Cathepsin D / Q000378:metabolism*; D045304:Cytochromes c / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D007608:Kainic Acid / Q000633:toxicity*; D008297:Male; D017628:Microglia / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D009474:Neurons / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D017207:Rats, Sprague-Dawley; D017527:Receptor, IGF Type 2 / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: C494828:Bax protein, rat; D017527:Receptor, IGF Type 2; D051028:bcl-2-Associated X Protein; C034304:cation-dependent mannose-6-phosphate receptor; D045304:Cytochromes c; C505410:Casp3 protein, rat; D053148:Caspase 3; D002401:Cathepsin B; C533916:Ctsb protein, rat; D002402:Cathepsin D; C533924:Ctsd protein, rat; D007608:Kainic Acid
keywords: cathepsins; epilepsy; hippocampus; insulin-like growth factor-II receptor; neurodegeneration; seizures