Calpain activation is involved in early caspase-independent neurodegeneration in the hippocampus following status epilepticus.
Evidence for increased calpain activity has been described in the hippocampus of rodent models of temporal lobe epilepsy. However, it is not known whether calpains are involved in the cell death that accompanies seizures. In this work, we characterized calpain activation by examining the proteolysis of calpain substrates and in parallel we followed cell death in the hippocampus of epileptic rats. Male Wistar rats were injected with kainic acid (10 mg/kg) intraperitoneally and killed 24 h later, after development of grade 5 seizures. We observed a strong Fluoro-Jade labeling in the CA1 and CA3 areas of the hippocampus in the rats that received kainic acid, when compared with saline-treated rats. Immunohistochemistry and western blot analysis for the calpain-derived breakdown products of spectrin showed evidence of increased calpain activity in the same regions of the hippocampus where cell death is observed. No evidence was found for caspase activation, in the same conditions. Treatment with the calpain inhibitor MDL 28170 significantly prevented the neurodegeneration observed in CA1. Taken together, our data suggest that early calpain activation, but not caspase activation, is involved in neurotoxicity in the hippocampus after status epilepticus.
Araújo
Inês M
IM
Center for Neuroscience and Cell Biology, Department of Zoology, University of Coimbra, Coimbra, Portugal. inaraujo@cnc.cj.uc.pt
Gil
Joana M
JM
Carreira
Bruno P
BP
Mohapel
Paul
P
Petersen
Asa
A
Pinheiro
Paulo S
PS
Soulet
Denis
D
Bahr
Ben A
BA
Brundin
Patrik
P
Carvalho
Caetana M
CM
D000818:Animals; D002154:Calpain / Q000378:metabolism*; D020169:Caspases / Q000378:metabolism; D003292:Convulsants; D004151:Dipeptides / Q000494:pharmacology; D004195:Disease Models, Animal; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004827:Epilepsy / Q000139:chemically induced / Q000201:enzymology* / Q000503:physiopathology; D005452:Fluoresceins; D006624:Hippocampus / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D007608:Kainic Acid; D008297:Male; D009410:Nerve Degeneration / Q000201:enzymology* / Q000209:etiology / Q000503:physiopathology; D009930:Organic Chemicals; D051381:Rats; D017208:Rats, Wistar; D013049:Spectrin / Q000378:metabolism; D013226:Status Epilepticus / Q000139:chemically induced / Q000201:enzymology* / Q000503:physiopathology; D013997:Time Factors
D003292:Convulsants; D004151:Dipeptides; D004791:Enzyme Inhibitors; D005452:Fluoresceins; D009930:Organic Chemicals; C435731:fluoro jade; D013049:Spectrin; D002154:Calpain; D020169:Caspases; D007608:Kainic Acid; C058076:calpain inhibitor III