Caspase inhibitors increase short-term survival of progenitor-cell progeny in the adult rat dentate gyrus following status epilepticus.
The dentate gyrus (DG) is one of the few regions in the brain that continues to produce new neurons throughout adulthood. Seizures not only increase neurogenesis, but also lead to death of DG neurons. We investigated the relationship between cell death and neurogenesis following seizures in the DG of adult rats by blocking caspases, which are key components of apoptotic cell death. Multiple intracerebroventricular infusions of caspase inhibitors (pancaspase inhibitor zVADfmk, and caspase 3 and 9 inhibitor) prior to, just after, 1 day after, and 1 week following 2 h of lithium-pilocarpine-induced status epilepticus reduced the number of terminal deoxynucleotidyl transferase-mediated fluorescein-dUTP nick-end labelled (TUNEL) cells and increased the number of bromodeoxyuridine (BrdU) -stained proliferated cells in the subgranular zone at 1 week. The caspase inhibitor-treated group did not differ from control at 2 days or 5 weeks following the epileptic insult. Our findings suggest that caspases modulate seizure-induced neurogenesis in the DG, probably by regulating apoptosis of newly born neurons, and that this action can be suppressed transiently by caspase inhibitors. Furthermore, although previous studies have indicated that increased neuronal death can trigger neurogenesis, we show here that reduction in apoptotic death may be associated with increased neurogenesis.
Ekdahl
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Section of Restorative Neurology, Wallenberg Neuroscience Center, BMC A11, SE-221 84 Lund, Sweden.
Mohapel
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Elmér
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Lindvall
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D000818:Animals; D000963:Antimetabolites / Q000494:pharmacology; D001973:Bromodeoxyuridine / Q000494:pharmacology; D061945:Caspase Inhibitors; D002452:Cell Count; D002470:Cell Survival / Q000187:drug effects; D003292:Convulsants; D018891:Dentate Gyrus / Q000473:pathology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D007276:Injections, Intraventricular; D008094:Lithium; D008297:Male; D010862:Pilocarpine; D051381:Rats; D017207:Rats, Sprague-Dawley; D013226:Status Epilepticus / Q000139:chemically induced / Q000473:pathology*; D013234:Stem Cells / Q000187:drug effects / Q000473:pathology*; D016707:Tissue Fixation
D000963:Antimetabolites; D061945:Caspase Inhibitors; D003292:Convulsants; D004791:Enzyme Inhibitors; D005904:Glial Fibrillary Acidic Protein; D010862:Pilocarpine; D008094:Lithium; D001973:Bromodeoxyuridine