Caspase-mediated death of newly formed neurons in the adult rat dentate gyrus following status epilepticus.
A large proportion of cells that proliferate in the adult dentate gyrus under normal conditions or in response to brain insults exhibit only short-term survival. Here, we sought to determine which cell death pathways are involved in the degeneration of newly formed neurons in the rat dentate gyrus following 2 h of electrically induced status epilepticus. We investigated the role of three families of cysteine proteases, caspases, calpains, and cathepsins, which can all participate in apoptotic cell death. Status epilepticus increased the number of bromodeoxyuridine (BrdU)-positive proliferated cells in the subgranular zone of the dentate gyrus. At the time of maximum cell proliferation, immunohistochemical analyses revealed protein expression of active caspase-cleaved poly (ADP-ribose) polymerase (PARP) in approximately 66% of the BrdU-positive cells, while none of them expressed cathepsin B or the 150-kDa calpain-produced fodrin breakdown product. To evaluate the importance of cysteine proteases in regulating survival of the newly formed neurons, we administered intracerebroventricular infusions of a caspase inhibitor cocktail (zVAD-fmk, zDEVD-fmk and zLEHD-fmk) over a 2-week period, sufficient to allow for neuronal differentiation, starting 1 week after the epileptic insult. Increased numbers of cells double-labelled with BrdU and neuron-specific nuclear protein (NeuN) marker were detected in the subgranular zone and granule cell layer of the caspase inhibitor-treated rats. Our data indicate that caspase-mediated cell death pathways are active in progenitor cell progeny generated by status epilepticus and compromise survival during neuronal differentiation.
Ekdahl
Christine T
CT
Section of Restorative Neurology, Wallenberg Neuroscience Center, BMC A11, 221 84 Lund, Sweden. christine.ekdahl@neurol.lu.se
Mohapel
Paul
P
Weber
Ekkehard
E
Bahr
Ben
B
Blomgren
Klas
K
Lindvall
Olle
O
D000818:Animals; D001973:Bromodeoxyuridine; D002352:Carrier Proteins / Q000378:metabolism; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism*; D002401:Cathepsin B / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects / Q000502:physiology*; D002455:Cell Division / Q000502:physiology; D018891:Dentate Gyrus / Q000187:drug effects / Q000201:enzymology / Q000503:physiopathology; D004558:Electric Stimulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007150:Immunohistochemistry; D008297:Male; D008840:Microfilament Proteins / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000201:enzymology*; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D011506:Proteins / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013226:Status Epilepticus / Q000201:enzymology* / Q000503:physiopathology; D013234:Stem Cells / Q000187:drug effects / Q000201:enzymology*; D013049:Spectrin
D001973:Bromodeoxyuridine; D002352:Carrier Proteins; D061945:Caspase Inhibitors; D020169:Caspases; D002401:Cathepsin B; D004791:Enzyme Inhibitors; D008840:Microfilament Proteins; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D011506:Proteins; D013049:Spectrin; C499322:Parp1 protein, rat