PMID- 16996500 OWN - NLM STAT- MEDLINE DCOM- 20070103 LR - 20091119 IS - 0014-4886 (Print) IS - 0014-4886 (Linking) VI - 202 IP - 2 DP - 2006 Dec TI - Identification of a biphasic signaling pathway involved in ischemic resistance of the hippocampal dentate gyrus. PG - 357-72 AB - Dentate gyrus is usually assumed to be resistant to ischemia. However, the mechanisms underlying this functional plasticity are not fully understood. Herein, we aimed at identifying a neuroprotective mechanism in the dentate gyrus of the adult rat after global ischemia. Cyclic AMP response element (CRE)-binding protein (CREB), brain-derived neurotrophic factor (BDNF) and calcium/calmodulin-dependent protein kinase IV (CaMKIV) are known to be mediators of neuronal survival and plasticity. Involvement of CaMKIV, BDNF and CREB in ischemic resistance was therefore examined using intracerebroventricular injections of pharmacological agents such as inhibitors, antibodies and consensus oligonucleotides followed by immunohistochemical and Western blot analysis. We provide evidence that ischemia triggers activation of a biphasic pathway during the resistance period of dentate neurons: (1) CaMKIV mediates the early phosphorylation of CREB which drives a prominent synthesis of BDNF; (2) this BDNF synthesis, in turn, induces a second peak of CREB phosphorylation which is required for the maintenance of BDNF synthesis. In addition, we show that: (1) impairment of these transduction signals by the pharmacological agents causes tissular damages and apoptotic deaths in the post-ischemic dentate gyrus; (2) some similar disturbances also occur beyond the resistance period in the dentate gyrus of untreated ischemic rats; (3) these disturbing effects are mainly observed in the suprapyramidal dentate subfield. Collectively, the present results suggest that activation of the CaMKIV/CREB/BDNF pathway plays principally an early protective role in the suprapyramidal subfield of the dentate gyrus. FAU - Blanquet, Pierre R AU - Blanquet PR AD - Laboratoire Developpement et Vieillissement du Systeme Nerveux, UMR 7102 CNRS-UPMC, Neurobiologie des Processus Adaptatifs, Universite P. and M. Curie, 9 Quai Saint-Bernard, Paris, France. pierre.blanquet@snv.jussieu.fr FAU - Mariani, Jean AU - Mariani J FAU - Fournier, Betty AU - Fournier B LA - eng PT - Comparative Study PT - Journal Article DEP - 20060925 PL - United States TA - Exp Neurol JT - Experimental neurology JID - 0370712 RN - 0 (Antibodies) RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Cyclic AMP Response Element-Binding Protein) RN - 0 (Enzyme Inhibitors) RN - 0 (Oligonucleotides) RN - EC 2.7.- (Protein Kinases) RN - EC 2.7.11.17 (Calcium-Calmodulin-Dependent Protein Kinase Type 4) RN - EC 2.7.11.17 (Camk4 protein, rat) RN - EC 4.2.1.11 (Phosphopyruvate Hydratase) SB - IM MH - Animals MH - Antibodies/pharmacology MH - Blotting, Western/methods MH - Brain-Derived Neurotrophic Factor/immunology/metabolism/pharmacology MH - Calcium-Calmodulin-Dependent Protein Kinase Type 4 MH - Cell Survival/drug effects/physiology MH - Cyclic AMP Response Element-Binding Protein/chemistry/metabolism/pharmacology MH - Dentate Gyrus/pathology/*physiopathology MH - Enzyme Activation/drug effects MH - Enzyme Inhibitors/pharmacology MH - Immunohistochemistry/methods MH - In Situ Nick-End Labeling/methods MH - Injections, Intraventricular/methods MH - Ischemic Attack, Transient/*pathology/physiopathology MH - Male MH - Models, Biological MH - Neurons/drug effects/*physiology MH - Oligonucleotides/pharmacology MH - Phosphopyruvate Hydratase/metabolism MH - Protein Kinases/metabolism MH - Rats MH - Rats, Wistar MH - Reperfusion/methods MH - Signal Transduction/drug effects/*physiology MH - Time Factors EDAT- 2006/09/26 09:00 MHDA- 2007/01/04 09:00 CRDT- 2006/09/26 09:00 PHST- 2006/02/27 00:00 [received] PHST- 2006/05/26 00:00 [revised] PHST- 2006/06/24 00:00 [accepted] PHST- 2006/09/26 09:00 [pubmed] PHST- 2007/01/04 09:00 [medline] PHST- 2006/09/26 09:00 [entrez] AID - S0014-4886(06)00392-X [pii] AID - 10.1016/j.expneurol.2006.06.016 [doi] PST - ppublish SO - Exp Neurol. 2006 Dec;202(2):357-72. doi: 10.1016/j.expneurol.2006.06.016. Epub 2006 Sep 25.