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Brain Res ; 1302: 10-20, 2009 Dec 11.
Article in English | MEDLINE | ID: mdl-19765564


Hippocampal dentate gyrus possesses an exceptional capacity of adaptation to ischemic insults. Recently, using a transient global ischemic model in the adult rat, we identified a neuroprotective signalling cascade in the dentate gyrus involving calcium/calmodulin-dependent protein kinase IV (CaMKIV), cyclic AMP response element (CRE)-binding protein (CREB) and brain-derived neurotrophic factor (BDNF), a major regulator of survival. We have shown that intracerebroventricular injections of anti-BDNF and anti-CREB are sufficient to cause substantial tissular damages and apoptotic deaths in late periods (48-72 h) after ischemia. Herein, we provide immunohistochemical and biochemical evidence that antibody-induced impairment of the protective CaMKIV/CREB/BDNF pathway induces an apparent duality of response in the dentate gyrus. The experimental protocol is performed as follows: (a) rats are anesthetized and vertebral arteries are occluded by electrocauterization; (b) on the following day, transient global ischemia is produced by occlusion of carotid arteries for 25 min; (c) finally, rats are infused with the pharmacologic agents into the left cerebral ventricle and then perfusion-fixed at different time points after ischemia for immunohistochemical and immunoblotting analyses. After infusion with anti-CaMKIV, phosphorylation of mitogen-activated protein kinases (MAPK) MKK3, MKK6 and p38 and phospho-acetylation of histone H3 occur at 6 h after ischemia without presence of any caspase-9 activation and cellular injuries. In contrast, infusion of anti-BDNF or anti-CREB surprisingly results in a remarkable stimulation of casein kinase 2 (CK2) and caspase-9 activities at 48-72 h post-insult. This is accompanied by the disappearance of phosphorylation of MKK(3/6) and p38 and phospho-acetylation of histone H3. These results suggest that: (1) activation of a MKK(3/6)/p38/H3 cascade at early periods post-ischemia may be capable of causing a short transient protective effect in the dentate gyrus; (2) CK2 might be implicated in inhibition of activity of molecules such as MKK(3/6), p38 and deacetylases at late periods post-insult, thereby promoting injuries and cell deaths in the dentate cell layer.

Brain Ischemia/metabolism , Casein Kinase II/metabolism , Cytoprotection/physiology , Dentate Gyrus/metabolism , Histones/metabolism , MAP Kinase Signaling System/physiology , Animals , Brain Ischemia/physiopathology , Brain-Derived Neurotrophic Factor/metabolism , Calcium-Calmodulin-Dependent Protein Kinase Type 4/metabolism , Caspase 9/metabolism , Cell Death/drug effects , Cell Death/physiology , Cyclic AMP Response Element-Binding Protein/metabolism , Cytoprotection/drug effects , Dentate Gyrus/physiopathology , Disease Models, Animal , Enzyme Activation/drug effects , Enzyme Activation/physiology , Enzyme Inhibitors/pharmacology , MAP Kinase Signaling System/drug effects , Male , Phosphorylation/drug effects , Rats , Rats, Wistar , Signal Transduction/physiology , Time Factors