Journal
NEUROPHARMACOLOGY
Volume 55, Issue 4, Pages 509-516Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.neuropharm.2008.06.019
Keywords
metabotropic glutamate receptors; ischemic postconditioning; ischemic preconditioning; phosphatidylinositol 3-kinase; Akt; stroke
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Funding
- Italian Ministry of University and Research (MIUR, PRIN 2006 project)
- University of Florence
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Ischemic postconditioning is defined as a repetitive series of brief interruptions of reperfusion applied immediately after ischemia. In this study, postconditioning was investigated by first exposing rat organotypic hippocampal slices to 30 min oxygen-glucose deprivation (OGD), which promotes selective CA1 pyramidal cell death, and 5 min later to either a brief period (3 min) of OGD or to a low dose (10 mu M) of 3,5-dihydroxyphenylglycine (DHPG) for 30 min. Both protocols attenuated CA1 neuronal injury, as revealed 24 h later by measuring the intensity of propidium iodide fluorescence in this region. The beneficial effects were observed when DHPG postconditioning was applied up to 15 min after OGD, but not at later time points, and was not additive with the neuroprotective effects of a preconditioning DHPG treatment. The attenuation of the OGD-induced CA1 injury evoked by postconditioning was prevented when mGlu1 and mGlu5 receptor antagonists and inhibitors of phosphatidylinositol 3-kinase and Akt activity were present in the incubation medium during the 5 min recovery period after OGD and the 30 min exposure to DHPG. The PI3K inhibitor was also able to prevent the reduction of NMDA toxicity induced by the DHPG treatment. Finally, DHPG increased the phosphorylation of Akt in a transient and mGlu1/mGlu5-dependent manner. Our results show that activation of the mGlu1/mGlu5-PI3K-Akt signaling pathway plays a crucial role in the mechanisms of postconditioning evoked by DHPG and point to this strategy as a possible novel therapeutic tool for stroke and cerebral ischemia. (C) 2008 Elsevier Ltd. All rights reserved.
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