Reduced Matrix Metalloproteinase-9 Activity and Cell Death After Global Ischemia in the Brain Preconditioned with Hyperb
Matrix metalloproteinase-9 (MMP-9) plays a deleterious role in cell death after global cerebral ischemia. Preconditioning with hyperbaric oxygen (HBO-PC) reduces neuronal damage in the post-ischemic brain; however, its effect on ischemia-induced increase
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Abstract Matrix metalloproteinase-9 (MMP-9) plays a deleterious role in cell death after global cerebral ischemia. Preconditioning with hyperbaric oxygen (HBO-PC) reduces neuronal damage in the post-ischemic brain; however, its effect on ischemia-induced increase in MMP-9 activity and expression remains unexplored. We investigated effects of HBO-PC on alterations in MMP-9 activity/tissue expression accompanying neuronal death after transient global cerebral ischemia. Male SD rats (300–350 g), were allocated either to non-ischemic (naive control or sham-operated) or ischemic (four-vessel occlusion, 4VO; 10 min) groups that were HBO-preconditioned (2.5 ATA, 1 h daily for 5 days; the last session 24 h before ischemia) or not. Neurobehavioral deficits were assessed prior to collection of brain tissue for gel zymography (MMP-9) and histology (MMP-9 immunofluorescence, TUNEL) at 0 (without ischemia), 6, 24, 72 h and 7 days after 4VO. Both, MMP-9 levels and cell death increased in the hippocampus at 72 h after 4VO. HBO-PC suppressed postis chemic MMP-9 activity and CA1 cell damage, and improved functional performance. The increase in MMP-9 immunoreactivity in the brain was also detected after HBO-PC alone. HBO-PC suppresses MMP-9 activity and expression in the postischemic hippocampus. The mechanism of HBO preconditioning may depend on the induction of MMP-9 in the preischemic phase and may be in part mediated by exhaustion of MMP-9 stores in cerebral tissues. Keywords Matrix metalloproteinase-9 • global cerebral ischemia • hyperbaric oxygen preconditioning • cell death
J.H. Zhang (*) Department of Physiology and Pharmacology, Department of Neurosurgery, Department of Anesthesiology, Linda University School of Medicine, Risley Hall, Room 219, Loma Linda, CA, 92350, USA e-mail: [email protected] R.P. Ostrowski, V. Jadhav, and W. Chen Department of Physiology and Pharmacology, Linda University School of Medicine, Risley Hall, Room 219, Loma Linda, CA 92350, USA
Introduction The occlusion of four major vessels supplying the rat brain creates a model of global cerebral ischemia that may occur during major cardiovascular procedures, in liver transplant recipients and, to the extreme, during cardiac arrest, experienced by more than a thousand Americans daily (8). Ischemiainduced increase in MMP-9-mediated proteolysis may cause apoptotic neuronal death by hampering survival signals from extracellular matrix to cell interior and by degrading the matrix itself (11). Preconditioning with hyperbaric oxygen (HBO-PC) has been shown to protect against ischemic cell death; while HBO post-treatment following major cerebral ischemia may reduce MMP-9-mediated damage to the proteins forming neurovascular matrix (6,7). Therefore, the positive effects of HBO-PC may be through a reduction of ischemic MMP-9 activation, although it has yet to be examined (4). The aim of this study was to investigate the effects of preconditioning with hyperbaric oxygen on alterations in MMP-9 activity/tissue expression underlying neuronal death in the
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