Abstract
BackgroundRecent work by our laboratory and others has implicated NADPH oxidase as having an important role in reactive oxygen species (ROS) generation and neuronal damage following cerebral ischemia, although the mechanisms controlling NADPH oxidase in the brain remain poorly understood. The purpose of the current study was to examine the regulatory and functional role of the Rho GTPase, Rac1 in NADPH oxidase activation, ROS generation and neuronal cell death/cognitive dysfunction following global cerebral ischemia in the male rat.Methodology/Principal FindingsOur studies revealed that NADPH oxidase activity and superoxide (O2 −) production in the hippocampal CA1 region increased rapidly after cerebral ischemia to reach a peak at 3 h post-reperfusion, followed by a fall in levels by 24 h post-reperfusion. Administration of a Rac GTPase inhibitor (NSC23766) 15 min before cerebral ischemia significantly attenuated NADPH oxidase activation and O2 − production at 3 h after stroke as compared to vehicle-treated controls. NSC23766 also attenuated “in situ” O2 − production in the hippocampus after ischemia/reperfusion, as determined by fluorescent oxidized hydroethidine staining. Oxidative stress damage in the hippocampal CA1 after ischemia/reperfusion was also significantly attenuated by NSC23766 treatment, as evidenced by a marked attenuation of immunostaining for the oxidative stress damage markers, 4-HNE, 8-OHdG and H2AX at 24 h in the hippocampal CA1 region following cerebral ischemia. In addition, Morris Water maze testing revealed that Rac GTPase inhibition after ischemic injury significantly improved hippocampal-dependent memory and cognitive spatial abilities at 7–9 d post reperfusion as compared to vehicle-treated animals.Conclusions/SignificanceThe results of the study suggest that Rac1 GTPase has a critical role in mediating ischemia/reperfusion injury-induced NADPH oxidase activation, ROS generation and oxidative stress in the hippocampal CA1 region of the rat, and thus contributes significantly to neuronal degeneration and cognitive dysfunction following cerebral ischemia.
Highlights
Ischemic stroke is a significant clinical problem of complex neuropathology, and is the third leading cause of death in the United States of America
The current study adds to growing evidence of an important role of Rac1 GTPase in oxidative stress and neuronal cell death following cerebral ischemia
The elevation of Rac GTPase activation appears to contribute to the pathology following ischemic stress as evidenced by our finding that administration of a Rac GTPase inhibitor, NSC23766 or Rac1 antisense oligonucleotides [7] attenuated apoptotic neuronal cell death following global cerebral ischemia (GCI)
Summary
Ischemic stroke is a significant clinical problem of complex neuropathology, and is the third leading cause of death in the United States of America. Abundant evidence suggests that oxidative stress contributes significantly to the neuronal cell death that occurs following ischemic stroke. There is emerging evidence that a membrane enzyme, NADPH oxidase, contributes significantly to ROS generation following ischemic reperfusion [6,7,8]. Recent work by our laboratory and others has implicated NADPH oxidase as having an important role in reactive oxygen species (ROS) generation and neuronal damage following cerebral ischemia, the mechanisms controlling NADPH oxidase in the brain remain poorly understood. The purpose of the current study was to examine the regulatory and functional role of the Rho GTPase, Rac in NADPH oxidase activation, ROS generation and neuronal cell death/cognitive dysfunction following global cerebral ischemia in the male rat
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