Delayed treatment with NSC23766 in streptozotocin-induced diabetic rats ameliorates post-ischemic neuronal apoptosis through suppression of mitochondrial p53 translocation.

Abstract

NSC23766, a specific inhibitor of Rac1, has recently been shown to protect against cerebral ischemic injury, although the effects of NSC23766 in a diabetic model have not been examined. Therefore, the aim of our study was to investigate if NSC23766 provided neuroprotection in streptozotocin-induced diabetic rats and to determine the potential mechanism through which NSC23766 works. Diabetic Sprague-Dawley rats were subjected to right middle cerebral artery occlusion (MCAO) for 90 min. NSC23766 (10 or 30 mg kg(-1)) or isotonic saline were administered intraperitoneally twice daily starting 24 h after cerebral ischemia, for three consecutive days. Cerebral infarct volume, neurological deficit scores, neuronal apoptosis, and the release of cytochrome c, as well as the generation of ROS and mitochondrial integrity, were evaluated 96 h after reperfusion. In addition, the mitochondrial translocation of p53 and the expression of p53-upregulated modulator of apoptosis (PUMA) in the mitochondria of the cerebral ischemic cortex were determined by western blotting. NSC23766 not only ameliorated post-ischemic neuronal apoptosis but also decreased cerebral ischemia-induced mitochondrial p53 translocation and the expression of PUMA in mitochondria in diabetic rats. Thus, our data indicate that NSC23766 has therapeutic potential against cerebral ischemic reperfusion injury and that NSC23766 significantly ameliorates neuronal apoptosis by suppressing mitochondrial p53 translocation in streptozotocin-induced diabetic rats.

• Authors: Juan Liao, Zhi Ye, Guoqing Huang, Chang Xu, Qulian Guo, E Wang
• Journal: Neuropharmacology (Neuropharmacology) Vol. 85 Pg. 508-16 (Oct 2014) ISSN: 1873-7064 [Electronic] England
• PMID: 24953831 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Ltd. All rights reserved.

Chemical References

• Aminoquinolines
• Apoptosis Regulatory Proteins
• Bbc3 protein, rat
• NSC 23766
• Neuroprotective Agents
• Pyrimidines
• Reactive Oxygen Species
• Tumor Suppressor Protein p53
• Cytochromes c

Topics

• Aminoquinolines (pharmacology)
• Animals
• Apoptosis (drug effects, physiology)
• Apoptosis Regulatory Proteins (metabolism)
• Brain (drug effects, pathology, physiopathology)
• Cytochromes c (metabolism)
• Diabetes Mellitus, Experimental (physiopathology)
• Infarction, Middle Cerebral Artery (drug therapy, pathology, physiopathology)
• Male
• Mitochondria (drug effects, physiology)
• Neurons (drug effects, physiology)
• Neuroprotective Agents (pharmacology)
• Pyrimidines (pharmacology)
• Random Allocation
• Rats, Sprague-Dawley
• Reactive Oxygen Species (metabolism)
• Time Factors
• Tumor Suppressor Protein p53 (metabolism)