Both PI3K/Akt and ERK1/2 pathways participate in the protection by dexmedetomidine against transient focal cerebral ischemia/reperfusion injury in rats

• Published in: Brain research Vol. 1494; pp. 1 - 8
• Main Authors: Zhu, Yong-Man, Wang, Can-Can, Chen, Long, Qian, Ling-Bo, Ma, Lei-Lei, Yu, Jing, Zhu, Man-Hua, Wen, Chuan-Yun, Yu, Li-Na, Yan, Min
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 04.02.2013; Elsevier
• Subjects: 1-Phosphatidylinositol 3-kinase; adults; AKT protein; Animals; Biological and medical sciences; Brain; Brain Ischemia - complications; Brain Ischemia - drug therapy; Brain Ischemia - enzymology; Brain Ischemia - pathology; CA1 Region, Hippocampal - drug effects; CA1 Region, Hippocampal - pathology; Cell Death - drug effects; Cell survival; Cerebral blood flow; Cerebral Cortex - drug effects; Cerebral Cortex - pathology; Cerebral infarction; Cortex; Data processing; death; Dexmedetomidine; Dexmedetomidine - pharmacology; Edema; ERK1/2; Extracellular signal-regulated kinase; glycogen; Glycogen synthase kinase 3; Glycogen Synthase Kinase 3 - drug effects; Glycogen Synthase Kinase 3 - metabolism; Glycogen Synthase Kinase 3 beta; GSK-3β; infarction; Infarction, Middle Cerebral Artery - complications; Infarction, Middle Cerebral Artery - enzymology; Infarction, Middle Cerebral Artery - pathology; Injuries; Ischemia; Male; MAP Kinase Signaling System - drug effects; MCAO; Medical sciences; MEK inhibitors; mitogen-activated protein kinase; Mitogen-Activated Protein Kinase 1 - drug effects; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3 - drug effects; Mitogen-Activated Protein Kinase 3 - metabolism; Neurology; Neuropharmacology; Neuroprotection; Neuroprotective agent; Neuroprotective Agents - pharmacology; neuroprotective effect; Pharmacology. Drug treatments; phosphatidylinositol 3-kinase; Phosphatidylinositol 3-Kinase - drug effects; Phosphatidylinositol 3-Kinase - metabolism; Phosphorylation; PI3K; Protein Kinases - drug effects; Protein Kinases - metabolism; Rats; Rats, Sprague-Dawley; Reperfusion; Reperfusion Injury - enzymology; Reperfusion Injury - etiology; Reperfusion Injury - pathology; Reperfusion Injury - prevention & control; Signal Transduction - drug effects; Signal Transduction - physiology; Vascular diseases and vascular malformations of the nervous system; Western blotting; Wortmannin; MCAO; GSK-3β; ERK1/2; PI3K; Dexmedetomidine; Nervous system diseases; Rat; Enzyme; Rodentia; Central nervous system; Cardiovascular disease; Neuroprotective agent; Cerebral disorder; Encephalon; Vascular disease; Vertebrata; Mammalia; Reperfusion; Animal; Central nervous system disease; Brain ischemia; Lesion; Cerebrovascular disease
• ISSN: 0006-8993; 1872-6240
• DOI: 10.1016/j.brainres.2012.11.047

Abstract Dexmedetomidine (Dex) has been demonstrated to provide neuroprotection against ischemia/reperfusion (I/R) injury. However, the exact mechanism of this protection remains unknown. Here, we explored the neuroprotective effect of Dex in rats exposed to cerebral I/R-induced by middle cerebral artery occlusion (MCAO) and the role of phosphatidylinositol 3-kinase (PI3K)/Akt, extracellular signal-regulated kinase 1/2 (ERK1/2), and glycogen synthase kinase-3β (GSK-3β) in this protective action. Adult male Sprague–Dawley rats were subjected to MCAO for 90 min followed by reperfusion for 24 h and Dex (15 μg/kg, i.v.) was administered immediately after the onset of MCAO. The neurological deficit score, cerebral infarct volume, brain edema, and neuron survival were evaluated at 24 h of reperfusion. The effect of Dex on p-Akt, p-ERK1/2 and p-GSK-3β expression in the ischemic hemisphere was assayed by Western blot. Treatment of rats exposed to I/R with Dex caused not only marked reduction in the neurological deficit score, cerebral infarct volume, and brain edema (P <0.01 vs. I/R alone), but also a decrease in neuron death in hippocampal CA1 and cortex ( P <0.01 vs. I/R alone). The Dex-induced increment of neuron survival in the ischemic CA1 and cortex was diminished by the PI3K inhibitor LY294002 and the MEK inhibitor U0126. The increasing expressions of p-Akt and p-ERK1/2 induced by Dex in the ischemic hemisphere were markedly inhibited by LY294002 (or wortmannin) and U0126 (or PD98059), respectively. The up-regulation of p-GSK-3β by Dex in the ischemic hemisphere was significantly decreased by both LY294002 (or wortmannin) and U0126 (or PD98059). Our data demonstrated that treatment with Dex reduced cerebral injury in rats exposed to transient focal I/R, and this was mediated by the activation of the PI3K/Akt and ERK1/2 pathways as well the phosphorylation of downstream GSK-3β.