Activation of Canonical Notch Signaling Pathway Is Involved in the Ischemic Tolerance Induced by Sevoflurane Preconditioning in Mice
* Ph.D. Candidate, † Associate Professor, ‡ Associate Professor and Chief, § Research Assistant, # Professor, Department of Anesthesiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China. || Professor, Institute of Mental Health Research, Department of Psychiatry and Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada. Anesthesiology
(Impact Factor: 5.88).
08/2012; 117(5):996-1005. DOI: 10.1097/ALN.0b013e31826cb469
: A wealth of evidence has demonstrated that sevoflurane preconditioning induces brain ischemic tolerance, but the mechanism remains poorly understood. This study was designed to investigate the role of canonical Notch signaling in the neuroprotection induced by sevoflurane preconditioning in a mouse model.
: C57BL/6 mice were pretreated with 1-h sevoflurane exposure at a dose of 2.5% for 5 consecutive days. Twenty-four hours after the last exposure, all mice were subjected to focal cerebral ischemia by right middle cerebral artery occlusion for 60 min. Neurobehavioral scores, brain infarct volumes, and cellular apoptosis were determined at 72 h after reperfusion (n = 10 per group). The activation of Notch signaling was evaluated (n = 5 per group), and its role in ischemic tolerance was assessed by intraperitoneal administration of γ-secretase inhibitor DAPT (100 mg/kg, n = 10 per group) and conditional Notch-RBP-J knockout technique (n = 8 per group).
: Sevoflurane preconditioning reduced brain infarct volumes (42.5%), improved neurologic outcomes (P < 0.01 vs. control), and attenuated neuronal cell apoptosis (cells positive for terminal deoxynucleotidyl transferase-mediated 2'-deoxyuridine 5'-triphosphate nick-end labeling reduced to 21.2%). The expression of Notch1 intracellular domain (1.35 folds) and the transcriptions of Hes1 (1.95 times) and Hes5 (1.48 times) were up-regulated. DAPT augmented the brain infarcts (1.64-fold) and decreased neurologic scores (P = 0.43 vs. sevoflurane) in sevoflurane-preconditioned mice. Brain infarct volumes, neurobehavioral scores, and apoptotic cell numbers showed no significance between Notch knockout mice with sevoflurane preconditioning and wild-type mice without preconditioning.
: Sevoflurane preconditioning-induced protective effects against transient cerebral ischemic injuries are mediated by the activation of canonical Notch signaling pathway in mice.
Available from: link.springer.com
- "I/R) It is still controversial whether the activated canonical Notch signaling is beneficial to the ischemic cerebral tissues. Many researchers have found that the activation of Notch signaling was involved in the ischemic tolerance induced by inhalation anesthetics preconditioning (Zhang et al. 2014; Yang et al. 2012). However, other reports was consistent with the opinion that Notch signaling can induce neuronal cell death (Arumugam et al. 2011). "
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ABSTRACT: We have reported electroacupuncture (EA) pretreatment induced
the tolerance against focal cerebral ischemia through activation of canonical Notch pathway. However, the underlying mechanisms have not been fully understood. Evidences suggest that up-regulation of hypoxia inducible factor-1α (HIF-1α) contributes to neuroprotection against ischemia which could interact with Notch signaling pathway in this process. Therefore, the current study is to test that up-regulation of HIF-1α associated with Notch pathway contributes to the neuroprotection of EA pretreatment. Sprague–Dawley rats were treated with EA at the acupoint “Baihui (GV 20)” 30 min per day for successive 5 days before MCAO. HIF-1α levels were measured before and after reperfusion. Then, HIF-1α antagonist 2ME2 and γ-secretase inhibitor MW167 were used. Neurologic deficit scores, infarction volumes, neuronal apoptosis, and Bcl2/Bax were evaluated. HIF-1α and Notch1 intracellular domain (NICD) were assessed. The results showed EA pretreatment enhanced the neuronal expression of HIF-1α, reduced infarct volume, improved neurological outcome, inhibited neuronal apoptosis, up-regulated expression of Bcl-2, and down-regulated expression of Bax after reperfusion in the penumbra, while the beneficial effects were attenuated by 2ME2. Furthermore, intraventricular injection with MW167 efficiently suppressed both up-regulation of NICD and HIF-1α after reperfusion. However, administration with 2ME2 could only decrease the expression of HIF-1α in the penumbra. In conclusion, EA pretreatment exerts neuroprotection against ischemic injury through Notch pathway-mediated up-regulation of HIF-1α.
Available from: PubMed Central
- "The mice were fasted overnight with free access to tap water before surgery. Cerebral ischemia was induced by MCAO as previously described 22. The mice were then intraperitoneally anesthetized with pentobarbital sodium (60 mg/kg). "
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ABSTRACT: Stroke has severe consequences in postmenopausal women. As replacement therapy of estrogen have various adverse effects and the undermined outcomes. Genistein, a natural phytoestrogen, has been suggested to be a potential neuroprotective agent for such stroke patients. However, the role of genistein and its underlying mechanism in ovariectomized mice has not yet been evaluated. In the present study, ovariectomized mice were treated with genistein (10 mg/kg) or vehicle daily for two weeks before developing transient cerebral ischemia (middle cerebral artery occlusion). The neurological manifestation was evaluated, and infarct volumes were demonstrated by 2,3,5-triphenyltetrazolium chloride staining at 24 h after reperfusion. In addition, phosphorylation of extracellular signal-regulated kinase (ERK) was detected by Western blotting and immunofluorescence staining, and cellular apoptosis was evaluated in the ischemic penumbra. We found that treatment with genistein reduced infarct volumes, improved neurological outcomes and attenuated cellular apoptosis at 24 h after reperfusion. ERK1/2 showed increased phosphorylation by genistein treatment after reperfusion, and an ERK1/2 inhibitor U0126 abolished this protective effect of genistein in terms of infarct volumes, neurological scores and cellular apoptosis. Our findings indicate that treatment with genistein can reduce the severity of subsequent stroke episodes, and that this beneficial function is associated with ERK activation.
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ABSTRACT: We provide a review of both clinical and basic science literature from 2012 relevant to care of the patient with neurological disease. Our review addresses the following major areas: general neurosurgical procedures, stroke, traumatic brain injury, spine surgery, anesthetic neurotoxicity, neuroprotective strategies, electrophysiological monitoring, history, and graduate medical education. We have focused on research describing new and innovative concepts and recurring themes. This review is intended to be of interest to those working in the clinical arena and also to neuroscientists.
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