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mild hypothermia combined with a scaffold of Ng Rsilenced neural stem cells/Schwann cells to treat spinal cord injury

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Neural Regeneration Research 2014年第24期9卷 2189-2196页

作者： Dong Wang Jinhua Liang Jianjun Zhang Shuhong Liu Wenwen Sun Department of Neurosurgery the Fourth Center Clinical College of Tianjin Medical University Tianjin Fourth Central Hospital Department of Clinical Detection Hongqi Hospital of Mudanjiang Medical College Department of Epidemiology Logistics University of People’s Armed Police Force

Because the inhibition of Nogo proteins can promote neurite growth and nerve cell differentiation, a cell-scaffold complex seeded with Nogo receptor （NgR）-silenced neural stem cells and Schwann cells may be able to improve the microenvironment for spinal cord injury repair. Previous studies have found that mild hypothermia helps to attenuate secondary damage in the spinal cord and exerts a neuroprotective effect. Here, we constructed a cell-scaffold complex consisting of a poly（D,L-lactide-co-glycolic acid）（PLGA） scaffold seeded with NgR-silenced neural stem cells and Schwann cells, and determined the effects of mild hypothermia combined with the cell-scaffold complexes on the spinal cord hemi-transection injury in the T9 segment in rats. Compared with the PLGA group and the NgR-silencing cells ＋ PLGA group, hindlimb motor function and nerve electrophysiological function were dearly improved, pathological changes in the injured spinal cord were attenuated, and the number of surviving cells and nerve fibers were increased in the group treated with the NgR-silenced cell scaffold ＋ mild hypothermia at 34℃ for 6 hours. Furthermore, fewer pathological changes to the injured spinal cord and more surviving cells and nerve fibers were found after mild hypothermia therapy than in injuries not treated with mild hypothermia. These experimental results indicate that mild hypothermia combined with NgR gene-silenced cells in a PLGA scaffold may be an effective therapy for treating spinal cord injury.

关键词： nerve regeneration spinal cord injury neural stem cells Schwann cells mild hypothermia cell scaffold poly(D,L-lactide-co-glycolic acid) neurological function neural regeneration

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mild hypothermia effects on matrix metalloproteinase-9 expression in the perihematomal region of rats following experimental intracerebral hemorrhage

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Neural Regeneration Research 2008年第7期3卷 764-767页

作者： Minzhong Wang Xiaoyan Lin Xueping Liu Qingxi Fu Suming Zhang Department of Neurology Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan 430030 Hubei Province China Department of Neurology Shandong Provincial Hospital Jinan 250021 Shandong Province China Department of Pathology Shandong Provincial Hospital Jinan 250021 Shandong Province China

BACKGROUND： Matrix metalloproteinase-9 （MMP-9） expression increases with intracerebral hemorrhage, and participates in the pathophysiological processes of secondary brain injury after intracerebral hemorrhage. OBJECTIVE： To investigate the effects of mild hypothermia on MMP-9 expression and brain edema in the perihematomal region of experimental intracerebral hemorrhage rats. DESIGN, TIME AND SETTING： The randomized, controlled experiment was performed at the Central Laboratory of Shandong Provincial Hospital between May and September 2007. MATERIALS： Seventy-two, Wistar, male rats, 12-weeks old, were used for this study. Rabbit anti-MMP-9 primary antibody was purchased from Boster, China. METHODS： Wistar rats were equally and randomly divided into normothermia and mild hypothermia groups. The two groups each comprised control, 6-hour intracerebral hemorrhage, 24-hour intracerebral hemorrhage, 48-hour intracerebral hemorrhage, 72-hour intracerebral hemorrhage, and l-week intracerebral hemorrhage subgroups, with six rats in each subgroup. Rat models of intracerebral hemorrhage were established by injecting 100 μL of autologous blood into the rat caudate nucleus. Rats in the mild hypothermia group received four hours of local mild hypothermia immediately following the injection. lntracerebral temperature was maintained at （33 ± 0.5） ℃. Subsequently, intracerebral temperature was spontaneously recovered at 25 ℃. Rats in the control subgroup were not injected with autologous blood and received only with intracerebral hemorrhage. MAIN OUTCOME MEASURES： Brain water content and MMP-9 expression surrounding the hematoma region. RESULTS： MMP-9 expression increased at 6 hours, and brain edema reached a peak at 48 hours after intracerebral hemorrhage. MMP-9 expression was significantly decreased in the mild hypothermia group compared with the normothermia group at each time point （P 〈 0.05）. CONCLUSION： mild hypothermia can significantly inhibit MMP-9 overexpressio

关键词： intracerebral hemorrhage mild hypothermia brain edema matrix metalloproteinases

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mild hypothermia effects on intercellular adhesion molecule-1 and serum interleukin-6 expression in brain tissues of a rat focal ischemia model

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Neural Regeneration Research 2008年第10期3卷 1124-1127页

作者： Shengqi Fu Lei Yang Shuling Zhang Shilong Sun Xingai Mao Department of Neurology Fifth People＇s Hospital of Zhengzhou 450003 He＇nan Province China Department of Emergency He＇nan People＇s Hospital Zhengzhou 450003 He＇nan Province China Department of Neurology First Affiliated Hospital Xinxiang Medical College Weihui 453100 He＇nan Province China

BACKGROUND： Previous studies have confirmed the neuroprotective effect of mild hypothermia on ischemic brain injury. OBJECTIVE： To investigate the effects of mild hypothermia on intercellular adhesion molecule-1 expression and serum interleukin-6 levels in ischemic brain tissues of focal brain ischemia rats, and to explore the neuroprotective effects of mild hypothermia on ischemic brain injury. DESIGN, TIME AND SETTING： A randomized, controlled, neurobiological experiment was performed at the Central Laboratory, First Affiliated Hospital, Xinxiang Medical College, China from February to July 2006. MATERIALS： Thirty healthy, adult, Sprague Dawley rats were used to establish middle cerebral artery occlusion models using the suture method, The immunohistochemistry （streptavidin-biotin-peroxidase complex method） kit was purchased from Boster, China. Interleukin-6 radioimmunoassay was supplied by Institute of Radioimmunity, Technology Development Center, General Hospital of Chinese PLA. METHODS： The rats were equally and randomly assigned into mild hypothermia and control groups, and middle cerebral artery occlusion models were established. The rectal temperature was maintained at （37 ±0.5）℃ in the control group. In the mild hypothermia group, the rectal temperature was maintained at （33±1）℃. MAIN OUTCOME MEASURES： At 12 hours after model establishment, the ischemic brain hemispheres were coronally sliced at the level of the optic chiasm. The number of intercellular adhesion molecule-1-positive vessels per high-power field was observed with an optical microscope. Serum interleukin-6 levels were measured by radioimmunoassay. RESULTS： Compared with the control group, intercellular adhesion molecule-1 and serum interleukin-6 expressions were significantly decreased in ischemic brain tissues of the mild hypothermia group （P 〈 0.01）. CONCLUSION： mild hypothermia exhibits a neuroprotective effect by reducing serum interleukin-6 and intercellular adhesion molecule-1 expression

关键词： cerebral ischemia intercellular adhesion molecule-1 interleukin-6 mild hypothermia

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mild hypothermia for treatment of diffuse axonal injury: a quantitative analysis of diffusion tensor imaging

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Neural Regeneration Research 2014年第2期9卷 190-197页

作者： Guojie Jing Xiaoteng Yao Yiyi Li Yituan Xie Wang’an Li Kejun Liu Yingchao Jing Baisheng Li Yifan Lv Baoxin Ma Department of Neurosurgery Huizhou First People’s Hospital Huizhou Neurosurgery Institute Department of Neurosurgery Huizhou Central People’s Hospital

Fractional anisotropy values in diffusion tensor imaging can quantitatively reflect the consistency of nerve fibers after brain damage, where higher values generally indicate less damage to nerve fibers. Therefore, we hypothesized that diffusion tensor imaging could be used to evaluate the effect of mild hypothermia on diffuse axona[ injury. A total of 102 patients with diffuse axonal injury were randomly divided into two groups： normothermic and mild hypothermic treatment groups. Patient＇s modified Rankin scale scores 2 months after mild hypothermia were significant- ly lower than those for the normothermia group. The difference in average fractional anisotropy value for each region of interest before and after mild hypothermia was 1.32-1.36 times higher than the value in the normothermia group. Quantitative assessment of diffusion tensor imaging indicates that mild hypothermia therapy may be beneficial for patients with diffuse axonal injury.

关键词： nerve regeneration brain injury mild hypothermia diffuse axonal injury diffusiontensor imaging region of interest fractional anisotropy modified Rankin scale the Natural ScienceFoundation of Guangdong Province in China neural regeneration

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mild hypothermia in improving multiple organ dysfunction after cardiac arrest

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World Journal of Emergency Medicine 2010年第3期1卷 196-200页

作者： LinYang Xu-ming Zhao Li-junLiu Department of Emergency and Critical Care Medicine the Second Affiliated Hospital of Soochow UniversitySuzhou215004China

BACKGROUND： Resuscitation after cardiac arrest （CA） with a whole-body ischemia–reperfusion injury causes brain injury and multiple organ dysfunction （MODS）. This study aimed to determine whether mild systemic hypothermia could decrease multiple organ dysfunctions after resuscitation from cardiac ***： The patients who had been resuscitated after cardiac arrest were reviewed. During the resuscitation they had been assigned to undergo therapeutic hypothermia （target temperature, 32°C to 34°C, measured in the rectum） over a period of 24 to 36 hours or to receive standard treatment with normothermia. Markers of different organ injury were evaluated for the ？ rst 72 hours after recovery of spontaneous circulation （ROSC）.RESULTS： At 72 hours after ROSC, 23 patients in the hypothermia group for whom data were available had favorable neurologic, myocardial, hepatic and pulmonic outcomes as compared with 26 patients in the normothermia group. The values of renal function were not signi？ cantly different between the two groups. However, blood coagulation function was badly injured in the hypothermia ***： In the patients who have been successfully resuscitated after cardiac arrest, therapeutic mild hypothermia can alleviate dysfunction after resuscitation from cardiac arrest.

关键词： Cardiac arrest Ischemia reperfusion injury mild hypothermia Multiple organ dysfunction

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Neuroprotective effects of cold-inducible RNA-binding protein during mild hypothermia on traumatic brain injury

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Neural Regeneration Research 2016年第5期11卷 771-778页

作者： Guan Wang Jian-ning Zhang Jia-kui Guo Ying Cai Hong-sheng Sun Kun Dong Cheng-gang Wu Postgraduate Institution Tianjin Medical University Department of Neurosurgery Second Affiliated Hospital of Tianjin University of Traditional Chinese Medicine Department of Neurosurgery General Hospital of Tianjin Medical University Department of Neurosurgery Tianjin Huanhu Hospital

Cold-inducible RNA-binding protein（CIRP）, a key regulatory protein, could be facilitated by mild hypothermia in the brain, heart and liver. This study observed the effects of mild hypothermia at 31 ± 0.5℃ on traumatic brain injury in rats. Results demonstrated that mild hypothermia suppressed apoptosis in the cortex, hippocampus and hypothalamus, facilitated CIRP m RNA and protein expression in these regions, especially in the hypothalamus. The anti-apoptotic effect of mild hypothermia disappeared after CIRP silencing. There was no correlation between mitogen-activated extracellular signal-regulated kinase activation and CIRP silencing. CIRP silencing inhibited extracellular signal-regulated kinase-1/2 activation. These indicate that CIRP inhibits apoptosis by affecting extracellular signal-regulated kinase-1/2 activation, and exerts a neuroprotective effect during mild hypothermia for traumatic brain injury.

关键词： nerve regeneration traumatic brain injury mild hypothermia cold-inducible RNA-binding protein mitogen-activated extracellular signal-regulated kinase anti-apoptosis neural regeneration

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Efficacy of mild hypothermia for the Treatment of Patients with Cardiac Arrest

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Chinese Medical Journal 2015年第11期128卷 1536-1542页

作者： Yu Gao Kang-Li Hui Yu-Jie Wang Lin Wu Man-Lin Duan Jian-Guo Xu De-Xin Li Jinling Hospital Medical School of Nanjing University Nanjing Jiangsu 210000 China Department of Anesthesiology Jinling Hospital School of Medicine Nanjing University Nanjing Jiangsu 210000 China

Background： Therapeutic hypothermia has been recommended for the treatment of cardiac arrest patients who remain comatose after the return of spontaneous circulation. The aim of this study was to evaluate the effectiveness and safety of mild hypothermia on patients with cardiac arrest by conducting a meta-analysis. Methods： The relevant trials were searched in Cochrane Library, PubMed, Web of Science, Embase, CNKI and Wan Fang Data from the date of their establishment to October 2014. Thereafter, the studies retrieved were screened based on predeflned inclusion and exclusion criteria. Data were extracted, and the quality of the included studies was evaluated. A meta-analysis was conducted using the Cochrane Collaboration Review Manager 5.2 sottware. Results： Six randomized controlled trials involving 531 cases were included, among which 273 cases were assigned to the treatment group and the other 258 cases to the control group. The meta-analysis indicated that mild hypothermia therapy alter cardiac arrest produced significant differences ill survival rate （relative risk [RR] =1.23, 95% confidence interval [C/]： 1.02-1.48, P = 0.03） and neurological function （RR - 1.33, 95% （.7： 1.08-1.65, P - 0.007） alter 6 months compared with normothermia therapy. However, no significant differences were observed in the survival to the hospital discharge （RR = 1.35, 95% CI： 0.87-2.10, P - 0.1 8）, favorable neurological outcome at hospital discharge （RR = 1.53, 95% CI： 0.95 2.45, P = 0.08） and adverse events. Conclusions： The meta-analysis demonstrated that mild hypothermia can improve the survival rate and neurological function of patients with cardiac arrest after 6 months. On the other hand, regarding the survival to hospital discharge, favorable neurological outcome at hospital discharge, and adverse events, our meta-analysis produced nonsignificant results.

关键词： Cardiac Arrest Cardiopulmonary Resuscitation mild hypothermia Neurological Function Survival Rate

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The pathways by which mild hypothermia inhibits neuronal apoptosis following ischemia/reperfusion injury

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Neural Regeneration Research 2015年第1期10卷 153-158页

作者： Chun Luo Su-yue Pan Department of Neurology Nanfang HospitalSouthern Medical University Department of Neurology Guangxi Minzu Hospital

Several studies have demonstrated that mild hypothermia exhibits a neuroprotective role and it can inhibit endothelial cell apoptosis following ischemia/reperfusion injury by decreasing casp- ase-3 expression, It is hypothesized that mild hypothermia exhibits neuroprotective effects on neurons exposed to ischemia/reperfusion condition produced by oxygen-glucose deprivation. mild hypothermia significantly reduced the number of apoptotic neurons, decreased the expres- sion of pro-apoptotic protein Bax and increased mitochondrial membrane potential, with the peak of anti-apoptotic effect appearing between 6 and 12 hours after the injury. These findings indicate that mild hypothermia inhibits neuronal apoptosis following ischemia/reperfusion injury by protecting the mitochondria and that the effective time window is 6-12 hours after ischemia/reperfusion injury.

关键词： nerve regeneration mild hypothermia oxygen-glucose deprivation cell apoptosis neu-rons mitochondrial membrane potential Bax ischemia/reperfusion neural regeneration

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mild hypothermia prevents NO-induced cytotoxicity in human neuroblastoma cells via COX-2 induction

Mild hypothermia prevents NO-induced cytotoxicity in human n...

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中国生物化学与分子生物学会第十二届全国会员代表大会暨2018年全国学术会议

作者： Xin Yuan Fei Ju Hai-Jie Yang School of Life Science and Technology Xinxiang Medical University

mild hypothermia and cold-inducible protein RBM3 can protect neural cells from nitric oxide(NO)-induced ***,it is known that cyclooxygenase(COX)-2 is upregulated by cold-inducible protein RBM3 in various types of ***,it is unclear whether COX-2 contributes to the protective effects of mild hypothermia/RBM3 against NO insults in neural *** SH-SY5 Y neural cell line as a model,it was demonstrated that NO strongly downregulates the expression of COX-2 at both mRNA and protein *** COX-2 was overexpressed,NO-induced apoptosis in SHSY5 Y cells was drastically inhibited,indicating a pro-survival role of ***,the gene silencing of COX-2 boosted the apoptosis induced by *** mild hypothermia pre-treatment,COX-2 was strongly induced at both mRNA and protein levels,but either the silencing or overexpression of RBM3 had no effect on the ***,mild hypothermia-related protective effects against NO-induced apoptosis was markedly abrogated when COX-2 was *** findings suggest that mild hypothermia could protect neuroblastoma cells from NO-induced apoptosis by inducing COX-2 in a way that does not rely on RBM3.

关键词： mild hypothermia RBM3 COX-2 neuroprotection nitric oxide

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Effects of immediate and delayed mild hypothermia on endogenous antioxidant enzymes and energy metabolites following global cerebral ischemia

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Chinese Medical Journal 2011年第17期124卷 2764-2766页

作者： ZHANG Hong ZHANG Jun-jian MEI Yuan-wu SUN Sheng-gang TONG E-tang Department of Neurology Zhongnan Hospital of Wuhan University Center for Cerebral Vascular Diseases Medical College of Wuhan University Wuhan Hubei 430071 China Department of Neuroiogy Union Hospital of Tongji Medical College Huazhong University of Science & Technology Wuhan Hubei 430022 China

Background The optimal time window for the administration of hypothermia following cerebral ischemia has been studied for decades, with disparity outcomes. In this study, the efficacy of mild brain hypothermia beginning at different time intervals on brain endogenous antioxidant enzyme and energy metabolites was investigated in a model of global cerebral ischemia. Methods Forty-eight male Sprague-Dawley rats were divided into a sham-operated group, a normothermia （37℃-38℃） ischemic group and a mild hypothermic （31℃-32℃） ischemia groups. Rats in the last group were subdivided into four groups： 240 minutes of hypothermia, 30 minutes of normothermia plus 210 minutes of hypothermia, 60 minutes of normothermia plus 180 minutes of hypothermia and 90 minutes of normothermia plus 150 minutes of hypothermia （n=8）. Global cerebral ischemia was established using the Pulsinelli four-vessel occlusion model for 20 minutes and mild hypothermia was applied after 20 minutes of ischemia. *** was collected following 20 minutes of cerebral ischemia and 240 minutes of reperfusion, and used to measure the levels of superoxide dismutase （SOD）, glutathione peroxidase （GSH-Px）, reduced glutathione （GSH） and adenosine triphosphate （ATP）. Results mild hypothermia that was started within 0 to 60 minutes delayed the consumption of SOD, GSH-Px, GSH, and ATP （P 〈0.05 or P 〈0.01） in ischemic tissue, as compared to a normothermic ischemia group. In contrast, mild hypothermia beginning at 90 minutes had little effect on the levels of SOD, GSH-Px, GSH, and ATP （P〉0.05）. Conclusions Postischemic mild brain hypothermia can significantly delay the consumption of endogenous antioxidant enzymes and energy metabolites, which are critical to the process of cerebral protection by mild hypothermia. These results show that mild hypothermia limits ischemic injury if started within 60 minutes, but loses its protective effects when delayed until 90 minutes following cerebral ischemia.

关键词： ischemic reperfusion antioxidant enzymes energy metabolites mild hypothermia therapeutic time window

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