Di Wu1, Xinglong Zhi2, Yunxia Duan3, Mo Zhang4, Hong An3, Wenjing Wei3, Kai Dong5, Ying Zhang3, Jingfei Shi6, Xiaoduo He3, Jun Zhang3, Chuanjie Wu5, Ran Meng3, Yuchuan Ding7, Xunming Ji8. 1. China-America Institute of Neuroscience, Xuanwu Hospital, Capital Medical University, Beijing, China; Beijing Key Laboratory of Hypoxia Conditioning Translational Medicine, China; Center of Stroke, Beijing Institute for Brain Disorders, China. 2. Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing, China. 3. China-America Institute of Neuroscience, Xuanwu Hospital, Capital Medical University, Beijing, China. 4. Department of Radiology, Xuanwu Hospital, Capital Medical University, Beijing, China. 5. Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China. 6. China-America Institute of Neuroscience, Xuanwu Hospital, Capital Medical University, Beijing, China; Beijing Key Laboratory of Hypoxia Conditioning Translational Medicine, China. 7. China-America Institute of Neuroscience, Xuanwu Hospital, Capital Medical University, Beijing, China; Department of Neurosurgery, Wayne State University School of Medicine, Detroit, MI, USA. 8. China-America Institute of Neuroscience, Xuanwu Hospital, Capital Medical University, Beijing, China; Beijing Key Laboratory of Hypoxia Conditioning Translational Medicine, China; Center of Stroke, Beijing Institute for Brain Disorders, China; Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing, China. Electronic address: jixm@ccmu.edu.cn.
Abstract
OBJECTIVE: The combination of pharmacological hypothermia - dihydrocapsaicin (DHC) and intra-arterial regional cooling infusions (RCI) was found to enhance the efficiency of hypothermia and efficacy of hypothermia-induced neuroprotection in acute ischemic stroke. The aim of this study was to explore whether the combination could induce a long-term neuroprotective effects, as well as the underlying mechanism. METHODS: Sprague-Dawley rats were subjected to middle cerebral artery occlusion (MCAO) for 2 h using intraluminal hollow filament. The ischemic rats were randomized to receive pharmacological hypothermia by intraperitoneal (i.p.) injection of DHC, physical hypothermia by RCI of 6 ml cold saline (4 °C), the combination, and no treatment. Over a 21-day period, brain damage was determined by infarct volume with MRI, and neurological deficit with grid-walking and beam balance tests. Blood brain barrier (BBB) was assessed by Evans-Blue (EB) contents. Inflammatory cytokines were determined in peri-infarct area by antibody array and ELISA. RESULTS: The combination of DHC and RCI reduced (p < 0.05) infarct volume and neurologic deficit after stroke. BBB leakage and pro-inflammatory cytokines (IFN-γ, IL-2, and TNF-α) were significantly decreased (p < 0.05) because of the combination, while protective cytokines (IL-4 and IL-10) were increased (p < 0.05) in the peri-infarct area. CONCLUSIONS: The combination approach enhanced the efficacy of hypothermia-induced neuroprotection following ischemic stroke. Our findings provide a hint to translate the combination method from bench to bedside.
OBJECTIVE: The combination of pharmacological hypothermia - dihydrocapsaicin (DHC) and intra-arterial regional cooling infusions (RCI) was found to enhance the efficiency of hypothermia and efficacy of hypothermia-induced neuroprotection in acute ischemic stroke. The aim of this study was to explore whether the combination could induce a long-term neuroprotective effects, as well as the underlying mechanism. METHODS:Sprague-Dawley rats were subjected to middle cerebral artery occlusion (MCAO) for 2 h using intraluminal hollow filament. The ischemicrats were randomized to receive pharmacological hypothermia by intraperitoneal (i.p.) injection of DHC, physical hypothermia by RCI of 6 ml cold saline (4 °C), the combination, and no treatment. Over a 21-day period, brain damage was determined by infarct volume with MRI, and neurological deficit with grid-walking and beam balance tests. Blood brain barrier (BBB) was assessed by Evans-Blue (EB) contents. Inflammatory cytokines were determined in peri-infarct area by antibody array and ELISA. RESULTS: The combination of DHC and RCI reduced (p < 0.05) infarct volume and neurologic deficit after stroke. BBB leakage and pro-inflammatory cytokines (IFN-γ, IL-2, and TNF-α) were significantly decreased (p < 0.05) because of the combination, while protective cytokines (IL-4 and IL-10) were increased (p < 0.05) in the peri-infarct area. CONCLUSIONS: The combination approach enhanced the efficacy of hypothermia-induced neuroprotection following ischemic stroke. Our findings provide a hint to translate the combination method from bench to bedside.
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