Enhanced oxidative stress response and neuroprotection of combined limb remote ischemic conditioning and atorvastatin after transient ischemic stroke in rats
Changhong Ren1, Sijie Li2, Kaiyin Liu3, Gary B Rajah3, Anbo Zhang2, Rongrong Han1, Yuanyuan Liu4, Qingjian Huang1, Haiyan Li1, Yuchuan Ding3, Xunming Ji5
1 Institute of Hypoxia Medicine, Xuanwu Hospital, Capital Medical University; Beijing Key Laboratory of Hypoxia Conditioning Translational Medicine; Center of Stroke, Beijing Institute for Brain Disorder, Beijing, China
2 Beijing Key Laboratory of Hypoxia Conditioning Translational Medicine, Beijing, China
3 Department of Neurosurgery, Wayne State University School of Medicine, Detroit, MI 48201, USA
4 Department of Endocrinology, Beijing, China, Huai'an First People's Hospital, Nanjing Medical University, Huai'an 223300, Jiangsu Province, China
5 Beijing Key Laboratory of Hypoxia Conditioning Translational Medicine; Center of Stroke, Beijing Institute for Brain Disorder, Beijing, China
Dr. Xunming Ji
Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, Chang Chun Road 45, Beijing 100053
Source of Support: None, Conflict of Interest: None
BACKGROUND: Limb remote ischemic conditioning (LRIC) and atorvastatin (AtS) both provide neuroprotection in stroke. We evaluated the enhanced neuroprotective effect of combining these two treatments in preventing ischemia/reperfusion (I/R)-induced cerebral injury in a rat model and investigated the corresponding molecular mechanisms.
MATERIALS AND METHODS: Transient cerebral ischemia was induced in Sprague–Dawley male rats by middle cerebral artery occlusion (MCAO) for 90 min followed by reperfusion (I/R). Rats were divided into 5 groups, sham, I/R, I/R + AtS, I/R + LRIC and I/R + AtS + LRIC. Pretreatment with LRIC and/or AtS for 14 days before MCAO surgery. Infarct volume, neurological score, Western blot, immuno-histochemical analyses were performed.
RESULTS: The combination of LRIC plus AtS pretreatment decreased infarct volume and inhibited neuronal apoptosis. Combination treatment achieved stronger neuroprotection than monotherapy with LRIC or AtS. These therapies reduced reactive oxygen species production in the peri-ischemia region, associated with significantly increased expression and activation of superoxide dismutase 1, hemeoxygenase 1 and nuclear factor erythroid 2-related factor 2.
CONCLUSIONS: Both LRIC and AtS + LRIC treatments conferred neuroprotection in ischemic stroke by reducing brain oxidative stress. AtS plus LRIC is an attractive translational research option due to its ease of use, tolerability, economical, and tremendous neuroprotective potential in stroke.