2. Academic Validation
  3. AVE 0991 attenuates oxidative stress and neuronal apoptosis via Mas/PKA/CREB/UCP-2 pathway after subarachnoid hemorrhage in rats

AVE 0991 attenuates oxidative stress and neuronal apoptosis via Mas/PKA/CREB/UCP-2 pathway after subarachnoid hemorrhage in rats

  • Redox Biol. 2019 Jan;20:75-86. doi: 10.1016/j.redox.2018.09.022.
Jun Mo 1,  Budbazar Enkhjargal 2,  Zachary D Travis 3,  Keren Zhou 4,  Pei Wu 2,  Guangyu Zhang 5,  Qiquan Zhu 2,  Tongyu Zhang 2,  Jianhua Peng 2,  Weilin Xu 4,  Umut Ocak 2,  Yili Chen 6,  Jiping Tang 2,  Jianmin Zhang 7,  John H Zhang 8
Affiliations

Affiliations

  • 1 Department of Neurosurgery, The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu 322000, Zhejiang, China; Department of Physiology and Pharmacology, Loma Linda University, Loma Linda, CA 92350, USA; Department of Neurosurgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang, China.
  • 2 Department of Physiology and Pharmacology, Loma Linda University, Loma Linda, CA 92350, USA.
  • 3 Department of Earth and Biological Sciences, Loma Linda University, Loma Linda, CA 92350, USA.
  • 4 Department of Physiology and Pharmacology, Loma Linda University, Loma Linda, CA 92350, USA; Department of Neurosurgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang, China.
  • 5 Mass Spectrometry Core Facility, Loma Linda University, Loma Linda, CA 92350, USA.
  • 6 Department of Neurosurgery, The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu 322000, Zhejiang, China.
  • 7 Department of Neurosurgery, The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu 322000, Zhejiang, China; Department of Neurosurgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang, China; Brain Research Institute, Zhejiang University, Hangzhou 310000, Zhejiang, China. Electronic address: zjm135@zju.edu.cn.
  • 8 Department of Physiology and Pharmacology, Loma Linda University, Loma Linda, CA 92350, USA; Department of Anesthesiology, Loma Linda University, Loma Linda, CA 92350, USA; Department of Neurosurgery, Loma Linda University, Loma Linda, CA 92350, USA. Electronic address: jhzhang@llu.edu.
PMID: 30296700 DOI: 10.1016/j.redox.2018.09.022
Abstract

Oxidative stress and neuronal Apoptosis have been demonstrated to be key features in early brain injury (EBI) after subarachnoid hemorrhage (SAH). Previous studies have indicated that Mas receptor activation initiates an anti-oxidative and anti-apoptotic role in the brain. However, whether Mas activation can attenuate oxidative stress and neuronal Apoptosis after SAH remains unknown. To investigate the beneficial effect of Mas on oxidative stress injury and neuronal Apoptosis induced by SAH, a total of 196 rats were subjected to an endovascular perforation model of SAH. AVE 0991 (AVE), a selective agonist of Mas, was administered intranasally 1 h after SAH induction. A779, a selective inhibitor of Mas, and small interfering ribonucleic acid (siRNA) for UCP-2 were administered by intracerebroventricular (i.c.v) injection at 1 h and 48 h before SAH induction respectively. Neurological tests, immunofluorescence, TUNEL, Fluoro-Jade C, DHE staining, and Western blot experiments were performed. We found that Mas activation with AVE significantly improved neurobehavioral scores and reduced oxidative stress and neuronal Apoptosis in SAH+AVE group compared with SAH+vehicle group. Moreover, AVE treatment significantly promoted phosphorylation of CREB and the expression UCP-2, as well as upregulated expression of Bcl-2 and downregulation of Romo-1 and Bax. The protective effects of AVE were reversed by i.c.v injection of A779 and UCP-2 siRNA in SAH+AVE+A779 and SAH+AVE+UCP-2 siRNA groups, respectively. In conclusion, our data provides evidence that Mas activation with AVE reduces oxidative stress injury and neuronal Apoptosis through Mas/PKA/p-CREB/UCP-2 pathway after SAH. Furthermore, our study indicates that Mas may be a novel therapeutic treatment target in early brain injury of SAH.

Keywords

AVE 0991; Mas; Neuronal apoptosis; Oxidative stress; Subarachnoid hemorrhage; UCP-2.

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