The current lack of effective treatments for acute stroke necessitates exploring innovative concepts that may eventually lead to clinical applications. One such technique is ischemic postconditioning. We have demonstrated that both rapid and delayed ischemic postconditioning reduces infarction in rats. Stroke was induced by a 30 min bCCA occlusion plus permanent distal middle cerebral artery (MCA) occlusion. The bCCA release allows partial reperfusion, which mimics the frequent clinical cases that occur in stroke patients. Rapid postconditioning is applied immediately after reperfusion while delayed postconditioning is conducted 5.5 h after reperfusion. Despite confirmation of the protective effects of postconditioning by several independent research groups, the underlying protective mechanisms are not understood. We have preliminary data showing that rapid postconditioning attenuates reactive oxygen species (ROS) activity, suggesting a correlation between postconditioning and ROS reduction. Whether ROS reduction truly contributes to postconditioning's protective effects is not known. In addition, ROS activity directly results in dysfunction of the neuronal survival signaling pathway, Akt/PRAS40 pathway, and Akt dysfunction leads to inflammation. However, the roles of the Akt/PRAS40 pathway and inflammation in the protective effects of ischemic postconditioning have not been well studied. In this grant, we will first identify subcellular sources of ROS activity that are involved in postconditioning's protective effects. We will then study the relationship between ROS reduction and Akt/PRAS40 activity in both rats and PRAS40 knockout mice, which has never been used in any studies. Finally, we will study how Akt/PRAS40 regulates the inflammatory response, including its effects on the pro-inflammatory factors HMGB1 and Cox-2, and the novel galectin-9/Tim-3 inflammatory pathway. Through these studies, we will fill significant gaps in our knowledge about the protective mechanisms and clinical translation of ischemic postconditioning.
Specific Aim 1. To identify the subcellular regulatory sources of ROS reduction that play critical roles in the protective effects of ischemic postconditioning.
Specific Aim 2. To study whether ROS inhibition improves the Akt/PRAS40 activity.
Specific Aim 3. To examine the protective effects of the Akt/PRAS40 pathway on the pro-inflammatory response of HMGB1 and Cox-2, and the galectin-9/Tim-3 inflammatory pathway.
Both rapid and delayed postconditioning after stroke reduce ischemic damage, opening up a new avenue for research in stroke treatment, which may eventually be clinically applicable for stroke patients.
|Xiong, Xiaoxing; Gu, Lijuan; Wang, Yan et al. (2016) Glycyrrhizin protects against focal cerebral ischemia via inhibition of T cell activity and HMGB1-mediated mechanisms. J Neuroinflammation 13:241|
|Vemuganti, Raghu; Zhao, Heng (2015) Mechanisms and therapies for acute CNS insults. Metab Brain Dis 30:353|
|Wei, Dingtai; Xiong, Xiaoxing; Zhao, Heng (2015) Tim-3 cell signaling and iNOS are involved in the protective effects of ischemic postconditioning against focal ischemia in rats. Metab Brain Dis 30:483-90|
|Xie, Rong; Wang, Peng; Cheng, Michelle et al. (2014) Mammalian target of rapamycin cell signaling pathway contributes to the protective effects of ischemic postconditioning against stroke. Stroke 45:2769-76|
|Gu, Li-Juan; Xiong, Xiao-Xing; Ito, Takashi et al. (2014) Moderate hypothermia inhibits brain inflammation and attenuates stroke-induced immunodepression in rats. CNS Neurosci Ther 20:67-75|
|Xiong, Xiaoxing; Xie, Rong; Zhang, Hongfei et al. (2014) PRAS40 plays a pivotal role in protecting against stroke by linking the Akt and mTOR pathways. Neurobiol Dis 66:43-52|
|Xie, Rong; Cheng, Michelle; Li, Mei et al. (2013) Akt isoforms differentially protect against stroke-induced neuronal injury by regulating mTOR activities. J Cereb Blood Flow Metab 33:1875-85|
|Xie, Rong; Wang, Peng; Ji, Xunming et al. (2013) Ischemic post-conditioning facilitates brain recovery after stroke by promoting Akt/mTOR activity in nude rats. J Neurochem 127:723-32|
|Xiong, Xiaoxing; Gu, Lijuan; Zhang, Hongfei et al. (2013) The protective effects of T cell deficiency against brain injury are ischemic model-dependent in rats. Neurochem Int 62:265-70|
|Zhao, Heng; Joo, Sungpil; Xie, Weiying et al. (2013) Using hormetic strategies to improve ischemic preconditioning and postconditioning against stroke. Int J Physiol Pathophysiol Pharmacol 5:61-72|
Showing the most recent 10 out of 23 publications