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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS064136-04
Application #
8474850
Study Section
Brain Injury and Neurovascular Pathologies Study Section (BINP)
Program Officer
Bosetti, Francesca
Project Start
2010-09-01
Project End
2015-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
4
Fiscal Year
2013
Total Cost
$327,696
Indirect Cost
$120,824
Name
Stanford University
Department
Neurosurgery
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
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
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; 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
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
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
Gu, Lijuan; Xiong, Xiaoxing; Wei, Dingtai et al. (2013) T cells contribute to stroke-induced lymphopenia in rats. PLoS One 8:e59602
Zhao, Heng (2013) Hurdles to clear before clinical translation of ischemic postconditioning against stroke. Transl Stroke Res 4:63-70
Joo, S P; Xie, W; Xiong, X et al. (2013) Ischemic postconditioning protects against focal cerebral ischemia by inhibiting brain inflammation while attenuating peripheral lymphopenia in mice. Neuroscience 243:149-57

Showing the most recent 10 out of 14 publications