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.
|Wang, Peng; Xie, Rong; Cheng, Michelle et al. (2018) The mTOR cell signaling pathway is crucial to the long-term protective effects of ischemic postconditioning against stroke. Neurosci Lett 676:58-65|
|Yang, Jian; Liu, Cuiying; Du, Xiangnan et al. (2018) Hypoxia Inducible Factor 1? Plays a Key Role in Remote Ischemic Preconditioning Against Stroke by Modulating Inflammatory Responses in Rats. J Am Heart Assoc 7:|
|Xie, Rong; Li, Jinquan; Zhao, Heng (2018) The underlying mechanisms involved in the protective effects of ischemic postconditioning. Cond Med 1:73-79|
|Liu, Cuiying; Yang, Jian; Zhang, Chencheng et al. (2018) Analysis of long non-coding RNA expression profiles following focal cerebral ischemia in mice. Neurosci Lett 665:123-129|
|Zhou, Xin; Jiao, Zinan; Ji, Juling et al. (2017) Characterization of mouse serum exosomal small RNA content: The origins and their roles in modulating inflammatory response. Oncotarget 8:42712-42727|
|Liu, Cuiying; Zhang, Chencheng; Yang, Jian et al. (2017) Screening circular RNA expression patterns following focal cerebral ischemia in mice. Oncotarget 8:86535-86547|
|Li, Sijie; Hafeez, Adam; Noorulla, Fatima et al. (2017) Preconditioning in neuroprotection: From hypoxia to ischemia. Prog Neurobiol 157:79-91|
|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|
|Ji, Qiuhong; Ji, Yuhua; Peng, Jingwen et al. (2016) Increased Brain-Specific MiR-9 and MiR-124 in the Serum Exosomes of Acute Ischemic Stroke Patients. PLoS One 11:e0163645|
|Fan, Yifang; Xiong, Xiaoxing; Zhang, Yongming et al. (2016) MKEY, a Peptide Inhibitor of CXCL4-CCL5 Heterodimer Formation, Protects Against Stroke in Mice. J Am Heart Assoc 5:|
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