Ischemic brain injury such as stroke is a leading cause of neurological disability and death in the States. There is, however, no effective strategy to protect the brain from ischemic injury. Recently, we have made exciting observations on effect of electro-acupuncture (EA) on cerebral ischemia. The most striking finding is that EA remarkably reduces brain infarction due to the occlusion of middle cerebral artery, which is dependent on the EA-triggered cellular/molecular events in the brain. Since our studies and those of others have shown that 1) activation of delta-opioid receptor (DOR) attenuates hypoxic/ischemic disruption of ionic homeostasis that triggers neuronal apoptosis and death;2) DOR up-regulation enhances intracellular survival signals;3) opioid receptor activation inhibits inflammatory responses, e.g., production of inflammatory cytokines that plays a critical role in ischemic injury;and 4) DOR inhibition largely attenuates the EA-induced protection against ischemic injury, it is likely that the EA-induced protection represents the outcome of cellular and molecular regulation at multiple levels in the brain. Specifically, it may depend on DOR up-regulation and the DOR-mediated stabilization of ionic homeostasis and modulation of survival/death signals. The general hypothesis of this proposal is that EA protects against cerebral ischemia mainly through DOR up-regulation and the DOR-mediated modulation of cellular and molecular signaling in neurons.. With molecular, transgenic and electrophysiological approaches, this proposal is designed to accomplish 3 specific aims: 1) to investigate if EA protects the brain from cerebral ischemia via DOR up-regulation;2) to investigate if the EA protection is mediated by DOR-based stabilization of ionic homeostasis;and 3) to investigate if the EA protection relies on DOR-mediated inhibition of inflammatory responses to ischemia. The outcome data of this project may yield important information on the mechanism underlying the EA-induced protection from cerebral ischemia and may provide novel clues for therapeutic solutions of stroke.

Public Health Relevance

Stroke is a leading cause of neurological disability and death in the United States. However, there is no effective therapy to date to protect the brain from stroke-induced brain injury. To seek novel approaches to prevent/treat stroke, we have recently made exciting observations on the effect of electro- acupuncture (EA) on stroke-induced injury. The most striking and surprising finding is that EA, through little needles without any other treatment, remarkably reduces stroke-induced brain injury via the regulation of delta-opioid receptor (a cell membrane protein). Also, functional studies showed that EA promotes the recovery of brain function after stroke. Our finding thus suggests important therapeutic potential for EA in stroke. In this application, we propose to use modern techniques including molecular, transgenic and electrophysiological approaches to test three specific hypotheses for exploring mechanisms underlying the EA protection against stroke. Our preliminary studies have shown that this proposal is feasible and will very likely yield important information on the EA-induced protection and eventually shed light on new therapeutic modalities of stroke.

Agency
National Institute of Health (NIH)
Institute
National Center for Complementary & Alternative Medicine (NCCAM)
Type
Research Project (R01)
Project #
5R01AT004422-06
Application #
8462913
Study Section
Clinical Neuroscience and Disease Study Section (CND)
Program Officer
Huntley, Kristen V
Project Start
2009-02-01
Project End
2015-01-31
Budget Start
2013-02-01
Budget End
2015-01-31
Support Year
6
Fiscal Year
2013
Total Cost
$356,511
Indirect Cost
$118,837
Name
University of Texas Health Science Center Houston
Department
Neurosurgery
Type
Schools of Medicine
DUNS #
800771594
City
Houston
State
TX
Country
United States
Zip Code
77225
Chao, Dongman; Wang, Qinyu; Balboni, Gianfranco et al. (2016) Attenuating Ischemic Disruption of K(+) Homeostasis in the Cortex of Hypoxic-Ischemic Neonatal Rats: DOR Activation vs. Acupuncture Treatment. Mol Neurobiol 53:7213-7227
Cao, Shan; Chao, Dongman; Zhou, Honghao et al. (2015) A novel mechanism for cytoprotection against hypoxic injury: δ-opioid receptor-mediated increase in Nrf2 translocation. Br J Pharmacol 172:1869-81
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Shi, Jian; Luo, Fengbao; Shi, Qianqian et al. (2015) Increased circulating follicular helper T cells with decreased programmed death-1 in chronic renal allograft rejection. BMC Nephrol 16:182
Xu, Yunqi; Wei, Xiaobo; Liu, Xu et al. (2015) Low Cerebral Glucose Metabolism: A Potential Predictor for the Severity of Vascular Parkinsonism and Parkinson's Disease. Aging Dis 6:426-36
Yang, Yilin; Sandhu, Harleen K; Zhi, Feng et al. (2015) Effects of hypoxia and ischemia on microRNAs in the brain. Curr Med Chem 22:1292-301
Wang, Qinyu; Chao, Dongman; Chen, Tao et al. (2014) δ-Opioid receptors and inflammatory cytokines in hypoxia: differential regulation between glial and neuron-like cells. Transl Stroke Res 5:476-83
Fenoy, Albert J; Goetz, Laurent; Chabardès, Stéphan et al. (2014) Deep brain stimulation: are astrocytes a key driver behind the scene? CNS Neurosci Ther 20:191-201
Liang, Jianfeng; Chao, Dongman; Sandhu, Harleen K et al. (2014) δ-Opioid receptors up-regulate excitatory amino acid transporters in mouse astrocytes. Br J Pharmacol 171:5417-30
Chen, Fan; Qi, Zhifeng; Luo, Yuming et al. (2014) Non-pharmaceutical therapies for stroke: mechanisms and clinical implications. Prog Neurobiol 115:246-69

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