Prolonged oxygen deprivation is a common clinical condition and may render victims vulnerable to a variety of neurological disorders. However, there is little known about membrane properties, especially neuronal excitability in prolonged hypoxia during development. Previous work from this laboratory has suggested that chronic hypoxia causes cortical dysfunction, rendering immature neurons more excitable and susceptible to subsequent stress than naive neurons via Na+ channel dysregulation. Recent studies further suggest that cortical delta-opioid receptors (DOR) play a protective role in neuronal response to hypoxic stress. DOR activation protects cortical neurons from neuroexcitotoxicity and hypoxic insults via differential regulation of MAP kinase subtypes. Chronic hypoxia decreases DOR expression in the cortex, while DOR up-expression potentiates ionic homeostasis in the cortex under hypoxia. The general hypothesis of this project is that hypoxic impairment of DOR expression may contribute to cortical dysfunction via Na+ channel dysregulation, while electro-acupuncture induced upregulation of the DOR system is a therapeutic strategy against hypoxic injury and dysfunction in the cortex. Using electrophysiological, transgenic and molecular approaches, this project will accomplish three specific aims: 1) to determine if DOR up-expression protects from hypoxic dysregulation of cortical excitability;2) to determine if DOR protection is dependent on alterations in Na+ channel expression and/or function;and 3) to determine if electro-acupuncture induces DOR expression and alleviates the hypoxic dysfunction via MAP kinases. The outcome of this proposal will improve the understanding of neuronal dysfunction resulting from hypoxic stress and provide clues to develop novel and alternative solutions for hypoxic/ischemic insults to the brain.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD034852-12
Application #
7776887
Study Section
Brain Injury and Neurovascular Pathologies Study Section (BINP)
Program Officer
Vitkovic, Ljubisa
Project Start
1997-09-01
Project End
2010-05-06
Budget Start
2010-03-01
Budget End
2010-05-06
Support Year
12
Fiscal Year
2010
Total Cost
$87,622
Indirect Cost
Name
Yale University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
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
Jiang, B; Shen, R F; Bi, J et al. (2015) Catalpol: a potential therapeutic for neurodegenerative diseases. Curr Med Chem 22:1278-91
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
Cao, Shan; Chao, Dongman; Zhou, Honghao et al. (2015) A novel mechanism for cytoprotection against hypoxic injury: ?-opioid receptor-mediated increase in Nrf2 translocation. Br J Pharmacol 172:1869-81
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
Fenoy, Albert J; Goetz, Laurent; Chabard├Ęs, St├ęphan et al. (2014) Deep brain stimulation: are astrocytes a key driver behind the scene? CNS Neurosci Ther 20:191-201
Wang, Qinyu; Chao, Dongman; Chen, Tao et al. (2014) ?-Opioid receptors and inflammatory cytokines in hypoxia: differential regulation between glial and neuron-like cells. Transl Stroke Res 5:476-83
Chen, Tao; Li, Jessica; Chao, Dongman et al. (2014) ?-Opioid receptor activation reduces ?-synuclein overexpression and oligomer formation induced by MPP(+) and/or hypoxia. Exp Neurol 255:127-36
Liang, Jianfeng; Chao, Dongman; Sandhu, Harleen K et al. (2014) ?-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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