Journal
EXPERIMENTAL NEUROLOGY
Volume 236, Issue 2, Pages 228-239Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.expneurol.2012.05.006
Keywords
Delta-opioid receptor; Ionic homeostasis; Na+ influx; Na+ channel; Neuroprotection; Hypoxia/ischemia
Categories
Funding
- National Institutes of Health [HD-034852, AT-004422]
- Vivian L Smith Neurological Foundation
- Division of Intramural Research of NIEHS
- CSB [CS20092015]
- CHB [ZD200903]
- NSFC [31071046]
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Activation of delta-opioid receptors (DOR) is neuroprotective against hypoxic/ischemic injury in the cortex, which is at least partially related to its action against hypoxic/ischemic disruption of ionic homeostasis that triggers neuronal injury. Na+ influx through TTX-sensitive voltage-gated Na+ channels may be a main mechanism for hypoxia-induced disruption of K+ homeostasis, with DOR activation attenuating the disruption of ionic homeostasis by targeting voltage-gated Na+ channels. In the present study we examined the role of DOR in the regulation of Na+ influx in anoxia and simulated ischemia (oxygen-glucose deprivation) as well as the effect of DOR activation on the Na+ influx induced by a Na+ channel opener without anoxic/ischemic stress and explored a potential PKC mechanism underlying the DOR action. We directly measured extracellular Na+ activity in mouse cortical slices with Na+ selective electrodes and found that (1) anoxia-induced Na+ influx occurred mainly through TTX-sensitive Na+ channels; (2) DOR activation inhibited the anoxia/ischemia-induced Na+ influx; (3) veratridine, a Na+ channel opener, enhanced the anoxia-induced Na+ influx; this could be attenuated by DOR activation; (4) DOR activation did not reduce the anoxia-induced Na+ influx in the presence of chelerythrine, a broad-spectrum PKC blocker; and (5) DOR effects were blocked by PKC beta II peptide inhibitor, and PKC theta pseudosubstrate inhibitor, respectively. We conclude that DOR activation inhibits anoxia-induced Na+ influx through Na+ channels via PKC (especially PKC beta II and PKC theta isoforms) dependent mechanisms in the cortex. (C) 2012 Elsevier Inc. All rights reserved.
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