Abstract
Activation of swelling-induced Cl− current (ICl,swell) during neonatal hypoxia-ischemia (HI) may induce brain damage. Hypoxic-ischemic brain injury causes chronic neurological morbidity in neonates as well as acute mortality. In this study, we investigated the role of ICl,swell in hypoxic-ischemic brain injury using a selective blocker, 4-(2-butyl-6,7-dichloro-2-cyclopentylindan-1-on-5-yl) oxybutyric acid (DCPIB). In primary cultured cortical neurons perfusion of a 30% hypotonic solution activated ICl,swell, which was completely blocked by the application of DCPIB (10 μmol/L). The role of ICl,swell in neonatal hypoxic-ischemic brain injury in vivo was evaluated in a modified neonatal hypoxic-ischemic brain injury model. Before receiving the ischemic insult, the mouse pups were injected with DCPIB (10 mg/kg, ip). We found that pretreatment with DCPIB significantly reduced the brain damage assessed using TTC staining, Nissl staining and whole brain imaging, and improved the sensorimotor and vestibular recovery outcomes evaluated in neurobehavioural tests (i.e. geotaxis reflex, and cliff avoidance reflex). These results show that DCPIB has neuroprotective effects on neonatal hypoxic-ischemic brain injury, and that the ICl,swell may serve as a therapeutic target for treatment of hypoxic-ischemic encephalopathy.
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Acknowledgements
This work was supported by the following grants: Natural Sciences and Engineering Research Council of Canada (NSERC) Discovery Grants to Hong-shuo SUN (RGPIN-2016-04574); a Canadian Institutes of Health Research (CIHR) China-Canada Joint Health Research Initiative (CIHR, FRN #132571) to Hong-shuo SUN; Natural Sciences and Engineering Research Council of Canada (NSERC) Discovery Grants to Zhong-ping FENG (RGPIN-2014-06471) and to Hong-shuo SUN (RGPIN-2016-04574); the NSFC-CIHR Joint Health Research Initiative Proposal (No 81361128011) to Guan-lei WANG; a NSERC Postgraduate Scholarship-Doctoral to Raymond WANG.
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Wong, R., Abussaud, A., Leung, J. et al. Blockade of the swelling-induced chloride current attenuates the mouse neonatal hypoxic-ischemic brain injury in vivo. Acta Pharmacol Sin 39, 858–865 (2018). https://doi.org/10.1038/aps.2018.1
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