Abstract
Aim:
To evaluate the role of swelling-induced activation of volume-regulated anion channels (VRACs) in a neonatal hypoxic-ischemic injury model using the selective VRAC blocker 4-(2-butyl-6,7-dichloro-2-cyclopentyl-indan-1-on5-yl) oxobutyric acid (DCPIB).
Methods:
Cerebral hypoxic-ischemic injury was induced in 7-day-old mouse pups with Rice-Vannucci method. Prior to the onset of ischemia, the animals were ip administered DCPIB (10 mg/kg). The animals were sacrificed 24 h afterwards, coronal sections of the brains were cut and the areas of infarct were examined using TTC staining and an image-analysis system. Cultured PC12 cells were subjected to oxygen-glucose deprivation (OGD) for 4 h. The cellular viability was assessed using Cell Counting Kit 8. Intracellular chloride concentration [Cl−]i was measured using 6-methoxy-N-ethylquinolinium iodide.
Results:
DCPIB-treated mice showed a significant reduction in hemispheric corrected infarct volume (26.65%±2.23%) compared to that in vehicle-treated mice (45.52%±1.45%, P<0.001). DCPIB-treated mice also showed better functional recovery as they were more active than vehicle-treated mice at 4 and 24 h post injury. In cultured PC12 cells, DCPIB (10 μmol/L) significantly reduced OGD-induced cell death. Moreover, DCPIB (20 μmol/L) blocked hypotonic-induced decrease in [Cl−]i in PC12 cells of both control and OGD groups.
Conclusion:
The results further support the pathophysiological role of VRACs in ischemic brain injury, and suggest DCPIB as a potential, easily administrable agent targeting VRACs in the context of perinatal and neonatal hypoxic-ischemic brain injury.
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Acknowledgements
This work was supported by a Grant-in Aid from Heart and Stroke Foundation of Canada to Hong-shuo SUN, and by a General Program from National Natural Science Foundation of China (No 30873059) to Guan-lei WANG. Ammar ALIBRAHIM is a recipient of the Saudi Arabian Cultural Bureau Scholarship. Christine You-jin BAE is a recipient of Ontario Graduate Scholarship.
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Alibrahim, A., Zhao, Ly., Bae, Cj. et al. Neuroprotective effects of volume-regulated anion channel blocker DCPIB on neonatal hypoxic-ischemic injury. Acta Pharmacol Sin 34, 113–118 (2013). https://doi.org/10.1038/aps.2012.148
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DOI: https://doi.org/10.1038/aps.2012.148
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