Abstract
Although naloxone has been documented to exert neuroprotection in animal model of cerebral ischemia, the mechanism is not well understood. In this present study we investigated whether naloxone affected the mitochondrial apoptotic pathway in ischemic brain injury of rats. SD rats were subjected to a permanent middle cerebral artery occlusion surgery, and received naloxone (0.5, 1, 2 mg/kg, i.v.) immediately after ischemia. Neurological deficits were evaluated 24 h after ischemia using the McGraw Stroke Index, and then the rats were killed, and the brains were collected for further analyses. We show that naloxone treatment dose-dependently decreased the infarction volume and morphological injury, improved motor behavioral function, and markedly curtailed brain edema. Furthermore, naloxone administration significantly inhibited the nuclear translocation of NF-κB p65 and decreased the levels of nuclear NF-κB p65 in the ischemic penumbra. Naloxone administration also dose-dependently increased the NF-κB inhibitory protein (IκBα) levels and attenuated phosphorylated NIK and IKKα levels in the ischemic penumbra. In addition, naloxone administration dose-dependently increased Bcl-2 levels, decreased Bax levels, stabilized the mitochondrial transmembrane potential, and inhibited cytochrome c release and caspase 3 and caspase 9 activation. These results indicate that the neuroprotective effects of naloxone against ischemic brain injury involve the inhibition of NF-κB activation via the suppression of the NIK/IKKα/IκBα pathway and the obstruction of the mitochondrial apoptotic pathway in neurons.
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Acknowledgements
This work was supported by the Research Program of the Committee of Science and Technology of Putuo District, Shanghai (PKW15102), National Natural Science Foundation of China Grants (81272603; 81472179), the Shanghai Shenkang Program (SHDC22014008) and the Three-year Planning for Strengthening the Construction of the Public Health System in Shanghai (2015-2017) (15GWZK0301).
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DL and C-mJ designed the study and edited the manuscript; XW contributed to the analysis, interpretation, manuscript writing, and final approval of the manuscript; Z-jS, J-lW and W-qQ performed the research; W-dX and HC contributed new reagents, analytic tools, and manuscript writing; All authors read and approved the final manuscript.
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Wang, X., Sun, Zj., Wu, Jl. et al. Naloxone attenuates ischemic brain injury in rats through suppressing the NIK/IKKα/NF-κB and neuronal apoptotic pathways. Acta Pharmacol Sin 40, 170–179 (2019). https://doi.org/10.1038/s41401-018-0053-3
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DOI: https://doi.org/10.1038/s41401-018-0053-3
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