Abstract
Dysfunction of energy metabolism exerts a central role in triggering neuron death following cerebral ischemia. Neuronal energy metabolism is highly dependent on glucose. O-GlcNAcylation, a post-translational modification, is a novel pro-survival pathway that modulates glucose homeostasis in ischemic stroke. Here, we explored whether activation O-GlcNAcylation and maintaining energy homeostasis mediated the neuroprotective effect of 2-(4-methoxyphenyl)ethyl-2-acetamido-2-deoxy-β-d-pyranoside, a synthetic salidroside analog (named SalA-4 g) which was previously developed in our laboratory. For in vivo analyses, SalA-4 g improved the outcome after transient middle cerebral artery occlusion (MCAO). 18F-FDG PET/MRI indicated that SalA-4 g accelerated the recovery of energy metabolism in the ipsilateral hippocampus in MCAO rats. In vitro analyses showed that glucose uptake was markedly increased, and O-GlcNAcylation was also activated by SalA-4 g in hippocampal neurons under both normal and oxygen glucose deprivation (OGD) conditions. Moreover, SalA-4 g exerted obvious neuroprotective effects in hippocampal neurons against moderate OGD injury. Our study indicates that boosting a pro-survival pathway—GlcNAcylation—and regulating energy homeostasis are important biochemical mechanisms responsible for SalA-4 g neuroprotection.
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Acknowledgements
This work was supported by the National Key Basic Research Program of China (973 Program, Grant No. 2014CB542203), National Natural Science Foundation of China (Grant No. 81401094), and the Undergraduate Innovation Training Programs of Nantong University (Grant No. 201810304104X), a Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD).
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Xu, H., Gu, H., Yang, Y. et al. 2-(4-Methoxyphenyl)Ethyl-2-Acetamido-2-Deoxy-β-d-Pyranoside Exerts a Neuroprotective Effect through Regulation of Energy Homeostasis and O-GlcNAcylation. J Mol Neurosci 69, 177–187 (2019). https://doi.org/10.1007/s12031-019-01347-3
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DOI: https://doi.org/10.1007/s12031-019-01347-3