2-(4-Methoxyphenyl)Ethyl-2-Acetamido-2-Deoxy-β-d-Pyranoside Exerts a Neuroprotective Effect through Regulation of Energy Homeostasis and O-GlcNAcylation
- 23 Downloads
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.
Keywords2-(4-Methoxyphenyl)ethyl-2-acetamido-2-deoxy-β-d-pyranoside Neuroprotection Energy homeostasis O-GlcNAcylation Ischemic stroke
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).
Compliance with Ethical Standards
Conflict of Interest
The authors declare that they have no conflict of interest.
- Dawson TM, Dawson VL (2017) Mitochondrial mechanisms of neuronal cell death: potential therapeutics. Annu Rev Pharmacol Toxicol 57:437–454. https://doi.org/10.1146/annurev-pharmtox-010716-105001 CrossRefGoogle Scholar
- Jiang M, Yu S, Yu Z, Sheng H, Li Y, Liu S, Warner DS, Paschen W, Yang W (2017) XBP1 (X-box-binding Protein-1)-dependent O-GlcNAcylation is neuroprotective in ischemic stroke in young mice and its impairment in aged mice is rescued by Thiamet-G. Stroke 48:1646–1654. https://doi.org/10.1161/STROKEAHA.117.016579 CrossRefGoogle Scholar
- Liu J, Pang Y, Chang T, Bounelis P, Chatham JC, Marchase RB (2006) Increased hexosamine biosynthesis and protein O-GlcNAc levels associated with myocardial protection against calcium paradox and ischemia. J Mol Cell Cardiol 40:303–312. https://doi.org/10.1016/j.yjmcc.2005.11.003 CrossRefGoogle Scholar
- Taninishi H, Pearlstein M, Sheng H, Izutsu M, Chaparro RE, Goldstein LB, Warner DS (2016) Video training and certification program improves reliability of postischemic neurologic deficit measurement in the rat. J Cereb Blood Flow Metab 36:2203–2210. https://doi.org/10.1177/0271678X15616980 CrossRefGoogle Scholar
- Yu S, Cheng Q, Li L, Liu M, Yang Y, Ding F (2014a) 2-(4-Methoxyphenyl)ethyl-2-acetamido-2-deoxy-beta-d-pyranoside confers neuroprotection in cell and animal models of ischemic stroke through calpain1/PKA/CREB-mediated induction of neuronal glucose transporter 3. Toxicol Appl Pharmacol 277:259–269. https://doi.org/10.1016/j.taap.2014.03.025 CrossRefGoogle Scholar
- Yu S, Wang C, Cheng Q, Xu H, Zhang S, Li L, Zhang Q, Gu X, Ding F (2014b) An active component of Achyranthes bidentata polypeptides provides neuroprotection through inhibition of mitochondrial-dependent apoptotic pathway in cultured neurons and in animal models of cerebral ischemia. PLoS One 9:e109923. https://doi.org/10.1371/journal.pone.0109923 CrossRefGoogle Scholar
- Yu S, Wei L, Chi X, Xu H, Ding F (2018a) 2-(4-Methoxyphenyl)ethyl-2-acetamido-2-deoxy-beta-D-pyranoside, an analog of salidroside, contributes to neuroprotection in cerebral ischemic injury in vitro and in vivo. Neuroreport 29:426–431. https://doi.org/10.1097/WNR.0000000000000987 CrossRefGoogle Scholar
- Yu S, Xu H, Chi X, Wei L, Cheng Q, Yang Y, Zhou C, Ding F (2018b) 2-(4-Methoxyphenyl)ethyl-2-Acetamido-2-deoxy-beta-d-pyranoside (a Salidroside analog) confers neuroprotection with a wide therapeutic window by regulating local glucose metabolism in a rat model of cerebral ischemic injury. Neuroscience 391:60–72. https://doi.org/10.1016/j.neuroscience.2018.09.006 CrossRefGoogle Scholar
- Zuo X, Hou Q, Jin J, Chen X, Zhan L, Tang Y, Shi Z, Sun W, Xu E (2018) Inhibition of Cathepsins B induces neuroprotection against secondary degeneration in ipsilateral substantia Nigra after focal cortical infarction in adult male rats. Front Aging Neurosci 10:125. https://doi.org/10.3389/fnagi.2018.00125 CrossRefGoogle Scholar