2-(4-Methoxyphenyl)Ethyl-2-Acetamido-2-Deoxy-β-d-Pyranoside Exerts a Neuroprotective Effect through Regulation of Energy Homeostasis and O-GlcNAcylation

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). 18 F-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.