Abstract
Salidroside, extracted from the root of Rhodiola rosea L, is known for its pharmacological properties, in particular its neuroprotective effects. 2-(4-Methoxyphenyl) ethyl-2-acetamido-2-deoxy-β-D- pyranoside (GlcNAc-Sal), an analog of salidroside, was recently synthesized and shown to possess neuroprotective properties. The purpose of the current study was to investigate the neuroprotective effects of GlcNAc-Sal against oxygen–glucose deprivation-reperfusion (OGD-R)-induced neurotoxicity in vitro and global cerebral ischemia-reperfusion (GCI-R) injury in vivo. Cell viability tests and Hoechst 33342 staining confirmed that GlcNAc-Sal pretreatment markedly attenuated OGD-R induced apoptotic cell death in immortalized mouse hippocampal HT22 cells. Western blot, immunofluorescence and PCR analyses revealed that GlcNAc-Sal pretreatment restored the balance of pro- and anti-apoptotic proteins and inhibited the activation of caspase-3 and PARP induced by OGD-R treatment. Further analyses showed that GlcNAc-Sal pretreatment antagonized reactive oxygen species (ROS) generation, iNOS-derived NO production and NO-related apoptotic cell death during OGD-R stimulation. GCI-R was induced by bilateral common carotid artery occlusion (BCCAO) and reperfusion in mice in vivo. Western blot analysis showed that GlcNAc-Sal pretreatment decreased the expression of caspase-3 and increased the expression of Bcl-2 (B-cell lymphoma 2)/Bax (Bcl-2-associated X protein) induced by GCI-R treatment. Our findings suggest that GlcNAc-Sal pretreatment prevents brain ischemia reperfusion injury by the direct or indirect suppression of cell apoptosis and GlcNAc-Sal could be developed as a broad-spectrum agent for the prevention and/or treatment of cerebral ischemic injury.
Highlights
Cerebral ischemic injury is one of the leading causes of death and disability
The viability of HT22 cells exposed to OGD insult was assessed using the MTT assay, which showed that the cell death caused by OGD occurred in a time-dependent manner (Fig. 2A)
oxygen-glucose deprivation followed by reperfusion (OGD-R) insult decreased the viability of HT22 neurons by 65.1063.59%, and treatment with GlcNAc-Sal at low concentrations (e.g. 100 mM) had no neuroprotective effect (Fig. 2C)
Summary
Cerebral ischemic injury is one of the leading causes of death and disability. Ischemic stroke, which results in insufficient supply of glucose and oxygen to brain tissues, causes significant damage to cells associated with oxidative stress, the regulation of proapoptotic and anti-apoptotic factors, and dysfunction of neuronal signaling pathways [1,2,3,4]. The hippocampus is responsible for many central nervous system functions including cognition, learning, and memory, but it is one of the most vulnerable brain regions as regards to various neurological insults such as hypoxia–ischemia, seizure and prolonged stress [14]. Based on these considerations, hippocampus is widely used to explore the neuroprotective effects of pharmacological compounds to brain ischemic induced by OGD-R in vitro or GCI-R in vivo
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