Abstract
The neuroprotective role of schizandrin (SA) in cerebral ischemia-reperfusion (I/R) was recently highlighted. However, whether SA plays a regulatory role on autophagy in cerebral I/R injury is still unclear. This study aimed to explore whether the neuroprotective mechanisms of SA were linked to its regulation of AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR)/autophagy pathway in vivo and in vitro. The present study confirmed that SA significantly improved oxygen-glucose deprivation/re-oxygenation (OGD/R)-induced PC12 cells injury. The results of immunoblotting and confocal microscope showed that SA decreased autophagy in OGD/R-injured PC12 cells, which was reflected by the decreased Beclin-1 and LC3-II expression, autophagy flux level, and LC3 puncta formation. In addition, the autophagy inducer rapamycin partially prevented the effects of SA on cell viability and autophagy after OGD/R, whereas the autophagy inhibitor 3-methyladenine (3-MA) exerted the opposite effect. The results of Western blotting showed that SA markedly decreased the phosphorylation of AMPK (p-AMPK), whereas the phosphor-mTOR (p-mTOR) levels increased in the presence of OGD/R insult. Furthermore, pretreatment with the AMPK inducer AICAR partially reversed the protective effects and autophagy inhibition of SA. However, AMPK inhibitor Compound C pretreatment further promoted the inhibition of SA on autophagy induction and cell damage induced by OGD/R. Taken together, these findings demonstrate that SA protects against OGD/R insult by inhibiting autophagy through the regulation of the AMPK-mTOR pathway and that SA may have therapeutic value for protecting neurons from cerebral ischemia.
Highlights
Ischemic stroke, known as cerebrovascular accident, is characterized by an insufficient oxygen supply and restoration of blood flow [1]
An OGD/R model was utilized with differentiated PC12 cells to further investigate the neuroprotective effects of SA in vitro
We investigated whether SA could Pathway regulateinautophagy affectingin the pathway in PC12 cells
Summary
Known as cerebrovascular accident, is characterized by an insufficient oxygen supply and restoration of blood flow [1]. Stroke has a significant global impact; currently, the only Food and Drug Administration (FDA)-approved pharmacotherapy for acute stroke includes intravenous thrombolytic treatment with a recombinant tissue plasminogen activator (rtPA). This strategy has a short therapeutic window and Molecules 2019, 24, 3624; doi:10.3390/molecules24193624 www.mdpi.com/journal/molecules. Cutting-edge research for novel targets and drugs to manage stroke is strongly needed. Autophagy is an evolutionarily conserved process for the bulk degradation and recycling of cytosolic proteins and organelles [5]. As a degradation/recirculation system, autophagy is believed to play an important role in pathological conditions in many organs, including cerebral ischemia [6,7]
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