Abstract
The current study tested the potential neuroprotective function of Tanshinone IIA (ThIIA) in neuronal cells with oxygen-glucose deprivation (ODG) and re-oxygenation (OGDR). In SH-SY5Y neuronal cells and primary murine cortical neurons, ThIIA pre-treatment attenuated OGDR-induced viability reduction and apoptosis. Further, OGDR-induced mitochondrial depolarization, reactive oxygen species production, lipid peroxidation and DNA damages in neuronal cells were significantly attenuated by ThIIA. ThIIA activated AMP-activated protein kinase (AMPK) signaling, which was essential for neuroprotection against OGDR. AMPKα1 knockdown or complete knockout in SH-SY5Y cells abolished ThIIA-induced AMPK activation and neuroprotection against OGDR. Further studies found that ThIIA up-regulated microRNA-135b to downregulate the AMPK phosphatase Ppm1e. Notably, knockdown of Ppm1e by targeted shRNA or forced microRNA-135b expression also activated AMPK and protected SH-SY5Y cells from OGDR. Together, AMPK activation by ThIIA protects neuronal cells from OGDR. microRNA-135b-mediated silence of Ppm1e could be the key mechanism of AMPK activation by ThIIA.
Highlights
Ischemia-reperfusion shall cause damages to neurons [1, 2]
Www.impactjournals.com/oncotarget cells exposure to oxygen glucose deprivation (OGD) and re-oxygenation (ODGR) resulted in significant cell viability (“MTT optic density, OD) reduction [3], which was largely inhibited by pre-treatment of Tanshinone IIA (ThIIA) (Figure 1A)
OGDR-induced SH-SY5Y cell death was reflected by the increase of lactate dehydrogenase (LDH) release to the medium (Figure 1B)
Summary
Ischemia-reperfusion shall cause damages to neurons [1, 2]. Oxygen-glucose deprivation (ODG) and re-oxygenation (OGDR) was applied to mimic the ischemia-reperfusion injuries [3,4,5,6]. Maintaining the physiological energy level in the neurons is vital for key cerebral behaviors. AMP-activated protein kinase (AMPK) is a key energy sensor [9,10,11,12]. Existing literatures have indicated that physiological AMPK participates in brain development, neuronal polarization and other neuronal activities [9,10,11,12]. Deregulation of AMPK signaling could be involved in the development of neurodegenerative diseases [9,10,11,12]
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