Abstract
Lyciumamide A (LyA), a dimer of phenolic amide isolated from the fruits of Lycium barbarum, has been confirmed to possess potent antioxidant activity. This study was aimed to investigate the neuroprotection and molecular mechanisms of LyA against cerebral ischemia/reperfusion (I/R) injury via improving antioxidant activity. The model of middle cerebral artery occlusion (MCAO) and SH-SY5Y cells induced by oxygen and glucose deprivation (OGD) were adopted to verify the neuroprotective effects and the potential pharmacology mechanisms of LyA in vivo and in vitro. In MCAO model, treatment with LyA significantly improved neurologic score, reduced infarct volume, and relieved oxidative stress injury at 48 h after reperfusion. Meanwhile, LyA markedly increased the transcription Nrf2 and HO-1 expressions in the ischemic cerebral cortex. In vitro results showed that LyA protected differentiated SH-SY5Y cells against OGD-induced injury. LyA significantly decreased the expression of caspase-3 and the Bax/Bcl-2 ratio. But knockdown of Nrf2 or HO-1 attenuated the protective effect of LyA. Similarly, knockdown of protein kinase Cε (PKCε) inhibited LyA-induced Nrf2/HO-1 activation, and abated its protective effects. In conclusion, this study firstly demonstrated that LyA protects against cerebral I/R injury, ameliorates oxidative damage and neuronal apoptosis, partly via activation of PKCε/Nrf2/HO-1 pathway.
Highlights
Stroke is the second leading cause of death in the world and is a major cause of adult disability [1]
Our results showed that Lyciumamide A (LyA) decreased reactive oxygen species (ROS), malondialdehyde (MDA) production, and increased superoxide dismutase (SOD) and glutathione peroxidase (GPx) activity by inhibiting oxidative stress
These results showed that pretreatment with LyA (10, 20, 40 μΜ) before treatment with oxygen and glucose deprivation (OGD) could distinctly reduce the percentage of apoptotic cells in a concentration-dependent manner
Summary
Stroke is the second leading cause of death in the world and is a major cause of adult disability [1]. After stroke, during the cerebral ischemia/reperfusion injury (I/R), excessive levels of reactive oxygen species (ROS) can due to an imbalance between oxidants and antioxidants leading to oxidative stress and play a vital role [2, 3]. It has been reported that heme oxygenase-1 (HO1) has the most antioxidant-responsive elements (AREs) on its promoter, making it a highly effective therapeutic target for preventing brain damage after ischemic stroke [8,9,10]. It has been shown that the activation of PKC mediates the stimulation of Nrf in response to oxidative stress [12]. These findings have motivated us to explore natural Chinese herbal compounds with potential antioxidant effects to prevent cerebral ischemic stroke
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