Probucol inhibits neural cell apoptosis via inhibition of mTOR signaling pathway after spinal cord injury
Graphical abstract
Introduction
Spinal cord injury (SCI) is widely recognized as a worldwide medical problem (Wyndaele and Wyndaele, 2006). The related secondary injuries including inflammation, oxidative stress, apoptosis, and autophagy significantly affect SCI prognosis (Hayashi et al., 2000, Dery et al., 2009). The difficulties in SCI treatment can be attributed to autophagy and apoptosis, which perform major roles in physical and functional deficits (Blight, 2002, Rabchevsky et al., 2011). Standard treatment options for SCI have not been established; thus, an effective treatment is urgently needed (Courtine et al., 2011). In recent studies, neural cell autophagy performed a significant part in SCI. The increase in autophagy level can reduce nerve cell apoptosis and promote neural functional recovery after SCI (Komatsu et al., 2006, Chen et al., 2008, Ching et al., 2014). In addition, a lot of studies have demonstrated the important functions of mammalian target of rapamycin (mTOR) signaling pathway to regulate the level of autophagy (Kanno et al., 2012). Under lack of energy or stress, the mTOR signaling pathway is suppressed mainly through the mechanism of AMP-activated protein kinase (AMPK) activation (Inoki et al., 2012). In the research of Lin et al. (2014), mTOR activation in Merkel cell carcinoma was found to inhibit autophagy, whereas mTOR inhibition can induce autophagy. Wu et al. (2013) also found that the induction of autophagy simultaneously increases AMPK phosphorylation level, accompanied by phosphorylation of reducing S6 kinase p70 subtype (p70S6K). The findings suggest that ethanol extracts induce autophagy and the AMPK/mTOR pathway, further proving that the signal through mTOR pathway induces autophagy.
Probucol is a lipid-lowering drug with a variety of effects such as anti-inflammatory and anti-oxidation, used to lower cholesterol and prevent coronary atherosclerotic and heart disease in clinical. (Yamashita et al., 2008, Yamashita and Matsuzawa, 2009). Recently, an increasing number of studies have reported that probucol performs a protective function in neurotoxicity and neurodegeneration models, such as Alzheimer’s disease and Huntington’s disease (Santos et al., 2012, Ribeiro et al., 2013). However, Falk et al. (2011) found that probucol has significantly more effective and sustained beneficial effects in mitochondrial respiratory chain disease, in addition to activating PPAR signaling pathways. And then based on this study, Peng et al. showed probucol also inhibits mTORC1 to induced autophagy (Peng et al., 2015). It can directly inhibit mTORC1-regulated downstream activities. But few reports have elucidated the effect of probucol on autophagy level after SCI through the mTOR signaling pathway.
In this research, we used a rat model of SCI to investigate the possible neuroprotective mechanism of SCI treatment by probucol. The results of our research may supply a new molecular basis by which probucol exerts its therapeutic action in SCI treatment and may have potential clinical application value in the future.
Section snippets
Animals and probucol treatment
Adult male Sprague–Dawley rats (weight range 180–220 g) were bought from the Laboratory Animal Center of Jinzhou Medical University. All experimental procedures were approved by the Animal Care and Use Committee of Jinzhou Medical University. All rats were fed under a specific-pathogen-free laboratory at 22 ± 1 °C with a normal circadian cycle and the right amount of water and food was added. After adaptation to the new environment, the rats were divided into the following three groups with the
Probucol improves motor functional recovery after SCI
Evaluation of functional motor recovery was done after SCI by using BBB scores at 0, 1, 3, 7, 14, 21, and 28 days. The chart shows the change based on the score trend (Fig. 1). We found that, starting from the 7th day after SCI, the score of the probucol group presented an ascending trend, so that strongly significant differences exist between the scores of vehicle group (P < 0.01). The results indicate that probucol could strongly induce motor function recovery after SCI. In addition, on the 14th
Discussion
Owing to its lipid regulating and anti-lipid peroxidation activity, probucol has been widely used clinically for the treatment of hypercholesterolemia, protection in vascular smooth muscle cells, improvement of blood vessel function, regulation of local lipid metabolism, prevention of restenosis, and/or improvement of coronary bypass effectiveness (Yamashita et al., 2008, Yamashita and Matsuzawa, 2009). Recent studies have shown that anti-lipid peroxidation effect of probucol can promote
Conclusion
Probucol induces autophagy by inhibiting the mTOR signaling pathway and inhibiting neural cell apoptosis after SCI. However, effects of probucol on nerve cells after SCI in a variety of integrated functions and molecular mechanisms need further investigation.
Acknowledgments
This work was supported by the National Natural Science Foundation of China (NSFC) (no. 81471854). The authors thank the other researchers for their valuable technical assistance in this work.
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