Resveratrol protects against spinal cord injury by activating autophagy and inhibiting apoptosis mediated by the SIRT1/AMPK signaling pathway.

Spinal cord injury (SCI) is a devastating condition with few effective treatments. Resveratrol, a polyphenolic compound, has exhibited neuroprotective effects in many neurodegenerative diseases. However, the explicit effect and mechanism of resveratrol on SCI is still unclear. Adenosine 5' monophosphate-activated protein kinase (AMPK) and Sirtuin 1 (SIRT1), the downstream protein, play key roles in metabolizing of energy, resisting of resistance, and cellular protein homeostasis. In this study, we determined the effects of resveratrol on SCI and their potential relationship with SIRT1/AMPK signaling pathway, autophagy and apoptosis. To determine the effect of resveratrol on SCI recovery, a spinal cord contusion model was employed. Rats received treatment with resveratrol or DMSO immediately following contusion. We determined that Basso, Beattie, and Bresnahan (BBB) scores were significantly higher for injured rats treated with resveratrol. Nissl and HE staining revealed that resveratrol treatment significantly reduced the loss of motor neurons and lesion size in the spinal cord of injured rats when compared to vehicle-treated animals. Spinal cord tissue was assessed by Western blot, reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemical analyses 7days after injury for changes in expression of SIRT1/AMPK signaling pathway, autophagy and apoptosis proteins. Expression of SIRT1, p-AMPK, Beclin-1, LC3-B, and Bcl-2 was elevated in resveratrol-treated animals, whereas expression of p62, Cleaved Caspase-3, Caspase-9, and Bcl-2 associated X protein (Bax) was inhibited. Immunofluorescence analysis of primary neurons treated with resveratrol alone or in combination with Compound C (AMPK inhibitor) or EX527 (SIRT1 inhibitor) revealed that treatment with the inhibitors blocks the increased LC3-B expression in cells and increases the portion of TUNEL-positive cells. Taken together, these results suggest that resveratrol exerts neuroprotective effects on SCI by regulating autophagy and apoptosis mediated by the SIRT1-AMPK signaling pathway.

Zhao H ，Chen S ，Gao K ，Zhou Z ，Wang C ，Shen Z ，Guo Y ，Li Z ，Wan Z ，Liu C ，Mei X ... -  《-》

Neuroprotection of melatonin on spinal cord injury by activating autophagy and inhibiting apoptosis via SIRT1/AMPK signaling pathway.

Gao K ，Niu J ，Dang X 《-》

Resveratrol improves neurological outcome and neuroinflammation following spinal cord injury through enhancing autophagy involving the AMPK/mTOR pathway.

Meng HY ，Shao DC ，Li H ，Huang XD ，Yang G ，Xu B ，Niu HY ... -  《-》

Probucol inhibits neural cell apoptosis via inhibition of mTOR signaling pathway after spinal cord injury.

Autophagy plays an essential role in neurodevelopment, axonal guidance, neuropathic pain remission, and neuronal survival. Inhibiting the mammalian target of rapamycin (mTOR) signaling pathway can induce the occurrence of autophagy. In this study, we initially detected the effect of probucol on autophagy after spinal cord injury (SCI) by intraperitoneally injecting spinal cord-injured rats with probucol for 7days. The levels of Beclin1 and LC3B were evidently enhanced at 7days post-operation. However, the increase in the phosphorylated AMP-activated protein kinase (AMPK) protein and the decrease in ribosomal protein S6 kinase p70 subtype (p70S6K) phosphorylation level simultaneously occurred after SCI. Moreover, the expression levels of apoptosis-related proteins of Caspase-3, Caspase-9, and Bax were significantly reduced. Immunofluorescence results indicated that the expression of Caspase-3 protein was evidently decreased and that of Beclin-1 protein was increased by probucol. Nissl staining and Basso, Beattie, and Bresnahan scores showed that the quantity and function of motor neurons were visibly preserved by probucol after SCI. This study showed that probucol inhibited the mTOR signaling pathway to induce autophagy, reduce neural cell apoptosis and promote recovery of neurological function after SCI.

Zhou Z ，Chen S ，Zhao H ，Wang C ，Gao K ，Guo Y ，Shen Z ，Wang Y ，Wang H ，Mei X ... -  《-》

Neuroprotective Effects of Oxymatrine via Triggering Autophagy and Inhibiting Apoptosis Following Spinal Cord Injury in Rats.

Spinal cord injury (SCI) is a devastating neurological disorder characterized by high morbidity and disability. However, there is still a lack of effective treatments for it. The identification of drugs that promote autophagy and inhibit apoptosis in neurons is critical for improving patient outcomes following SCI. Previous studies have shown that increasing the activity of silent information regulator 1 (SIRT1) and downstream protein AMP-activated protein kinase (AMPK) in rat models of SCI is highly neuroprotective. Oxymatrine (OMT), a quinolizidine alkaloid, has exhibited neuroprotective effects in various central nervous system (CNS) diseases. However, its explicit effect and molecular mechanism in SCI are still unclear. Herein, we aimed to investigate the therapeutic effects of OMT and explore the potential role of autophagy regulation following SCI in rats. A modified compressive device (weight 35 g, time 5 min) was applied to induce moderate SCI in all groups except the sham group. After treatment with drugs or vehicle (saline), our results indicated that OMT treatment significantly reduced the lesion size, promoted survival of motor neurons, and subsequently attenuated motor dysfunction following SCI in rats. OMT significantly enhanced autophagy activity, inhibited apoptosis in neurons, and increased SIRT1 and p-AMPK expression levels. Interestingly, these effects of OMT on SCI were partially prevented by co-treatment with SIRT1 inhibitor EX527. Furthermore, combining OMT with the potent autophagy inhibitor chloroquine (CQ) could effectively abolish its promotion of autophagic flux. Taken together, these data revealed that OMT exerts a neuroprotective role in functional recovery against SCI in rats, and these effects are potentially associated with OMT-induced activation of autophagy via the SIRT1/AMPK signaling pathway.

Li J ，Cao Y ，Li LN ，Chu X ，Wang YS ，Cai JJ ，Zhao J ，Ma S ，Li G ，Fan ZK ... -  《-》