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

Abstract

Resveratrol, a natural phenolic compound, provides neuroprotective effects, however, the specific mechanisms of action remain to be elucidated. The purpose of the present study was to examine the neuroprotective effect of resveratrol on spinal cord injury (SCI) and the potential molecular mechanisms of action. A rat model of SCI was induced using Allen's method, and resveratrol (100 mg/kg) was intraperitoneally injected 1 day following surgery. The recovery of neurological function was assessed using the Basso, Beattie, Bresnahan scoring system and an inclined plane test. The concentrations of pro‑ and anti‑inflammatory factors were measured using ELISA. The expression and location of autophagy markers were measured using western blot and immunofluorescence analyses. The results suggested that resveratrol administration resulted in functional improvement of locomotor activity and reduced neuroinflammation following the induction of SCI. In addition, autophagy was activated following SCI, as demonstrated by the significantly increased ratio of microtubule‑associated protein light chain 3 (LC3)‑II/LC3‑I and expression of Beclin‑1 in the injured spinal cord. Of note, the enhancement of phosphorylated (p)‑AMP‑activated protein kinase (AMPK) and the reduction of p‑mammalian target of rapamycin (mTOR) following SCI indicated that the SCI‑induced activation of autophagy was associated with the AMPK/mTOR signaling pathway. Resveratrol treatment further enhanced the activation of autophagy via the AMPK/mTOR pathway following SCI. By contrast, the autophagic inhibitor, 3‑methyladenine, partially inhibited the neuroprotective effects of resveratrol treatment. Together, these findings suggested that resveratrol promoted functional recovery and inhibited neuroinflammation through the activation of autophagy mediated by the AMPK/mTOR pathway following SCI.

Health benefits of resveratrol: Evidence from clinical studies

“…Similarly, restoring autophagic flux by resveratrol may be a promising approach in the prevention of cellular senescence and amelioration of insulin resistance . Resveratrol was found to exhibit neuroprotective effects by activating AMPK/mTOR‐mediated autophagy in a rat model of spinal cord injury . In clinical trials, resveratrol has been shown to modulate autophagy‐related pathways such as AMPK and SIRT1 …”

“…217 Resveratrol was found to exhibit neuroprotective effects by activating AMPK/mTOR-mediated autophagy in a rat model of spinal cord injury. 218 In clinical trials, resveratrol has been shown to modulate autophagy-related pathways such as AMPK and SIRT1. 204 Resveratrol may find utility to lower the toxicity of chemotherapeutic drugs.…”

Crosstalks between inflammasome and autophagy in cancer

“…Resveratrol can induce apoptosis and inhibit angiogenesis, thereby suppressing tumor growth and metastasis [105]. Importantly, resveratrol induced autophagy in various in vitro and in vivo disease models, by activating AMPK [106][107][108][109]. However, the mechanisms underlying the autophagy-and inflammasome-modulating effects of resveratrol in the context of cancer remain unclear.…”

Treatment With 2-BFI Attenuated Spinal Cord Injury by Inhibiting Oxidative Stress and Neuronal Apoptosis via the Nrf2 Signaling Pathway

“…Although the pathophysiology of SCI has been continuously investigated, the precise pathogenesis has not yet been fully elucidated. Several studies revealed the pathophysiology of injury, including neuronal inflammation, reactive changes in the glia, oxidative stress, neuronal degeneration and apoptosis (Chen et al, 2018;Lu et al, 2018;Meng et al, 2018). Disturbances in the spinal cord blood flow (SCBF), severely reduced oxygen levels, perfusion defects, hemorrhage, ischemia, and hypoxia have been demonstrated as a focus of post-injury pathophysiological changes of acute SCI (Huo et al, 2019).…”