An Agonist of the Protective Factor SIRT1 Improves Functional Recovery and Promotes Neuronal Survival by Attenuating Inflammation after Spinal Cord Injury

Abstract

Targeting posttraumatic inflammation is crucial for improving locomotor function. SIRT1 has been shown to play a critical role in disease processes such as hepatic inflammation, rheumatoid arthritis, and acute lung inflammation by regulating inflammation. However, the role of SIRT1 in spinal cord injury (SCI) is unknown. We hypothesized that SIRT1 plays an important role in improving locomotor function after SCI by regulating neuroinflammation. In this study, we investigate the effect of SIRT1 in SCI using pharmacological intervention (SRT1720) and the Mx1-Cre/loxP recombination system to knock out target genes. First, we found that SIRT1 expression at the injured lesion site of wild-type (WT) mice (C57BL/6) decreased 4 h after SCI and lasted for 3 d. Moreover, administration of SRT1720, an agonist of SIRT1, to WT mice significantly improved functional recovery for up to 28 d after injury by reducing the levels of proinflammatory cytokines, the number of M1 macrophages, the number of macrophages/microglia, and the accumulation of perivascular macrophages. In contrast, administration of SRT1720 to SIRT1 knock-out (KO) mice did not improve locomotor recovery or attenuate inflammation. Furthermore, SIRT1 KO mice exhibited worse locomotor recovery, increased levels of inflammatory cytokines, and more M1 macrophages and perivascular macrophages than those of WT mice after SCI. Together, these findings indicate that SRT1720, an SIRT1 agonist, can improve functional recovery by attenuating inflammation after SCI. Therefore, SIRT1 is not only a protective factor but also an anti-inflammatory molecule that exerts beneficial effects on locomotor function after SCI.

Resveratrol decreases CD45+CD206− subtype macrophages in LPS‐induced murine acute lung injury by SOCS3 signalling pathway

“…It is documented that SIRT1 is critically involved in variable cell biological function . Loss of SIRT1 in SIRT1 knock‐out mice delayed locomotor recovery, in association with more expression of pro‐inflammatory cytokines and population of M1 type macrophages in a mouse model with spinal cord injury . Consistent with the previous report, we observed that Res up‐regulated the expression of SIRT1, whereas LPS moderately reduced the expression of SIRT1 in BMDMs.…”

“…[22][23][24] Loss of SIRT1 in SIRT1 knock-out mice delayed locomotor recovery, in association with more expression of pro-inflammatory cytokines and population of M1 type macrophages in a mouse model with spinal cord injury. 25 Consistent with the previous report, 22 we observed that Res up-regulated the expression of SIRT1, whereas LPS moderately reduced the expression of SIRT1 in BMDMs. The results were consistent with previously reports, in which there was lower SIRT1 expression in the inflammatory lungs of animal models with LPS-induced ALI and pulmonary contusion.…”

MicroRNA-92a-3p enhances functional recovery and suppresses apoptosis after spinal cord injury via targeting phosphatase and tensin homolog

“…SCI is a neurological disease that is commonly caused by traumatic events on the spinal cords [2,3]. Based on previous results derived from studies using animal models of SCI, the pathogenesis of SCI can be divided into the primary mechanical injury, and secondary damage that are characterized by various pathophysiologic mechanisms including oxidative stress [4], mitochondrial dysfunction [5] and inflammation [6]. The prognosis of SCI is significantly poor and could lead to permanent movement disorders and cognition impairment or even paralysis [7].…”

The Role of Metabolic Remodeling in Macrophage Polarization and Its Effect on Skeletal Muscle Regeneration

“…Resveratrol promotes M1-to-M2 plasticity and M1 cell death in murine and human MF by a mechanism involving Arg1 activation (53,177,250,292); however, it has controversially been reported that resveratrol inhibits TAM M2 polarization observed in vivo in mice (323). Synthetic SIRT1-activating compounds have been developed: They have a greater potency compared with resveratrol; among them, SRT1720 has an anti-inflammatory effect that acts by reducing the number of M1 in mice (44,48). The SIRT3 activator Honokiol inhibits iNOS expression, NF-jB and TNFa secretion in LPS-stimulated murine MF (39).…”