title: 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.SIGNIFICANCE STATEMENTPosttraumatic inflammation plays a central role in regulating the pathogenesis of spinal cord injury (SCI). Here, new data show that administration of SRT1720, an SIRT1 agonist, to wild-type (WT) mice significantly improved outcomes after SCI, most likely by reducing the levels of inflammatory cytokines, the number of macrophages/microglia, perivascular macrophages, and M1 macrophages. In contrast, SIRT1 KO mice exhibited worse locomotor recovery than that of WT mice due to aggravated inflammation. Taken together, the results of this study expand upon the previous understanding of the functions and mechanisms of SIRT1 in neuroinflammation following injury to the CNS, suggesting that SIRT1 plays a critical role in regulating neuroinflammation following CNS injury and may be a novel therapeutic target for post-SCI intervention.
authors.affiliation: Departments of Orthopedics and.
authors.forename: Haihong
authors.identifier: 0000-0002-7584-0229
authors.initials: H
authors.lastname: Chen
authors.affiliation: Departments of Orthopedics and.
authors.forename: Hao
authors.identifier: 0000-0002-8755-3593
authors.initials: H
authors.lastname: Ji
authors.affiliation: Transplantation, Shanghai Jiao Tong University School of Medicine, Renji Hospital, Shanghai 200127, People's Republic of China.
authors.forename: Ming
authors.identifier: 0000-0002-6293-0700
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Departments of Orthopedics and.
authors.forename: Zude
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Departments of Orthopedics and.
authors.forename: Lifeng
authors.identifier: 0000-0001-6516-854X
authors.initials: L
authors.lastname: Lao
authors.affiliation: Departments of Orthopedics and.
authors.forename: Chao
authors.initials: C
authors.lastname: Deng
authors.affiliation: Departments of Orthopedics and.
authors.forename: Jianwei
authors.initials: J
authors.lastname: Chen
authors.affiliation: Departments of Orthopedics and zhonggb@foxmail.com.
authors.forename: Guibin
authors.identifier: 0000-0003-4990-3465
authors.initials: G
authors.lastname: Zhong
mesh_terms: D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D006576:Heterocyclic Compounds, 4 or More Rings / Q000008:administration & dosage*; D008124:Locomotion / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009187:Myelitis / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D018696:Neuroprotective Agents / Q000008:administration & dosage; D020127:Recovery of Function / Q000187:drug effects; D056564:Sirtuin 1 / Q000187:drug effects / Q000378:metabolism*; D013119:Spinal Cord Injuries / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology
chemical_list: D006576:Heterocyclic Compounds, 4 or More Rings; D018696:Neuroprotective Agents; C525422:SRT1720; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1
keywords: Mx1-cre; SIRT1; SRT1720; inflammatory cytokines; macrophage/microglia; spinal cord injury