srt2104 and Inflammation

Strategies for neuroprotection are the main targets of glaucoma research. The neuroprotective properties of SRT2104 administration have been proven in central nervous system degeneration diseases through the activation of nicotinamide adenine dinucleotide-dependent deacetylase-silence information regulator 1 (Sirt1). Here, we investigated whether SRT2104 could protect the retina from ischemia/reperfusion (I/R) injury and the underlying mechanisms.. SRT2104 was intravitreally injected immediately after I/R induction. RNA and protein expression were detected by quantitative real-time PCR and Western blot. Protein expression and distribution were examined by immunofluorescence staining. Retinal structure and function were analyzed by hematoxylin and eosin staining, optical coherence tomography, and electroretinogram. Optic nerve axons were quantified using toluidine blue staining. Cellular apoptosis and senescence were evaluated by TUNEL assay and SA-β-gal staining.. The protein expression of Sirt1 decreased dramatically after I/R injury and SRT2104 administration effectively enhanced the stability of Sirt1 protein without significantly influencing Sirt1 mRNA synthesis. SRT2104 administration alone exerted no influence on the structure and function of normal retinas. However, SRT2104 intervention significantly protected the inner retinal structure and neurons; partially restored retinal function after I/R injury. I/R-induced cellular apoptosis and senescence were effectively alleviated by SRT2104 administration. Additionally, SRT2104 intervention markedly reduced neuroinflammation, including reactive gliosis, retinal vascular inflammation, and the overexpression of pro-inflammatory cytokines after I/R injury. Mechanistically, I/R-induced acetylation of p53, NF-κB p65, and STAT3 was significantly reversed by SRT2104 intervention.. We demonstrated that SRT2104 exerted potent protective effects against I/R injury by enhancing Sirt1-mediated deacetylation and suppressing apoptosis, senescence, and neuroinflammation-related pathways.

Topics: Animals; Apoptosis; Inflammation; Ischemia; Mice; Neuroinflammatory Diseases; Neuroprotection; Reperfusion Injury; Sirtuin 1

Cerebral ischemic/reperfusion injury is the most common neurological disorder and the second leading cause of death worldwide. Modulating microglia polarization from pro-inflammatory M1 phenotype to anti-inflammatory M2 state has been suggested as a potential therapeutic approach in the treatment of this injury. SRT2104, a novel activator of histone deacetylase Sirtuin-1 (Sirt1), has recently been shown to have anti-inflammation properties. However, the effect of SRT2104 on cerebral ischemic/reperfusion injury has not been elucidated. Here, we found that SRT2104 inhibited neuron and microglia death directly and indirectly through microglia condition medium from an oxygen glucose deprivation/reoxygenation (OGD/R) -induced cell injury models. Moreover, SRT2104 treatment modulated the microglia polarization shift from the M1 phenotype and skewed toward the M2 phenotype. Additionally, we found that SRT2104 could significant inhibit the activation of NF-κB and enhanced Sirt1 expression in microglia. Mechanism studies using the BV2 microglial cell line confirmed that knockdown Sirt1 significantly reduced the effect of SRT2104 on the activation of NF-κB pathway and microglial phenotype shift. Altogether, our result shows SRT2104 protect OGD/R-induced injury through shifting microglia phenotype, which may have potential in further studies as a novel neuroprotective agent for cerebral ischemic/reperfusion injury therapy.

Topics: Animals; Anti-Inflammatory Agents; Glucose; Heterocyclic Compounds, 2-Ring; Inflammation; Mice, Inbred C57BL; Microglia; Neuroprotective Agents; NF-kappa B; Oxygen; Signal Transduction; Sirtuin 1

Although activated microglia-induced neuroinflammation link to the physiopathology of major depressive disorder, the homeostasis of switchable M1/M2 microglia in treating depression are unclear. Recent accumulating evidences suggest that Sirtuin 1 (SIRT1), an NAD+-dependent deacetylase, plays a key role in mood regulation, yet its role in the polarization of microglia acting on depressive behaviors remains unknown. Here, we intended to investigate whether activation of SIRT1 in hippocampus has antidepressant potential in relation to microglial phenotypic switch. Chronic unpredictable mild stress (CUMS) treatment was performed on C57BL/6 mice, followed by injecting with SRT2104, a selective SIRT1 agonists. We found that activation of SIRT1 in hippocampus ameliorate CUMS-induced depressive-like behaviors, as indicated by sucrose preference test, tail suspension test and forced swim test. Moreover, activation of SIRT1 abrogated the increased expression of M1 markers (IL-6, IL-1β and iNOS,) and decreased expression of M2 markers (IL-10, TGF-β and Arignase1) induced by CUMS. Notably, activation of SIRT1 shifted microglia polarization toward the M2 phenotype in CUMS-induced depressive-like behaviors of mice. In addition, SRT2104 treatment ameliorated CUMS-induced SIRT1 decreased expression in the hippocampus coincides with the up-regulation phosphorylation levels of GSK3β and PTEN. Taken together, these findings indicated that activation of SIRT1 ameliorate CUMS-induced depressive-like behaviors via shifting microglial polarization toward the M2 phenotype, thereby providing a novel and beneficial therapeutic approach for depression that may be translatable to depression patients in the future.

Topics: Animals; Behavior, Animal; Cytokines; Depression; Disease Models, Animal; Heterocyclic Compounds, 2-Ring; Hippocampus; Inflammation; Male; Mice; Mice, Inbred C57BL; Microglia; Sirtuin 1; Stress, Psychological