Abstract
BackgroundFollowing stroke, microglia can be driven to the “classically activated” pro-inflammatory (M1) phenotype and the “alternatively activated” anti-inflammatory (M2) phenotype. Salidroside (SLDS) is known to inhibit inflammation and to possess protective effects in neurological diseases, but to date, the exact mechanisms involved in these processes after stroke have yet to be elucidated. The purpose of this study was to determine the effects of SLDS on neuroprotection and microglial polarization after stroke.MethodsMale adult C57/BL6 mice were subjected to focal transient cerebral ischemia followed by intravenous SLDS injection. The optimal dose was determined by evaluation of cerebral infarct volume and neurological functions. RT-PCR and immunostaining were performed to assess microglial polarization. A transwell system and a direct-contact coculture system were used to elucidate the effects of SLDS-induced microglial polarization on oligodendrocyte differentiation and neuronal survival.ResultsSLDS significantly reduced cerebral infarction and improved neurological function after cerebral ischemia. SLDS treatment reduced the expression of M1 microglia/macrophage markers and increased the expression of M2 microglia/macrophage markers after stroke and induced primary microglia from M1 phenotype to M2 phenotype. Furthermore, SLDS treatment enhanced microglial phagocytosis and suppressed microglial-derived inflammatory cytokine release. Cocultures of oligodendrocytes and SLDS-treated M1 microglia resulted in increased oligodendrocyte differentiation. Moreover, SLDS protected neurons against oxygen glucose deprivation by promoting microglial M2 polarization.ConclusionsThese data demonstrate that SLDS protects against cerebral ischemia by modulating microglial polarization. An understanding of the mechanisms involved in SLDS-mediated microglial polarization may lead to new therapeutic opportunities after stroke.
Highlights
Following stroke, microglia can be driven to the “classically activated” pro-inflammatory (M1) phenotype and the “alternatively activated” anti-inflammatory (M2) phenotype
Infarct volume was significantly attenuated at 72 h after cerebral ischemia with SLDS treatment at incremental doses of 2.5, 5, 10, and 20 mg/kg, respectively (P < 0.05, P < 0.05, P < 0.01, and P < 0.01, respectively; Fig. 1d, e)
Maximal beneficial effects were observed at a dose of 10 mg/kg and as such, this dose was used in all subsequent experiments to explore the role of SLDS in microglial polarization after middle cerebral artery occlusion (MCAO)
Summary
Microglia can be driven to the “classically activated” pro-inflammatory (M1) phenotype and the “alternatively activated” anti-inflammatory (M2) phenotype. Salidroside (SLDS) is known to inhibit inflammation and to possess protective effects in neurological diseases, but to date, the exact mechanisms involved in these processes after stroke have yet to be elucidated. Microglia are primarily found in the resting state (M0), but are activated into two phenotypes, the “classically activated”. M1 and the “alternative activated” M2 phenotypes, following an imbalance to normal physiological conditions [2, 3]. M2 microglia produce anti-inflammatory cytokines, such as IL-10 and TGFβ, and are induced by IL-4 and/or IL-13 [2]. Recent evidence suggests that a shift from the M1 phenotype to the M2 phenotype is beneficial for recovery after stroke, and may provide novel therapeutic approaches to aide stroke victims [2, 3]
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