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Abstract
BackgroundActivated microglial cells release an excess of inflammatory mediators after an ischemic stroke. We reported previously that scutellarin effectively suppressed the inflammatory response induced by activated microglia in rats subjected to middle cerebral artery occlusion (MCAO); however, the mechanism via which scutellarin exerts its effects on microglial activation has not been explored. This study aimed to elucidate if scutellarin can regulate the Notch pathway that is linked to microglia activation in MCAO rat, and in lipopolysaccharide (LPS)-induced BV-2 microglia. Along with this, we also investigated some characteristic behavioral responses of activated microglia.MethodsExpression of various members of the Notch pathway, including Notch-1, intracellular Notch receptor domain (NICD), recombining binding protein suppressor of hairless (RBP-JK) and transcription factor hairy and enhancer of split-1 (Hes-1) in activated microglia was assessed by immunofluorescence staining and western blot after experimental MCAO and in vitro LPS activation. The effect of scutellarin on migration of microglia was determined by the transwell chamber assay as well as expression of monocyte chemoattractant protein-1 (MCP-1). The morphological change of microglia induced by scutellarin was detected by F-actin staining and electron microscopy.ResultsScutellarin markedly attenuated the expression of NF-κB, Notch-1, NICD, RBP-JK and Hes-1 both in vivo and in activated microglia. It decreased the expression of MCP-1 and microglial migration, but increased the ability of microglia adhesion. Scutellarin also altered the phenotype of microglia by causing rearrangement or reorganization of its cytoskeleton.ConclusionsThe results suggest that scutellarin regulates the activation of microglia via the Notch pathway and concurrently induces morphological and functional changes in activated microglia.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-014-0226-z) contains supplementary material, which is available to authorized users.
Highlights
Stroke is a cerebrovascular neuropathology that causes severe neurological deficits leading to long-term disability [1]
In light of the above, we aimed to investigate if scutellarin is able to affect the functions of activated microglia via regulation of the Notch pathway, through the use of the experimental middle cerebral artery occlusion (MCAO) model of ischemic stroke and in vitro LPS activation of BV-2 microglial cells
NFκB immunofluorescence in activated microglia in the penumbral zones was noticeably enhanced after MCAO, but it was reduced at 7 days following treatment with scutellarin
Summary
Stroke is a cerebrovascular neuropathology that causes severe neurological deficits leading to long-term disability [1]. In the event of a stroke, microglia, which are the innate immune cells of the central nervous system (CNS), are activated [4]. These activated microglia migrate to the infarct area to perform phagocytotic clearance of cellular debris [5], offering neuroprotection following ischemia. Activation of microglia following ischemia has been shown to occur over a period of several months after the initial attack [7]. This therapeutic window may be utilized to moderate microglial activation. We investigated some characteristic behavioral responses of activated microglia
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