Inflammatory responses play a critical role in ischemic brain injury. induces the expression of inflammatory cytokines, and acetylbritannilactone (ABL) exerts potent antiinflammatory actions by inhibiting expression of inflammation-related genes. However, the functions of miR-155 and the actual relationship between ABL and miR-155 in ischemia-induced cerebral inflammation remain unclear. In this study, cerebral ischemia of wild-type (WT) and miR-155 -/-mice was induced by permanent middle cerebral artery occlusion (MCAO). pAd-miR-155 was injected into the lateral cerebral ventricle 24 h before MCAO to induce miR-155 overexpression. MCAO mice and oxygen-glucose deprivation (OGD)-treated BV2 cells were used to examine the effects of ABL and miR-155 overexpression or deletion on the expression of proinflammatory cytokines. We demonstrated that ABL treatment significantly reduced neurological deficits and cerebral infarct volume by inhibiting tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) expression in ischemic cerebral tissue and OGD-treated BV2 cells. Mechanistic studies suggested that the observed decrease in TNF-α and IL-1β expression was attributable to the ABL-induced suppression of the expression of nuclear factorkappa B (NF-κB) and Toll-like receptor 4 (TLR4). We further found that miR-155 promoted TNF-α and IL-1β expression by upregulating TLR4 and downregulating the expression of suppressor of cytokine signaling 1 (SOCS1) and myeloid differentiation primary response gene 88 (MyD88), while ABL exerted an inhibitory effect on miR-155-mediated gene expression. In conclusion, miR-155 mediates inflammatory responses in ischemic cerebral tissue by modulating TLR4/MyD88 and SOCS1 expression, and ABL exerts its antiinflammatory action by suppressing miR-155 expression, suggesting a novel miR-155-based therapy for ischemic stroke. scription factors at the transcriptional level but also by microRNAs (miRNAs, miRs) at the posttranscriptional level. Emerging evidence suggest that miRNAs are involved in regulating several aspects of inflammation (10,11) and the response to cerebral ischemia (12). Among various miRNAs, miR-155 is an inflammation-related miRNA. Its expression is induced in inflammatory macrophages (11,13), as well as in the ischemic cerebral cortex by middle cerebral artery occlusion (MCAO) surgery (14) and, in turn, it enhances proinflammatory cytokine expression in macrophages by regulating the NF-κB signaling pathway (11,15). In addition, miR-155 can exert both pro-and antiinflammatory effects by targeting different mediators of inflammatory signaling, such as SHIP1, SOCS1, SMAD2 and TAB2 (16,17). Given the importance of miR-155 in the development of postischemic brain inflammation, understanding the role of miR-155 and the mechanism of miR-155 actions in ischemic cerebral injury will provide novel insights into ischemic stroke therapy. Pharmacological alleviation of inflammatory response is one of the most promising avenues for stroke therapy. Acetylbritannilactone (ABL) is a new antiin...

BACKGROUND AND PURPOSERecent findings suggest the importance of inflammation in the pathogenesis of cerebral ischaemia and its potential as a therapeutic target. Cinnamaldehyde is a diterpene with a wide range of anti-inflammatory effects thus may be advantageous in the treatment of cerebral ischaemia. The present study examined the potential therapeutic effects of cinnamaldehyde on cerebral ischaemia using a mouse model with permanent middle cerebral artery occlusion. EXPERIMENTAL APPROACHMale CD-1 mice, which had the middle cerebral artery occluded, were treated (i.p.) with cinnamaldehyde. Neuroprotection by cinnamaldehyde was analysed by evaluating neurological deficit scores, brain oedema and infarct volume. Expressionsof signal transduction molecules and inflammatory mediators were measured by Western blotting, qRT-PCR and immunohistochemical staining. Activation of NF-κB was assessed by Western blotting, immunohistochemistry and immunofluorescence. KEY RESULTSCinnamaldehyde reduced the neurological deficit scores, brain oedema and infarct volume. Cinnamaldehyde suppressed the activation of signal transduction molecules including toll-like receptor 4, tumour necrosis receptor-associated factor 6 and NF-κB, attenuated the increased levels of TNF-α, IL-1β, CCL2 and endothelial-leukocyte adhesion molecule-1 and ultimately reduced leukocyte infiltration into the ischaemic brain areas after cerebral ischaemia. CONCLUSIONS AND IMPLICATIONSCinnamaldehyde protects against cerebral ischaemia injury by inhibiting inflammation, partly mediated by reducing the expression of toll-like receptor 4, tumour necrosis receptor-associated factor 6 and the nuclear translocation of NF-κB. Our findings suggest that cinnamaldehyde may serve as a new candidate for further development as a treatment for stroke. AbbreviationsBBB, blood brain barrier; ELAM-1, endothelial leukocyte adhesion molecule-1; IHC, immunohistochemical staining; IRAK, IL-1 receptor-associated kinase; MAPKs, mitogen-activated protein kinases; MPO, myeloperoxidase; pMCAO, permanent middle cerebral artery occlusion; qRT-PCR, quantitative real-time polymerase chain reaction; rCBF, relative regional cerebral blood flow; TRAF6, tumour necrosis factor receptor-associated factor 6; TTC, 2,3,5-triphenyltetrazolium chloride BJP British Journal of Pharmacology

Background/Aims: Estradiol (EST) reduces the risk of stroke and decreases the incidence and progression of the disease because of its neuroprotective roles in inhibiting cell death that occurs in response to a variety of neuronal stimuli such as inflammation and oxidative stress. In this study, we determined the role played by autophagy and Nrf2-ARE signal pathways in the hippocampus regions in modulating cerebral ischemia under different EST conditions. Methods: Western blot analysis and ELISA were used to determine the protein expression of autophagy and Nrf2-ARE pathways; and the levels of pro-inflammatory cytokines (PICs) and a key marker of oxidative stress. Results: Lacking of EST amplifies autophagy and attenuates Nrf2-ARE pathway in the hippocampus CA1 region. Blocking autophagy alleviates neurological deficits following cerebral ischemia with lacking of EST levels and the effects of autophagy are associated with PIC and oxidative stress. Conclusions: EST influences the protein expression of autophagy and Nrf2-ARE signaling in the brain, which is linked to the pathophysiological processes of PICs and oxidative stress. Moreover, inhibition of autophagy plays a beneficial role in modulating neurological deficits after cerebral ischemia observed under conditions of a lower level of EST.

Post-stroke angiogenesis facilitates neurovascular remodeling process and promotes neurological recovery. Proangiogenic effects of Salvianolic acids (Sals) have been reported in various ischemic disorders. However, the underlying mechanisms are still poorly understood. Previous studies of our laboratory have demonstrated that activating Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) signaling pathway is involved in the protection against cerebral ischemia/reperfusion injury. In this study, we investigated the impacts of Sals on angiogenesis and long-term neurological recovery after ischemic stroke as well as the potential mechanisms. Male mice subjected to permanent distal middle cerebral artery occlusion were administrated with Sals, 5-bromo-2'-deoxyuridine, and JAK2 inhibitor AG490 once daily from day 1 to day 14 after distal middle cerebral artery occlusion. Compared with the control group, Sals treatment significantly improved neurological recovery at day 14 and 28 after ischemic stroke. Sals enhanced post-stroke angiogenesis, pericytes and astrocytic endfeet covered ratio in the peri-infarct area. The JAK2/STAT3 signaling pathway was activated by Sals in the angiogenesis process, and inhibition of JAK2/STAT3 signaling blocked the effects of Sals on post-stroke angiogenesis and neurological recovery as well as abolished the mediation of proangiogenic factors. In summary, these data suggest that Sals administration enhances cerebral angiogenesis and promotes neurological recovery after ischemic stroke, mediated by the activation of JAK2/STAT3 signaling pathway.