Abstract
Toll-like receptor 4 (TLR4) has been proven to play a critical role in neuroinflammation and to represent an important therapeutic target following subarachnoid hemorrhage (SAH). Resveratrol (RSV), a natural occurring polyphenolic compound, has a powerful anti-inflammatory property. However, the underlying molecular mechanisms of RSV in protecting against early brain injury (EBI) after SAH remain obscure. The purpose of this study was to investigate the effects of RSV on the TLR4-related inflammatory signaling pathway and EBI in rats after SAH. A prechiasmatic cistern SAH model was used in our experiment. The expressions of TLR4, high-mobility group box 1 (HMGB1), myeloid differentiation factor 88 (MyD88), and nuclear factor-κB (NF-κB) were evaluated by Western blot and immunohistochemistry. The expressions of Iba-1 and pro-inflammatory cytokines in brain cortex were determined by Western blot, immunofluorescence staining, or enzyme-linked immunosorbent assay. Neural apoptosis, brain edema, and neurological function were further evaluated to investigate the development of EBI. We found that post-SAH treatment with RSV could markedly inhibit the expressions of TLR4, HMGB1, MyD88, and NF-κB. Meanwhile, RSV significantly reduced microglia activation, as well as inflammatory cytokines leading to the amelioration of neural apoptosis, brain edema, and neurological behavior impairment at 24 h after SAH. However, RSV treatment failed to alleviate brain edema and neurological deficits at 72 h after SAH. These results indicated that RSV treatment could alleviate EBI after SAH, at least in part, via inhibition of TLR4-mediated inflammatory signaling pathway.
Highlights
Subarachnoid hemorrhage (SAH) is a fatal subtype of stroke with high mortality and morbidity rates
When treated with RSV, we found that the expression of Toll-like receptor 4 (TLR4)-mediated agents, including high-mobility group box 1 (HMGB1), myeloid differentiation factor 88 (MyD88), and nuclear factor-κB (NF-κB), was significantly inhibited
Given that these proteins play critical roles in SAH physiology [24,26,40,41], our experiment suggested that RSV could reduce neuroinflammation after SAH by inhibiting TLR4/MyD88/NF-κB signaling pathway
Summary
Subarachnoid hemorrhage (SAH) is a fatal subtype of stroke with high mortality and morbidity rates. Inhibiting TLR4 signaling pathway by pharmacological treatment can be against brain injury after SAH [14,15,16]. These indicate that suppressing TLR4 is a valid target for therapeutic intervention following SAH. Accumulating studies indicated that RSV could inhibit the activation of TLR4 and the subsequent downstream signaling pathways in different fields [24,25,26]. We designed this study to confirm the hypothesis that RSV could attenuate SAH-induced EBI by modulating the TLR4 signaling pathway
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