st2825 and Brain-Injuries

The present study was designed to investigate the role of microRNA‑451 (miRNA‑451) on cerebral ischemia‑reperfusion and to explore its possible mechanism. The expression of miRNA‑451 was downregulated in rats with cerebral ischemia‑reperfusion. In an in vitro model of cerebral ischemia‑reperfusion, the downregulation of miRNA‑451 increased inflammation, demonstrated by increased levels of tumor necrosis factor α, interleukin (IL)‑1b, IL‑6 and IL‑18. However, the upregulation of miRNA‑451 expression decreased inflammation in the same in vitro model of cerebral ischemia‑reperfusion. In addition, it was found that the downregulation of miRNA‑451 induced the expression of Toll‑like receptor 4 (TLR4), myeloid differentiation primary response protein MyD88 (MyD88) and nuclear factor‑κB (NF‑κB)/p65. Moreover, the administration of a MyD88 inhibitor, ST 2825, reduced the expression of MyD88 and NF‑κB/p65 in the in vitro model of cerebral ischemia‑reperfusion, inhibiting the effects of miRNA‑451 upregulation on inflammation. A TLR4 inhibitor, TAK‑242, was used to reduce the expression of TLR4 in the in vitro model of cerebral ischemia‑reperfusion. TAK‑242 suppressed the effects of miRNA‑451 downregulation on inflammation. The present study suggested that miRNA‑451 regulated cerebral ischemia‑reperfusion‑induced inflammation, which is mediated through the TLR4/MyD88/NF‑κB signaling pathway.

Topics: Animals; Brain Injuries; Cytokines; Heterocyclic Compounds, 2-Ring; Inflammation; Male; Mice; MicroRNAs; Myeloid Differentiation Factor 88; Reperfusion Injury; Signal Transduction; Spiro Compounds; Sulfonamides; Toll-Like Receptor 4; Transcription Factor RelA

Accumulating of evidence suggests that activation of nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinases (MAPKs) exacerbates early brain injury (EBI) following subarachnoid hemorrhage (SAH) by provoking pro-inflammatory and pro-apoptotic signaling. Myeloid differentiation primary response protein 88 (MyD88) is an endogenous adaptor protein in the toll-like receptors (TLRs) and interleukin (IL) -1β family signaling pathways and acts as a bottle neck in the NF-κB and MAPK pathways. Here, we used ST2825, a selective inhibitor of MyD88, to clarify whether inhibiting MyD88 could provide neuroprotection in EBI following SAH. Our results showed that the expression of MyD88 was markedly increased at 24 h post SAH. Intracerebroventricular injection of ST2825 significantly reduced the expression of MyD88 at 24 h post SAH. Involvement of MAPKs and NF-κB signaling pathways was revealed that ST2825 inhibited SAH-induced phosphorylation of TAK1, p38 and JNK, the nuclear translocation of NF-κB p65, and degradation of IκBα. Further, ST2825 administration diminished the SAH-induced inflammatory response and apoptosis. As a result, SAH-induced EBI was alleviated and neurological deficits caused by SAH were reversed. Our findings suggest that MyD88 inhibition confers marked neuroprotection against EBI following SAH. Therefore, MyD88 might be a promising new molecular target for the treatment of SAH.

Topics: Animals; Apoptosis; Brain Injuries; Cell Nucleus; Down-Regulation; Heterocyclic Compounds, 2-Ring; Inflammation; Male; MAP Kinase Signaling System; Myeloid Differentiation Factor 88; Neurons; Neuroprotection; NF-KappaB Inhibitor alpha; Protein Transport; Proteolysis; Rats, Sprague-Dawley; Spiro Compounds; Subarachnoid Hemorrhage; Transcription Factor RelA