Inhibition of myeloid differentiation primary response protein 88 provides neuroprotection in early brain injury following experimental subarachnoid hemorrhage

Abstract

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.

Microglia as target for anti-inflammatory approaches to prevent secondary brain injury after subarachnoid hemorrhage (SAH)

“…Given that microglia are phagocytic cells fulfilling their task as edaphic macrophages, the TLR4 pathway is essential for the immune response mediated by microglia [ 15 , 16 , 48 – 50 ]. Various components of this pathway have already been investigated in anti-inflammatory approaches regarding SAH; antagonizing inflammatory cytokines, especially IL1β or inhibition of the adapter protein MyD88 [ 51 ]. Our current results in accordance with these previous results support the significance of the TLR4 pathway in cerebral spreading inflammation after SAH.…”

WITHDRAWN: Long-term Elevated Siglec-10 in Cerebral Spinal Fluid Heralds Better Prognosis for Patients with Aneurysmal Subarachnoid Hemorrhage

“…Siglec-10 can also inhibit the function of NK cells and T cells and to interact with HSP70, HSP90, VAP-1 to reduce in ammation [15,20]. There are many consistent contents in the research area of aSAH, such as MyD88 / NF-κB Pathway, HMGB1 and DAMPs [30][31][32][33]. Our results showed that Siglec-10 rose to peak rapidly after aSAH and remained at a high concentration afterward, indicating that Siglec-10 did participate in the pathophysiological process after aSAH, and the possible mechanisms might be the ones mentioned above.…”

Neuroprotective Effect of Oridonin on Traumatic Brain Injury via Inhibiting NLRP3 Inflammasome in Experimental Mice

“…Nissl staining was performed as referred to our previous publication (Yan et al, 2017). Sections were stained with 1% toluidine blue at 50 • C for 20 min and then rinsed with doubledistilled water.…”