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

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 re...

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Bibliographic Details
Published in:Scientific reports 2017-11, Vol.7 (1), p.15797-11, Article 15797
Main Authors: Yan, Huiying, Zhang, Dingding, Wei, Yongxiang, Ni, Hongbin, Liang, Weibang, Zhang, Huasheng, Hao, Shuangying, Jin, Wei, Li, Kuanyu, Hang, Chun-Hua
Format: Article
Language:English
Subjects:
Adaptor proteins
Animals
Apoptosis
Apoptosis - drug effects
Brain
Brain Injuries - etiology
Brain Injuries - pathology
Brain Injuries - physiopathology
Brain injury
Cell Nucleus - drug effects
Cell Nucleus - metabolism
Down-Regulation - drug effects
Haemorrhage
Hemorrhage
Heterocyclic Compounds, 2-Ring - pharmacology
IL-1β
Inflammation
Inflammation - pathology
JNK protein
Kinases
Male
MAP kinase
MAP Kinase Signaling System - drug effects
MyD88 protein
Myeloid Differentiation Factor 88 - antagonists & inhibitors
Myeloid Differentiation Factor 88 - metabolism
Neurological diseases
Neurons - drug effects
Neurons - metabolism
Neurons - pathology
Neuroprotection
Neuroprotection - drug effects
NF-KappaB Inhibitor alpha - metabolism
NF-κB protein
Nuclear transport
Phosphorylation
Protein Transport - drug effects
Proteins
Proteolysis - drug effects
Rats, Sprague-Dawley
Signal transduction
Spiro Compounds - pharmacology
Subarachnoid hemorrhage
Subarachnoid Hemorrhage - complications
Subarachnoid Hemorrhage - pathology
Subarachnoid Hemorrhage - physiopathology
TAK1 protein
Toll-like receptors
Transcription Factor RelA - metabolism
Translocation
Traumatic brain injury
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Summary: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.
ISSN:2045-2322
2045-2322
DOI:10.1038/s41598-017-16124-8