Inhibition of myeloid differentiation factor 88(MyD88) by ST2825 provides neuroprotection after experimental traumatic brain injury in mice

Zhang, Huasheng; Li, Hua; Zhang, Dingding; Huang, Yan; Zhang, Zihuan; Zhou, Chenhui; Ye, Zhen-Nan; Chen, Qiang; Jiang, Tingwang; Liu, Jingpeng; Hang, Chun-Hua

doi:10.1016/j.brainres.2016.05.003

Cited by 31 publications

(12 citation statements)

References 39 publications

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“…The main inhibited molecules, due to the activity of ST2825, are IRAK1, IRAK4, TRAF6, p-IKK, p-IkBα, p-NF-κB and HIF-1α [ 48 , 49 ]. ST2825 has also been proposed as a novel drug targeting in diseases like lymphoma, leukaemia, human hepatocellular carcinoma, and traumatic brain injury [ 50 , 51 , 52 ]. However, its role as a possible inhibitor in the production of cytokines produced after stimulation with LPS remains undetermined.…”

Section: Discussionmentioning

confidence: 99%

Downregulation of Inflammatory Cytokine Release from IL-1β and LPS-Stimulated PBMC Orchestrated by ST2825, a MyD88 Dimerisation Inhibitor

et al. 2020

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The inflammatory process implicates homeostasis disruption and increased production of inflammatory mediators. Myeloid differentiation primary response 88 (MyD88) is an essential protein recruited after lipopolysaccharide (LPS) and interleukin (IL)-1β stimulation, a process that converges in nuclear factor kappa B (NF-κB) activation, as well as a transcription of several genes of both pro- and anti-inflammatory cytokines. The inhibition of MyD88 has shown efficacy by decrease inflammatory response, and has demonstrated potential application as a therapeutic target in chronic diseases. In this study, we investigate the effect of MyD88 dimerisation inhibitor ST2825 on cytokine production from rhIL-1β and LPS-stimulated peripheral blood mononuclear cells (PBMC) from healthy blood donors (HBD). ST2825 significantly downregulates the production of IFN-γ, IL-6, IL-12, IL-2, IL-15, IL-7, VEGF, IL-1Ra, IL-4, IL-5, IL-13 and IL-9 (p < 0.05) in LPS-stimulated PBMC. Moreover, ST2825 had a relatively low impact on IL-1β signalling pathway inhibition, showing that only a few specific cytokines, such as IFN-γ and IL-1Ra, are inhibited in rhIL-1β-stimulated PBMC (p < 0.01). In conclusion, MyD88 dimerisation inhibitor ST2825 showed high efficacy by inhibiting pro- and anti-inflammatory cytokine production in LPS-stimulated PBMC. Moreover, although rhIL-1β induced a sustained cytokine production (p < 0.05), ST2825 did not show a significant effect in the secretion of neither pro- nor anti-inflammatory cytokines in rhIL-1β-stimulated PBMC.

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Section: Discussionmentioning

confidence: 99%

Downregulation of Inflammatory Cytokine Release from IL-1β and LPS-Stimulated PBMC Orchestrated by ST2825, a MyD88 Dimerisation Inhibitor

et al. 2020

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“…Disruption of the TLR/MyD88/NF-κB signaling pathway was shown to be protective in the model of myocardial injury by attenuating NLRP3 inflammasome activation [76]. Moreover, alleviation or complete ablation of MyD88 signaling has been demonstrated as beneficial in several central nervous system pathologies, i.a., animal experimental autoimmune encephalomyelitis model [77], neuropathic pain [78], traumatic brain injury [79,80], epilepsy [81,82], Alzheimer's disease [83], hypoxic neonatal brain injury in LPS-sensitized mice [84], subarachnoid hemorrhage [85], as well as ischemic stroke [86,87]. However, there is also a disparate evidence from another study indicating that the infarct size was not decreased in MyD88-/-mice subjected to permanent cerebral ischemia [88] and yet another study demonstrating that specifically hematopoietic cells exhibit a neuroprotective function after stroke and this is mediated by MyD88 [89].…”

Section: Discussionmentioning

confidence: 99%

Intracerebral overexpression of miR-669c is protective in mouse ischemic stroke model by targeting MyD88 and inducing alternative microglial/macrophage activation

Kołosowska

Gotkiewicz

Dhungana

et al. 2020

J Neuroinflammation

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Background: Ischemic stroke is a devastating disease without a cure. The available treatments for ischemic stroke, thrombolysis by tissue plasminogen activator, and thrombectomy are suitable only to a fraction of patients and thus novel therapeutic approaches are urgently needed. The neuroinflammatory responses elicited secondary to the ischemic attack further aggravate the stroke-induced neuronal damage. It has been demonstrated that these responses are regulated at the level of non-coding RNAs, especially miRNAs. Methods: We utilized lentiviral vectors to overexpress miR-669c in BV2 microglial cells in order to modulate their polarization. To detect whether the modulation of microglial activation by miR-669c provides protection in a mouse model of transient focal ischemic stroke, miR-669c overexpression was driven by a lentiviral vector injected into the striatum prior to induction of ischemic stroke.

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“…The toll-like receptor (TLR) family owns the responsibility of initiating innate immunity response including inflammatory response in the stress status [ 28 ]. In addition, MyD88 and TIRAP act as binding proteins among TLR-mediated immunity response activity cases [ 29 – 31 ]. TLRs, MyD88, and TIRAP form a complex network structure of the TLR-mediated inflammatory cascade.…”

Section: Discussionmentioning

confidence: 99%

Biochanin A Reduces Inflammatory Injury and Neuronal Apoptosis following Subarachnoid Hemorrhage via Suppression of the TLRs/TIRAP/MyD88/NF-κB Pathway

Zhuang

et al. 2018

Behavioural Neurology

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Inflammatory injury and neuronal apoptosis participate in the period of early brain injury (EBI) after subarachnoid hemorrhage (SAH). Suppression of inflammation has recently been shown to reduce neuronal death and neurobehavioral dysfunction post SAH. Biochanin A (BCA), a natural bioactive isoflavonoid, has been confirmed to emerge the anti-inflammatory pharmacological function. This original study was aimed at evaluating and identifying the neuroprotective role of BCA and the underlying molecular mechanism in an experimental Sprague-Dawley rat SAH model. Neurobehavioral function was evaluated via the modified water maze test and modified Garcia neurologic score system. Thus, we confirmed that BCA markedly decreased the activated level of TLRs/TIRAP/MyD88/NF-κB pathway and the production of cytokines. BCA also significantly ameliorated neuronal apoptosis which correlated with the improvement of neurobehavioral dysfunction post SAH. These results indicated that BCA may provide neuroprotection against EBI through the inhibition of inflammatory injury and neuronal apoptosis partially via the TLRs/TIRAP/MyD88/NF-κB signal pathway.

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Inhibition of myeloid differentiation factor 88(MyD88) by ST2825 provides neuroprotection after experimental traumatic brain injury in mice

Cited by 31 publications

References 39 publications

Downregulation of Inflammatory Cytokine Release from IL-1β and LPS-Stimulated PBMC Orchestrated by ST2825, a MyD88 Dimerisation Inhibitor

Downregulation of Inflammatory Cytokine Release from IL-1β and LPS-Stimulated PBMC Orchestrated by ST2825, a MyD88 Dimerisation Inhibitor

Intracerebral overexpression of miR-669c is protective in mouse ischemic stroke model by targeting MyD88 and inducing alternative microglial/macrophage activation

Biochanin A Reduces Inflammatory Injury and Neuronal Apoptosis following Subarachnoid Hemorrhage via Suppression of the TLRs/TIRAP/MyD88/NF-κB Pathway

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