The effect of HMGB1 on sub-toxic chlorpyrifos exposure-induced neuroinflammation in amygdala of neonatal rats
Jing TianHongmei DaiYuanying DengJie ZhangYing LiJun ZhouMingyi ZhaoMengwen ZhaoChen ZhangYuxi ZhangPeipei WangGuoying BingLingling Zhao
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Abstract:
Chlorpyrifos (CPF), one of organophosphorus pesticides (OPs), is associated with developmental neurotoxicity. Inflammatory response is closely related with CPF-induced neurotoxicity. The present study aimed at exploring whether sub-toxic CPF exposure on neonatal rats results in neuroinflammation that mediated by HMGB1/TLR4/NF-κB signaling pathway in the amygdala. The neonatal rats were subcutaneously injected with 5mg/kg CPF for 4 consecutive days (postnatal day 11-14) with or without HMGB1 inhibitor, glycyrrhizin. We assessed the levels of pro-inflammatory cytokines at 12, 24, and 72 h after CPF exposure. The role of HMGB1 on neuroinflammation in sub-toxic exposure during brain development was studied. CPF-treated neonatal rats exhibited a significant increase in the expression of pro-inflammatory cytokines, such as IL-6, TNF-α and HMGB1, and a significant increase in the activation of NF-κB in the amygdala after CPF exposure. Inhibited HMGB1 reduced the release of IL-6 and TNF-α, and inhibited activation of NF-κB. Our findings indicate that CPF exposure on developmental brain might induce the activation of neuroinflammation mediated by HMGB1/TLR4/NF-κB pathway in the amygdala.Keywords:
Neurotoxicity
HMGB1
Background and Purpose Arctigenin, a major bioactive component of Fructus arctii , has been reported to have antidepressant‐like effects. However, the mechanisms underlying these effects are still unclear. Neuroinflammation can be caused by excessive production of proinflammatory cytokines in microglia via high‐mobility group box 1 (HMGB1)/TLR4/NF‐κB and TNF‐α/TNFR1/NF‐κB signalling pathways, leading to depression. In this study, we have investigated the antidepressant mechanism of arctigenin by conducting in vitro and in vivo studies. Experimental Approach The effects of chronic unpredictable mild stress (CUMS) on wild‐type (WT) and TLR4 −/− mice were examined. Antidepressant‐like effects of arctigenin were tested using the CUMS‐induced model of depression in WT mice. The effects of arctigenin were assessed on the HMGB1/TLR4/NF‐κB and TNF‐α/TNFR1/NF‐κB signalling pathways in the prefrontal cortex (PFC) of mouse brain and HMGB1‐ or TNF‐α‐stimulated primary cultured microglia. The interaction between HMGB1 and TLR4 or TNF‐α and TNFR1 with or without arctigenin was examined by localized surface plasmon resonance (LSPR) and co‐immunoprecipitation assays. Key Results The immobility times in the tail suspension test (TST) and forced swimming test (FST) were reduced in TLR4 −/− mice, compared with WT mice. Arctigenin exhibited antidepressant‐like effects. Arctigenin also inhibited microglia activation and inflammatory responses in the PFC of mouse brain. Arctigenin inhibited HMGB1 and TLR4 or TNF‐α and TNFR1 interactions, and suppressed both HMGB1/TLR4/NF‐κB and TNF‐α/TNFR1/NF‐κB signalling pathways. Conclusions and Implications Arctigenin has antidepressant‐like effects by attenuating excessive microglial activation and neuroinflammation through the HMGB1/TLR4/NF‐κB and TNF‐α/TNFR1/NF‐κB signalling pathways. This suggests that arctigenin has potential as a new drug candidate suitable for clinical trials to treat depression.
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Neurotoxicity
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Chlorpyrifos (CPF), one of organophosphorus pesticides (OPs), is associated with developmental neurotoxicity. Inflammatory response is closely related with CPF-induced neurotoxicity. The present study aimed at exploring whether sub-toxic CPF exposure on neonatal rats results in neuroinflammation that mediated by HMGB1/TLR4/NF-κB signaling pathway in the amygdala. The neonatal rats were subcutaneously injected with 5mg/kg CPF for 4 consecutive days (postnatal day 11-14) with or without HMGB1 inhibitor, glycyrrhizin. We assessed the levels of pro-inflammatory cytokines at 12, 24, and 72 h after CPF exposure. The role of HMGB1 on neuroinflammation in sub-toxic exposure during brain development was studied. CPF-treated neonatal rats exhibited a significant increase in the expression of pro-inflammatory cytokines, such as IL-6, TNF-α and HMGB1, and a significant increase in the activation of NF-κB in the amygdala after CPF exposure. Inhibited HMGB1 reduced the release of IL-6 and TNF-α, and inhibited activation of NF-κB. Our findings indicate that CPF exposure on developmental brain might induce the activation of neuroinflammation mediated by HMGB1/TLR4/NF-κB pathway in the amygdala.
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Lipopolysaccharide (LPS)-induced neuroinflammation triggers and accelerates the pathogenesis of Parkinson’s disease (PD). Carthamus tinctorius L., a traditional Chinese medicine, has been widely used for the treatment of cerebrovascular disease. Hydroxysafflor Yellow A (HSYA) is an active component of C. tinctorius. The purpose of this study was to investigate whether HSYA could attenuate LPS-induced neurotoxicity and neuroinflammation in primary mesencephalic cultures. Cell viability was measured by MTT and LDH assays. The number of tyrosine hydroxylase (TH) positive neuron was observed by immunohistochemistry. NF-κB p65 and iNOS expressions were evaluated with western blotting method. Pro-inflammatory cytokines including IL-1β and TNF-α were determined by ELISA kits. Nitric oxide (NO) content in the culture medium was assayed. The results showed that HSYA treatment significantly attenuated the LPS-induced dopaminergic neurons damage. HSYA partially inhibited the expressions of NF-κB p65 and iNOS. Furthermore, HSYA decreased the content of IL-1β, TNF-α and NO in the supernatants. Taken together, these results suggest that HSYA exerts protective effects on LPS-induced neurotoxicity in dopaminergic neurons and the mechanisms may be associated with the inhibition of inflammatory response.
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OF DISSERTATION FLAVONOIDS WITH NOVEL NICOTINIC ACTIVITY AS POTENTIAL PHARMACOTHERAPIES TO TREAT ETHANOL-INDUCED NEUROTOXICITY Ethanol causes neurotoxicity via several mechanisms at different points in the cycle of dependence, including neuroinflammation and oxidative stress during ethanol exposure as well as excitotoxicity during ethanol withdrawal. The primary therapeutic implication is that ethanol-induced neurotoxicity requires multifunctional pharmacotherapies which reduce all mechanisms. Using an innovative pharmacological high throughput screening method on a large plant extract library we discovered flavonoids with alpha7 nicotinic acetylcholine receptor (nAChR) activity. In addition to their well-known anti-inflammatory and antioxidant properties, this novel activity means they can potentially reduce excitotoxicity and therefore makes them ideal for inhibition of ethanol-induced neurotoxicity. Rhamnetin, the candidate compound, was first found to inhibit lipopolysaccharide induced inflammation in immortalized BV2 microglia, in part, via alpha7 nAChRs. We then established an in vitro model of ethanol inducedneurotoxicity using organotypic hippocampal slice cultures which incorporated both neuroinflammatory and excitotoxic components. Neuroinflammation enhanced excitotoxicity under control conditions but the reverse was observed during ethanol withdrawal. Both mechanisms are important but their interaction is not simple. Finally, rhamnetin was evaluated in this model and found to reduce neuroinflammation and excitotoxicity associated with ethanol withdrawal. In conclusion, the studies herein provide strong evidence for alpha7 nAChRs selective flavonoids as potential pharmacotherapies for the treatment of ethanol-induced neurotoxicity and further implicate neuroinflammation, excitotoxicity, and their interaction as critical mechanisms in this pathology.
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HMGB1 is a ubiquitous, highly conserved DNA-binding protein with well-established functions in the maintenance of nuclear homeostasis. Much of the recent work about its signaling functions in the brain has focused on its proinflammatory properties and relationship to known inflammatory receptors such as toll-like receptor 4 (TLR4). HMGB1 is massively released into the extracellular space immediately after ischemic insult and that it subsequently induces neuroinflammation in the postischemic brain, indicating that HMGB1 acts as a novel mediator in cerebral ischemic injury. Consistently, numerous reports point to TLR4 as a pivotal player in the ischemic brain. The use of HMGB1 and TLR4 ligand as preconditioning stimulus may be benefit of the outcome of cerebral ischemia. Therefore, this review presents the latest findings supporting the involvement of HMGB1 and TLR4 in cerebral ischemia. Targeting HMGB1/TLR4 signaling may provide a novel therapeutic approach for clinical prevention of cerebral ischemic injury.
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Identifying signal transduction pathways and understanding their role in microglia-mediated neuroinflammation and neurotoxicity may provide clinical benefits in neurodegenerative diseases. Microglia activation and inflammation is the first line of defense mechanism by the host to remove pathogen/injurious stimuli and initiate the tissue healing process. Inflammation should be tightly regulated. However, dysregulation leads to ‘bystander’ tissue damage in most neurodegenerative diseases. Evidence suggests that activated microglia excessively secretes chronic neurotoxic factors, including TNF-α, IL1-β, NO and reactive oxygen species (ROS), driving progressive neurotoxicity. The present study provides the molecular mechanisms involved in TLR4 mediated excessive inflammatory responses by microglia. We used LPS stimulated BV2 murine microglia cells, as an in vitro model system to examine TLR4 induced microglia-mediated chronic neuroinflammation. Here we demonstrate that β-amyloid and LPS enhanced TLR4 expression on microglia. LPS stimulation significantly enhanced inflammatory cytokines by microglia in time and dose dependent manner at mRNA and protein levels. Subsequently, phosphorylation of PI3 kinase was observed but it is partially involved in inflammation regulation. In addition, TLR4 activation markedly induces phosphorylation of JNK 1/2, p38 and ERK1/2 MAPKs. Our study revealed that JNK 1/2 and p38 MAPK are crucial players during TLR4 mediated inflammation and neurotoxicity. In addition, combined inhibition of p38 and JNK synergistically increases neuroprotection against Aβ induced neurotoxicity. In conclusion, our findings suggest that TLR4 activation by LPS and β-amyloid significantly increases inflammation while p38 MAPK and JNK 1/2 inhibition provides neuroprotection through negative regulation of NF-κB. Thus p38 MAPK and JNK 1/2 are good therapeutic targets in inflammatory neurodegenerative diseases like Alzheimer’s disease.
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Brain injuries are devastating conditions, representing a global cause of mortality and morbidity, with no effective treatment to date. Increased evidence supports the role of neuroinflammation in driving several forms of brain injuries. High mobility group box 1 (HMGB1) protein is a pro-inflammatory-like cytokine with an initiator role in neuroinflammation that has been implicated in Traumatic brain injury (TBI) as well as in early brain injury (EBI) after subarachnoid hemorrhage (SAH). Herein, we discuss the implication of HMGB1-induced neuroinflammatory responses in these brain injuries, mediated through binding to the receptor for advanced glycation end products (RAGE), toll-like receptor4 (TLR4) and other inflammatory mediators. Moreover, we provide evidence on the biomarker potential of HMGB1 and the significance of its nucleocytoplasmic translocation during brain injuries along with the promising neuroprotective effects observed upon HMGB1 inhibition/neutralization in TBI and EBI induced by SAH. Overall, this review addresses the current advances on neuroinflammation driven by HMGB1 in brain injuries indicating a future treatment opportunity that may overcome current therapeutic gaps.
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