Glibenclamide attenuates 2,5-hexanedione-induced neurotoxicity in the spinal cord of rats through mitigation of NLRP3 inflammasome activation, neuroinflammation and oxidative stress

Hou, Liyan; Yang, Jie; Li, Sheng; Huang, Ruixue; Zhang, Dongdong; Zhao, Jie; Wang, Qingshan

doi:10.1016/j.toxlet.2020.06.002

Cited by 23 publications

(12 citation statements)

References 45 publications

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“…In preclinical studies using experiment animals, high-dose HD intoxication was shown to cause more intensive neurological deficits including demyelinating damage in the spinal cord, which has been employed to evaluate the therapeutical efficacies of various reagents for demyelinating conditions in CNS [ 9 , 44 ]. In CNS, the repair of damaged myelin sheath is driven by OPCs, acting as glial stem cells, to differentiate into mature OLs to remyelinate the lesioned nerve [ 45 ].…”

Section: Discussionmentioning

confidence: 99%

“…The review by Huang CC also documented hexane-associated CNS symptoms such as cephalalgia, sleep problem and gait spasticity [ 4 ]. In experimental animals, high-dose HD intoxication was found to cause demyelination in PNS and spinal cords and has been used to study the mechanisms of HD neurotoxicity and evaluate the therapeutical potential of various reagents for demyelinating conditions [ 9 ].…”

Section: Introductionmentioning

confidence: 99%

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Bone marrow mesenchymal stem cells promote remyelination in spinal cord by driving oligodendrocyte progenitor cell differentiation via TNFα/RelB-Hes1 pathway: a rat model study of 2,5-hexanedione-induced neurotoxicity

Guan

Zhang

et al. 2021

Stem Cell Res Ther

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Background N-hexane, with its metabolite 2,5-hexanedine (HD), is an industrial hazardous material. Chronic hexane exposure causes segmental demyelination in the peripheral nerves, and high-dose intoxication may also affect central nervous system. Demyelinating conditions are difficult to treat and stem cell therapy using bone marrow mesenchymal stem cells (BMSCs) is a promising novel strategy. Our previous study found that BMSCs promoted motor function recovery in rats modeling hexane neurotoxicity. This work aimed to explore the underlying mechanisms and focused on the changes in spinal cord. Methods Sprague Dawley rats were intoxicated with HD (400 mg/kg/day, i.p, for 5 weeks). A bolus of BMSCs (5 × 107 cells/kg) was injected via tail vein. Demyelination and remyelination of the spinal cord before and after BMSC treatment were examined microscopically. Cultured oligodendrocyte progenitor cells (OPCs) were incubated with HD ± BMSC-derived conditional medium (BMSC-CM). OPC differentiation was studied by immunostaining and morphometric analysis. The expressional changes of Hes1, a transcription factor negatively regulating OPC-differentiation, were studied. The upstream Notch1 and TNFα/RelB pathways were studied, and some key signaling molecules were measured. The correlation between neurotrophin NGF and TNFα was also investigated. Statistical significance was evaluated using one-way ANOVA and performed using SPSS 13.0. Results The demyelinating damage by HD and remyelination by BMSCs were evidenced by electron microscopy, LFB staining and NG2/MBP immunohistochemistry. In vitro cultured OPCs showed more differentiation after incubation with BMSC-CM. Hes1 expression was found to be significantly increased by HD and decreased by BMSC or BMSC-CM. The change of Hes1 was found, however, independent of Notch1 activation, but dependent on TNFα/RelB signaling. HD was found to increase TNFα, RelB and Hes1 expression, and BMSCs were found to have the opposite effect. Addition of recombinant TNFα to OPCs or RelB overexpression similarly caused upregulation of Hes1 expression. The secretion of NGF by BMSC and activation of NGF receptor was found important for suppression of TNFα production in OPCs. Conclusions Our findings demonstrated that BMSCs promote remyelination in the spinal cord of HD-exposed rats via TNFα/RelB-Hes1 pathway, providing novel insights for evaluating and further exploring the therapeutical effect of BMSCs on demyelinating neurodegenerative disease.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Bone marrow mesenchymal stem cells promote remyelination in spinal cord by driving oligodendrocyte progenitor cell differentiation via TNFα/RelB-Hes1 pathway: a rat model study of 2,5-hexanedione-induced neurotoxicity

Guan

Zhang

et al. 2021

Stem Cell Res Ther

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“…Glibenclamide is an ATP-sensitive K + channel inhibitor used in the treatment of type 2 diabetes ( Carvalho et al., 2020 ). Additionally, glibenclamide demonstrates neuroprotective effects, which can reduce infarct volume, brain oedema, activation of microglial cells, production of inflammatory factors, protection of the blood-brain barrier, and restoration of tight junction expression in the brain ( Hou et al., 2020 ). Glibenclamide inhibited the NLRP3 inflammasome by inhibiting the ATPase activity of NLRP3 and downregulating TNF and IL-17 levels ( Carvalho et al., 2020 ); however, the high doses needed to achieve the inhibitory effects in vivo may cause fatal hypoglycaemia ( Kuwar et al., 2019 ).…”

Section: Specific Inhibitors Of Nlrp3 Inflammasomementioning

confidence: 99%

The Role of NLRP3 Inflammasome in Cerebrovascular Diseases Pathology and Possible Therapeutic Targets

et al. 2021

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Cerebrovascular diseases are pathological conditions involving impaired blood flow in the brain, primarily including ischaemic stroke, intracranial haemorrhage, and subarachnoid haemorrhage. The nucleotide-binding and oligomerisation (NOD) domain-like receptor (NLR) family pyrin domain (PYD)-containing 3 (NLRP3) inflammasome is a protein complex and a vital component of the immune system. Emerging evidence has indicated that the NLRP3 inflammasome plays an important role in cerebrovascular diseases. The function of the NLRP3 inflammasome in the pathogenesis of cerebrovascular diseases remains an interesting field of research. In this review, we first summarised the pathological mechanism of cerebrovascular diseases and the pathological mechanism of the NLRP3 inflammasome in aggravating atherosclerosis and cerebrovascular diseases. Second, we outlined signalling pathways through which the NLRP3 inflammasome participates in aggravating or mitigating cerebrovascular diseases. Reactive oxygen species (ROS)/nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), ROS/thioredoxin-interacting protein (TXNIP) and purinergic receptor-7 (P2X7R) signalling pathways can activate the NLRP3 inflammasome; activation of the NLRP3 inflammasome can aggravate cerebrovascular diseases by mediating apoptosis and pyroptosis. Autophagy/mitochondrial autophagy, nuclear factor E2-related factor-2 (Nrf2), interferon (IFN)-β, sirtuin (SIRT), and phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) reportedly alleviate cerebrovascular diseases by inhibiting NLRP3 inflammasome activation. Finally, we explored specific inhibitors of the NLRP3 inflammasome based on the two-step activation of the NLRP3 inflammasome, which can be developed as new drugs to treat cerebrovascular diseases.

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“…After 10 min of centrifugation at 10,000×g (4 °C), the contents of GSH and MDA in the collected supernatant were measured with commercial kits (GSH, S0052; MDA, S0131, Beyotime, Shanghai, China) according to the protocol provided by the manufacturer and previous studies. [42][43][44][45] The rationale for the measurement of GSH based on that GSH reacts with chromogenic substrate DTNB to produce yellow products and the amount of GSH can be detected by measuring absorption at A412. While, MDA can react with thiobarbituric acid (TBA) in high temperature and acidic environment to form red MDA-TBA adduct.…”

Section: Glutathione and Malondialdehyde Measurementmentioning

confidence: 99%

Microglial Activation Mediates Noradrenergic Locus Coeruleus Neurodegeneration via Complement Receptor 3 in a Rotenone-Induced Parkinson’s Disease Mouse Model

Lu¹,

Hou²,

Zhang³

et al. 2021

JIR

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Background Chronic exposure to the insecticide rotenone can damage dopaminergic neurons and lead to an increased risk of Parkinson’s disease (PD). Whereas it is not clear whether rotenone induces neurodegeneration of noradrenergic locus coeruleus (LC/NE) neurons. Chronic neuroinflammation mediated by microglia has been involved in the pathogenesis of PD. Evidence shows that complement receptor 3 (CR3) is a crucial regulator of microglial activation and related neurodegeneration. However, it is not clear whether CR3 mediates rotenone-elicited degeneration of LC/NE neurons through microglia-mediated neuroinflammation. Materials and Methods Wild type (WT) and CR3 knockout (KO) mice were treated with rotenone. PLX3397 and minocycline were used to deplete or inactivate the microglia. Leukadherin-1 (LA-1) was used to modulate CR3. LC/NE neurodegeneration, microglial phenotype, and expression of CR3 were determined by using immunohistochemistry, Western blot and real-time polymerase chain reaction (PCR) techniques. The glutathione (GSH) and malondialdehyde (MDA) contents were measured by using commercial kits. Results Rotenone exposure led to dose- and time-dependent LC/NE neuronal loss and microglial activation in mice. Depletion of microglia by PLX3397 or inhibition of microglial activation by minocycline significantly reduced rotenone-induced LC/NE neurodegeneration. Mechanistic studies revealed that CR3 played an essential role in the rotenone-induced activation of microglia and neurodegeneration of LC/NE neurons. Rotenone elevated the expression of CR3, and genetic ablation of CR3 markedly reduced rotenone-induced microglial activation and M1 polarization. LA-1 also suppressed rotenone-induced toxic microglial M1 activation. Furthermore, lack of CR3 or treatment with LA-1 reduced oxidative stress in the brainstem of rotenone-intoxicated mice. Finally, we found that mice deficient in CR3 or treated with LA-1 were more resistant to rotenone-induced LC/NE neurodegeneration than WT or vehicle-treated mice, respectively. Conclusion Our results indicate that CR3-mediated microglial activation participates in rotenone-induced LC/NE neurodegeneration, providing novel insight into environmental toxin-induced neurotoxicity and related Parkinsonism.

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Glibenclamide attenuates 2,5-hexanedione-induced neurotoxicity in the spinal cord of rats through mitigation of NLRP3 inflammasome activation, neuroinflammation and oxidative stress

Cited by 23 publications

References 45 publications

Bone marrow mesenchymal stem cells promote remyelination in spinal cord by driving oligodendrocyte progenitor cell differentiation via TNFα/RelB-Hes1 pathway: a rat model study of 2,5-hexanedione-induced neurotoxicity

Bone marrow mesenchymal stem cells promote remyelination in spinal cord by driving oligodendrocyte progenitor cell differentiation via TNFα/RelB-Hes1 pathway: a rat model study of 2,5-hexanedione-induced neurotoxicity

The Role of NLRP3 Inflammasome in Cerebrovascular Diseases Pathology and Possible Therapeutic Targets

Microglial Activation Mediates Noradrenergic Locus Coeruleus Neurodegeneration via Complement Receptor 3 in a Rotenone-Induced Parkinson’s Disease Mouse Model

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