Dopamine D1 Receptor Agonist A-68930 Inhibits NLRP3 Inflammasome Activation, Controls Inflammation, and Alleviates Histopathology in a Rat Model of Spinal Cord Injury

Jiang, Wu; Huang, Yan; He, Fangping; Jia, Liu; Li, Maoqiang; Sun, Tiansheng; Ren, Wencheng; Hou, Jingming; Zhu, Liangliang

doi:10.1097/brs.0000000000001287

Cited by 44 publications

(35 citation statements)

References 36 publications

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“…Moreover, MT could attenuate neuronal death by significantly reducing the activity of caspase-3 in SCI rats. [40][41][42] Furthermore, the expression of NLRP3 was dramatically increased at day 3 after the induction of SCI in a rat model. In this study, we established a rat model of SCI and treated SCI rats with MT.…”

Section: Discussionmentioning

confidence: 92%

“…These results are consistent with those published by Genovese et al 32 who showed that MT treatment could dramatically improve limb functions by playing strong anti-inflammatory roles in an animal model of SCI. 40,41 Moreover, microglia and neurons are major sources of ASC and NLRP3, respectively. The results showed that the BBB scores between SCI and SCI + MT groups showed no significant differences before day 3, but the BBB score in the SCI + MT group was significantly increased after day 7 compared with that in the SCI group.…”

Section: Discussionmentioning

confidence: 99%

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Melatonin ameliorates spinal cord injury by suppressing the activation of inflammasomes in rats

Shi

Zhi

et al. 2018

J of Cellular Biochemistry

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Background The activation of inflammasomes plays an important role in the pathogenesis of spinal cord injury (SCI). In addition, the administration of melatonin (MT) has been shown to suppress the activation of inflammasomes. In this study, we aimed to investigate the molecular mechanisms underlying the therapeutic effect of MT in the treatment of SCI. Methods Basso‐Beattie‐Bresnahan (BBB) locomotion scaling was conducted to evaluate the therapeutic effect of MT on post‐SCI locomotion recovery. In addition, the measurement of spinal cord water content was performed together with Nissl staining to evaluate the protective effect of MT against SCI. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay, immunohistochemistry (IHC) assay, Western blot analysis, and real‐time polymerase chain reaction (PCR) were also conducted to clarify the molecular mechanisms underlying the therapeutic effect of MT in the treatment of SCI. Results BBB scores of SCI + MT rats were increased compared with the BBB scores of SCI rats, thus confirming the beneficial role of MT treatment in post‐SCI functional recovery. Meanwhile, the administration of MT could alleviate SCI by reducing spinal cord water content and by exerting a neuroprotective effect on motor neurons. Furthermore, in the treatment of SCI, MT also attenuated cell apoptosis. Moreover, the relative expression of NLRP3, interleukin‐1β (IL‐1β), and caspase‐1 were markedly elevated in the SCI group compared with that in the sham group, while the administration of MT reduced the expression of NLRP3 in SCI rats. Conclusions MT treatment accelerated the recovery of SCI by suppressing the activation of inflammasomes.

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Section: Discussionmentioning

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Melatonin ameliorates spinal cord injury by suppressing the activation of inflammasomes in rats

Shi

Zhi

et al. 2018

J of Cellular Biochemistry

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“…20 In another study DRD1 agonist A-68930 was reported to improve neurological function through inhibition of NLRP3 inflammasome activation. 83 Similarly, in an in vitro study DRD2 receptors inhibited NLRP3 inflammasome activation in a β-arrestin2-dependent manner, whereas in MPTP-induced PD, DRD2 reduced the caspase-1 and IL-1β levels in the midbrain. 84 Thus, it clearly demonstrates a correlation between the level of DA and microglial NLRP3 inflammasome activation in PD.…”

Section: Dopamine Receptor-mediated Nlrp3mentioning

confidence: 95%

“…Recent findings have suggested that dopamine (DA) negatively regulates the NLRP3 inflammasome by activating dopamine D1 receptors (DRD1), and as a result, cAMP binds to NLRP3 and promotes its degradation via MARCH7, an E3 ubiquitin ligase . In another study DRD1 agonist A‐68930 was reported to improve neurological function through inhibition of NLRP3 inflammasome activation . Similarly, in an in vitro study DRD2 receptors inhibited NLRP3 inflammasome activation in a β‐arrestin2–dependent manner, whereas in MPTP‐induced PD, DRD2 reduced the caspase‐1 and IL‐1β levels in the midbrain .…”

Section: Nlrp3 Inflammasome‐mediated Inflammatory Pathways In Pdmentioning

confidence: 97%

Targeting the Microglial NLRP3 Inflammasome and Its Role in Parkinson's Disease

et al. 2019

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Excessive activation of microglia and subsequent release of proinflammatory cytokines play a crucial role in neuroinflammation and neurodegeneration in Parkinson's disease (PD). Components of the nucleotide‐binding oligomerization domain and leucine‐rich‐repeat‐ and pyrin‐domain‐containing 3 inflammasome complex, leucine‐rich‐repeat‐ and pyrin‐domain‐containing 3, caspase‐1, and apoptosis‐associated speck‐like protein containing a CARD, are highly expressed in activated microglia in PD patient brains. Findings suggest that neurotoxins, aggregation of α‐synuclein, mitochondrial reactive oxygen species, and disrupted mitophagy are the key regulators of microglial leucine‐rich‐repeat‐ and pyrin‐domain‐containing 3 inflammasome activation and release of interleukin‐1β and interleukin‐18 caspase‐1‐mediated pyroptotic cell death in the substantia nigra of the brain. Although this evidence suggests the leucine‐rich‐repeat‐ and pyrin‐domain‐containing 3 inflammasome may be a potential drug target for treatment of PD, the exact mechanism of how the microglia sense these stimuli and initiate leucine‐rich‐repeat‐ and pyrin‐domain‐containing 3 inflammasome signaling is unknown. Here, the molecular mechanism and regulation of microglial leucine‐rich‐repeat‐ and pyrin‐domain‐containing 3 inflammasome activation and its role in the pathogenesis of PD are discussed. Moreover, the potential of both endogenous and synthetic leucine‐rich‐repeat‐ and pyrin‐domain‐containing 3 inflammasome modulators, long noncoding RNA, microRNA to develop novel therapeutics to treat PD is presented. Overall, we recommend that the microglial leucine‐rich‐repeat‐ and pyrin‐domain‐containing 3 inflammasome can be a potential target for PD treatment. © 2019 International Parkinson and Movement Disorder Society

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“…Studies have reported NLRP3 inflammasome activation in microglia and neurons after oxygen-glucose deprivation (OGD)/reperfusion in vitro and in cerebral ischemia/reperfusion (Gong et al, 2018;Guo et al, 2018). There is post-SCI activation of NLRP3 inflammasome in an animal model involving microglia and spinal cord tissue (Grace et al, 2016;Jiang et al, 2016;Zendedel et al, 2016). Further, previous studies have reported means of reducing neuroinflammation and promoting functional recovery in SCI animals by suppressing NLRP3 inflammasome activity (Qian et al, 2017;Zhu et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

MCC950, a Selective Inhibitor of NLRP3 Inflammasome, Reduces the Inflammatory Response and Improves Neurological Outcomes in Mice Model of Spinal Cord Injury

Jiao

Zhao

Wang

et al. 2020

Front. Mol. Biosci.

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Spinal cord injury (SCI) is a serious condition that affects bodily function; however, there is no effective therapy in clinical practice. MCC950, a selective NOD-like receptor protein-3 (NLRP3) inflammasome inhibitor, has been reported to alleviate canonical and non-canonical NLRP3 inflammasome activation of the inflammatory response in vitro and in vivo. However, the effect of MCC950 treatment on neurological post-SCI recovery remains unclear. In this study, we assessed the pharmacological effect of MCC950 on an experimental SCI model in vivo and neuronal injury in vitro. We found that MCC950 improved the grip strength, hind limb movements, spinal cord edema, and pathological injury in the SCI mice. We demonstrated that it exerted this effect by blocking NLRP3 inflammasome assembly, including NLRP3-ASC and NLRP3-Caspase-1 complexes, as well as the release of pro-inflammatory cytokines TNF-α, IL-1β, and IL-18. Moreover, we found that MCC950 reduced spinal neuron injury and NLRP3 inflammasome activation, which had been induced by oxygen-glucose deprivation (OGD) or lipopolysaccharides (LPS) in vitro. In conclusion, our findings indicate that MCC950 alleviates inflammatory response and improves functional recovery in the acute mice model of SCI by blocking NLRP3 inflammasome assembly and alleviating downstream neuroinflammation. Therefore, these findings could prove useful in the development of effective therapeutic strategies for the treatment and prognosis of SCI.

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Dopamine D1 Receptor Agonist A-68930 Inhibits NLRP3 Inflammasome Activation, Controls Inflammation, and Alleviates Histopathology in a Rat Model of Spinal Cord Injury

Abstract: A-68930 can attenuate tissue damage and improve neurological function recovery, and the mechanism may be related to the inhibition of NLRP3 inflammasome activation.

Cited by 44 publications

References 36 publications

Melatonin ameliorates spinal cord injury by suppressing the activation of inflammasomes in rats

Melatonin ameliorates spinal cord injury by suppressing the activation of inflammasomes in rats

Targeting the Microglial NLRP3 Inflammasome and Its Role in Parkinson's Disease

MCC950, a Selective Inhibitor of NLRP3 Inflammasome, Reduces the Inflammatory Response and Improves Neurological Outcomes in Mice Model of Spinal Cord Injury

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