Anti-neuroinflammatory effects of dimethylaminomylide (DMAMCL, i.e., ACT001) are associated with attenuating the NLRP3 inﬂammasome in MPTP-induced Parkinson disease in mice

Liu, Qianqian; Guo, Xinyang; Huang, Ziwei; He, Qiujia; Zhu, Dashuai; Zhang, Shaozhi; Peng, Ziwei; Che, Yongzhe; Feng, Xizeng

doi:10.1016/j.bbr.2020.112539

Cited by 16 publications

(12 citation statements)

References 25 publications

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“…Besides its anticancer action, ACT001 ( Figure 1A ) has also been reported to alleviate neuroinflammatory responses in the CNS ( 16 ). However, the molecular target responsible for the immunosuppressive effects of ACT001 is not known.…”

Section: Manuscript Formattingmentioning

confidence: 99%

“…As a promising drug for the treatment of glioblastoma, ACT001 has an excellent effect on restraining the growth of glioblastoma in Phase I clinical trials and now it is currently undergoing Phase II clinical trials ( 14 , 15 ). ACT001, which can penetrate the blood–brain barrier (BBB) and accumulate in the brain, alleviates glial activation and neuroinflammation ( 16 , 17 ). As a foreign substance in CNS, it is not surprising that ACT001 would perturb the CNS immunity ( 16 , 17 ).…”

Section: Introductionmentioning

confidence: 99%

“…ACT001, which can penetrate the blood–brain barrier (BBB) and accumulate in the brain, alleviates glial activation and neuroinflammation ( 16 , 17 ). As a foreign substance in CNS, it is not surprising that ACT001 would perturb the CNS immunity ( 16 , 17 ). TLR4 is the key PRR of innate immune system, which detects PAMPs ( 18 ), DAMPs ( 19 ) and XMAPs ( 20 , 21 ).…”

Section: Introductionmentioning

confidence: 99%

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ACT001 Inhibits TLR4 Signaling by Targeting Co-Receptor MD2 and Attenuates Neuropathic Pain

Lin

Jiang

et al. 2022

Front. Immunol.

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Neuropathic pain is a common and challenging neurological disease, which renders an unmet need for safe and effective new therapies. Toll-like receptor 4 (TLR4) expressed on immune cells in the central nervous system arises as a novel target for treating neuropathic pain. In this study, ACT001, an orphan drug currently in clinical trials for the treatment of glioblastoma, was identified as a TLR4 antagonist. In vitro quenching titrations of intrinsic protein fluorescence and saturation transfer difference (STD)-NMR showed the direct binding of ACT001 to TLR4 co-receptor MD2. Cellular thermal shift assay (CETSA) showed that ACT001 binding affected the MD2 stability, which implies that MD2 is the endogenous target of ACT001. In silico simulations showed that ACT001 binding decreased the percentage of hydrophobic area in the buried solvent-accessible surface areas (SASA) of MD2 and rendered most regions of MD2 to be more flexible, which is consistent with experimental data that ACT001 binding decreased MD2 stability. In keeping with targeting MD2, ACT001 was found to restrain the formation of TLR4/MD2/MyD88 complex and the activation of TLR4 signaling axes of NF-κB and MAPKs, therefore blocking LPS-induced TLR4 signaling downstream pro-inflammatory factors NO, IL-6, TNF-α, and IL-1β. Furthermore, systemic administration of ACT001 attenuated allodynia induced by peripheral nerve injury and activation of microglia and astrocyte in vivo. Given the well-established role of neuroinflammation in neuropathic pain, these data imply that ACT001 could be a potential drug candidate for the treatment of chronic neuropathic pain.

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Section: Manuscript Formattingmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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ACT001 Inhibits TLR4 Signaling by Targeting Co-Receptor MD2 and Attenuates Neuropathic Pain

Lin

Jiang

et al. 2022

Front. Immunol.

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“…Micheliolide has the same anticancer structure as parthenolide but it is more stable 11,12 . ACT001, a derivative of micheliolide developed by Accendatech, has shown potent anticancer and anti‐inflammatory activities 13,14 . ACT001 has also been reported to inhibit the inflammatory response and activation of the NLRP3 inflammasome in the midbrain of 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP)‐induced PD mice 13 .…”

Section: Introductionmentioning

confidence: 99%

ACT001 inhibits the proliferation of non‐small cell lung cancer cells by upregulating NKTR expression

2022

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Background Lung cancer, the primary cause of cancer‐related deaths worldwide, is diagnosed at an advanced stage and has a poor prognosis. Non‐small cell lung cancer (NSCLC) is a major histological type of lung malignancy. This study investigated the effect of ACT001, a novel sesquiterpene lactone derivative, on the proliferation of NSCLC cells and explored the underlying mechanism. Methods The effect of ACT001 on cell proliferation was examined by clone formation and MTT assay. Differentially expressed genes and enrichment pathways were analyzed by RNA‐seq. Flow cytometry and cell cycle‐related protein expression analysis were performed to study the cell cycle. Phosphorylated AKT was detected to explore the mechanism in natural killer cell triggering receptor (NKTR) KD cells with AKT activator and/or inhibitor. The therapeutic effect of ACT001 in vivo was studied in the xenograft tumor model. Results ACT001 inhibited the proliferation and G1/S transition in NSCLC cell lines. By RNA‐seq analysis, NKTR may be the target of ACT001. Moreover, knockdown NKTR promoted cell proliferation and reversed the effects of ACT001. In addition, ACT001 inhibited AKT phosphorylation, but NKTR knockdown promoted AKT phosphorylation. Conclusion Our results suggested NKTR may be the target of ACT001 in NSCLC. ACT001 holds promise as a novel method for the treatment of NSCLC.

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“…Various studies reported on compounds affecting neuroinflammation and ameliorating PD symptoms; most recently, a novel Krf2 activator, KKPA4026, has been shown to attenuate motor deficit associated with PD and exhibit protective effect on dopaminergic neurons (39). Furthermore, inhibition of NLRP3 inflammasome by dimethylaminomylide alleviates neuroinflammation in MPTP-induced PD model (40). Administration of vitamin D for 10 consecutive days proved beneficial in PD animal model ( 41); whereas modulating microglia proliferation via inhibition of CSF1R by GSW2580 markedly reduced mRNA levels of pro-inflammatory mediators and mitigated the loss of dopaminergic neurons and motor deficits during PD (42).…”

Section: Discussionmentioning

confidence: 99%

Central inhibition of P2Y₁₂R differentially regulates survival and neuronal loss in MPTP-induced Parkinsonism in mice

Iring

Tóth

Baranyi

et al. 2021

Preprint

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Parkinson's disease (PD) is a chronic, progressive neurodegenerative condition; characterized with the degeneration of the nigrostriatal dopaminergic pathway and neuroinflammation. During PD progression, microglia, the resident immune cells in the central nervous system (CNS) display altered activity, but their role in maintaining PD development has remained unclear to date. The purinergic P2Y12 receptor (P2Y12R), which is exclusively expressed on the microglia in the CNS has been shown to regulate microglial activity and responses; however, the function of the P2Y12R in PD is unknown. Here we show that while pharmacological or genetic targeting of P2Y12R previous to disease onset augments acute mortality, these interventions protect against neurodegenerative cell loss and the development of neuroinflammation in vivo. Pharmacological inhibition of receptors during disease development reverses the symptoms of PD and halts disease progression. We found that P2Y12R regulate ROCK and p38 MAPK activity and control cytokine production. Understanding protective and detrimental P2Y12 receptor-mediated actions in the CNS may reveal novel approaches to control neuroinflammation and modify disease progression in PD.

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Anti-neuroinflammatory effects of dimethylaminomylide (DMAMCL, i.e., ACT001) are associated with attenuating the NLRP3 inﬂammasome in MPTP-induced Parkinson disease in mice

Cited by 16 publications

References 25 publications

ACT001 Inhibits TLR4 Signaling by Targeting Co-Receptor MD2 and Attenuates Neuropathic Pain

ACT001 Inhibits TLR4 Signaling by Targeting Co-Receptor MD2 and Attenuates Neuropathic Pain

ACT001 inhibits the proliferation of non‐small cell lung cancer cells by upregulating NKTR expression

Central inhibition of P2Y₁₂R differentially regulates survival and neuronal loss in MPTP-induced Parkinsonism in mice

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Anti-neuroinflammatory effects of dimethylaminomylide (DMAMCL, i.e., ACT001) are associated with attenuating the NLRP3 inﬂammasome in MPTP-induced Parkinson disease in mice

Cited by 16 publications

References 25 publications

ACT001 Inhibits TLR4 Signaling by Targeting Co-Receptor MD2 and Attenuates Neuropathic Pain

ACT001 Inhibits TLR4 Signaling by Targeting Co-Receptor MD2 and Attenuates Neuropathic Pain

ACT001 inhibits the proliferation of non‐small cell lung cancer cells by upregulating NKTR expression

Central inhibition of P2Y12R differentially regulates survival and neuronal loss in MPTP-induced Parkinsonism in mice

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Product

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Central inhibition of P2Y₁₂R differentially regulates survival and neuronal loss in MPTP-induced Parkinsonism in mice