5-(3,4-Difluorophenyl)-3-(6-methylpyridin-3-yl)-1,2,4-oxadiazole (DDO-7263), a novel Nrf2 activator targeting brain tissue, protects against MPTP-induced subacute Parkinson's disease in mice by inhibiting the NLRP3 inflammasome and protects PC12 cells against oxidative stress

Xu, Lili; Wu, Yufeng; Yan, Fang; Li, Cuicui; Dai, Zhen; You, Qidong; Jiang, Zhengyu; Di, Bin

doi:10.1016/j.freeradbiomed.2019.01.003

Cited by 63 publications

(49 citation statements)

References 46 publications

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Section: The Therapeutic Impact: a Glial Avenue For Nigrostriatal Resmentioning

confidence: 99%

“…[5-(3,4-Difluorophenyl)-3-(6-methylpyridin-3-yl)-1,2,4-oxadiazole], is a novel Nrf2 activator targeting the brain, that has been recently shown to protect against MPTP-induced subacute Parkinson's disease in mice by inhibiting the NLRP3 inflammasome, in vivo , and to protect PC12 cells against oxidative stress [ 310 ]. Here, DDO-7263 improved the behavioral abnormalities induced by MPTP in mice, significantly attenuated MPTP-induced Daergic neuron death in SN and striatum associating with a downmodulation of inflammatory markers [ 310 ]. In a cellular system (PC12 cells) widely used as an in vitro cell culture model for PD, DDO-7263 was able to promote neuroprotection against H 2 O 2 -induced oxidative damage via the activation of Nrf2-ARE signaling pathway and the inhibition of NLRP3 inflammasome activation, suggesting a therapeutic potential for this novel Nrf2 activator [ 310 ].…”

Section: The Therapeutic Impact: a Glial Avenue For Nigrostriatal Resmentioning

confidence: 99%

“…Here, DDO-7263 improved the behavioral abnormalities induced by MPTP in mice, significantly attenuated MPTP-induced Daergic neuron death in SN and striatum associating with a downmodulation of inflammatory markers [ 310 ]. In a cellular system (PC12 cells) widely used as an in vitro cell culture model for PD, DDO-7263 was able to promote neuroprotection against H 2 O 2 -induced oxidative damage via the activation of Nrf2-ARE signaling pathway and the inhibition of NLRP3 inflammasome activation, suggesting a therapeutic potential for this novel Nrf2 activator [ 310 ].…”

Section: The Therapeutic Impact: a Glial Avenue For Nigrostriatal Resmentioning

confidence: 99%

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Nrf2/Wnt resilience orchestrates rejuvenation of glia-neuron dialogue in Parkinson's disease

Marchetti

2020

Redox Biology

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Oxidative stress and inflammation have long been recognized to contribute to Parkinson's disease (PD), a common movement disorder characterized by the selective loss of midbrain dopaminergic neurons (mDAn) of the substantia nigra pars compacta (SNpc). The causes and mechanisms still remain elusive, but a complex interplay between several genes and a number of interconnected environmental factors, are chiefly involved in mDAn demise, as they intersect the key cellular functions affected in PD, such as the inflammatory response, mitochondrial, lysosomal, proteosomal and autophagic functions. Nuclear factor erythroid 2 -like 2 ( NFE2L2/Nrf2 ), the master regulator of cellular defense against oxidative stress and inflammation, and Wingless ( Wnt ) /β-catenin signaling cascade, a vital pathway for mDAn neurogenesis and neuroprotection, emerge as critical intertwinned actors in mDAn physiopathology, as a decline of an Nrf2/Wnt/β-catenin prosurvival axis with age underlying PD mutations and a variety of noxious environmental exposures drive PD neurodegeneration. Unexpectedly, astrocytes, the so-called “ star-shaped ” cells, harbouring an arsenal of “beneficial” and “harmful” molecules represent the turning point in the physiopathological and therapeutical scenario of PD. Fascinatingly, “ astrocyte's fil rouge” brings back to Nrf2/Wnt resilience, as boosting the Nrf2/Wnt resilience program rejuvenates astrocytes, in turn (i) mitigating nigrostriatal degeneration of aged mice, (ii) reactivating neural stem progenitor cell proliferation and neuron differentiation in the brain and (iii) promoting a beneficial immunomodulation via bidirectional communication with mDAns. Then, through resilience of Nrf2/Wnt/β-catenin anti-ageing, prosurvival and proregenerative molecular programs, it seems possible to boost the inherent endogenous self-repair mechanisms. Here, the cellular and molecular aspects as well as the therapeutical options for rejuvenating glia-neuron dialogue will be discussed together with major glial-derived mechanisms and therapies that will be fundamental to the identification of novel diagnostic tools and treatments for neurodegenerative diseases (NDs), to fight ageing and nigrostriatal DAergic degeneration and promote functional recovery.

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Section: The Therapeutic Impact: a Glial Avenue For Nigrostriatal Resmentioning

confidence: 99%

Section: The Therapeutic Impact: a Glial Avenue For Nigrostriatal Resmentioning

confidence: 99%

Section: The Therapeutic Impact: a Glial Avenue For Nigrostriatal Resmentioning

confidence: 99%

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Nrf2/Wnt resilience orchestrates rejuvenation of glia-neuron dialogue in Parkinson's disease

Marchetti

2020

Redox Biology

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“…6a). It's reported that Nrf2 activator DDO7263 can protect against the MPTP-induced PD like symptom via the inhibition of NLRP2 in ammasome [34]. Therefore, to ask whether the attenuation of NLRP3 by celastrol is dependent on the activation of Nrf2, western analysis was performed.…”

Section: The Effects Of Celastrol Are Mediated By Nrf2-nlrp3-caspase1mentioning

confidence: 99%

“…The activation of pyroptosis can further induce the release of IL1β to promote the in ammatory response, which may contribute to PD pathogenesis. Recently, it's reported that DDO7263, a novel Nrf2 activator targeting brain tissue, can protect against MPTP-induced PD model via inhibition of the NLRP3 in ammasome and oxidative stress [34]. Astragaloside IV can ameliorate motor de cits and the loss of dopaminergic neuron induced by MPTP through suppression of NLRP3 in ammasome [35].…”

mentioning

confidence: 99%

The Nrf2-NLRP3-Caspase1 axis mediates the neuroprotective effects of Celastrol in Parkinson's disease

Zhang

Zhao

Wang

et al. 2020

Preprint

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Background: Parkinson’s disease (PD) is characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta (SNc), accompanied by chronic neuroinflammation, oxidative stress, and widespread accumulation of α-synuclein. Celastrol (Cel), a potent anti-inflammatory and anti-oxidative pentacyclic triterpene, has emerged as a neuroprotective agent. However, the mechanisms by which celastrol is neuroprotective in PD has not yet been elucidated. Methods: The MPTP and AAV-mediated human wild-type α-syn overexpression within SNc induced PD mouse models were employed in this study. By using multiple genetically modified mice (Nrf2-KO, NLRP3-KO and Caspase1-KO), we identified that celastrol effectively inhibited the NLRP3 inflammasome activation, mitigated motor deficits and nigrostriatal dopaminergic degeneration through Nrf2-NLRP3-Caspase1 pathway. Results: Here we show that celastrol protected against the loss of dopaminergic neurons, mitigated the neuroinflammation and motor deficits in both MPTP-induced PD mouse model and AAV-mediated human α-syn overexpression PD model. Whole-genome deep sequencing analysis reveals that Nrf2, NLRP3 and Caspase1 in SNc may be associated with the neuroprotective actions of celastrol in PD. Conclusions: These findings suggest that Nrf2-NLRP3-Caspase1 axis may be a key target of celastrol in PD treatment, and highlight the favorable properties linked to neuroprotection of celastrol, making celastrol as a promising disease-modifying agent for PD.

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A comprehensive review of recent advances in the biological activities of 1,2,4‐oxadiazoles

Hendawy

2022

Archiv der Pharmazie

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Nitrogen heterocycles play an essential role in medication development. The 1,2,4‐oxadiazole heterocycle has been extensively studied, yielding a large variety of molecules with varied biological functions. The 1,2,4‐oxadiazole shows bioisosteric equivalency with ester and amide moieties. In recent years, the 1,2,4‐oxadiazole nucleus has received a lot of attention in medicinal chemistry. It was thought to be a pharmacophore component in the production of biologically intriguing drugs. This review presents a comprehensive overview of the recent achievements in the biological activities of 1,2,4‐oxadiazoles as potential antimicrobial, anticancer, anti‐inflammatory, neuroprotective, and antidiabetic agents. The structure–activity relationship and mechanisms of action are also reviewed.

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5-(3,4-Difluorophenyl)-3-(6-methylpyridin-3-yl)-1,2,4-oxadiazole (DDO-7263), a novel Nrf2 activator targeting brain tissue, protects against MPTP-induced subacute Parkinson's disease in mice by inhibiting the NLRP3 inflammasome and protects PC12 cells against oxidative stress

Cited by 63 publications

References 46 publications

Nrf2/Wnt resilience orchestrates rejuvenation of glia-neuron dialogue in Parkinson's disease

Nrf2/Wnt resilience orchestrates rejuvenation of glia-neuron dialogue in Parkinson's disease

The Nrf2-NLRP3-Caspase1 axis mediates the neuroprotective effects of Celastrol in Parkinson's disease

A comprehensive review of recent advances in the biological activities of 1,2,4‐oxadiazoles

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