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

• Published in: Free radical biology & medicine 2019-04, Vol.134, p.288-303
• Main Authors: Xu, Li-Li, Wu, Yu-Feng, Yan, Fang, Li, Cui-Cui, Dai, Zhen, You, Qi-Dong, Jiang, Zheng-Yu, Di, Bin
• Format: Article
• Language: English
• Subjects: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine - adverse effects; Animals; Brain - drug effects; Brain - metabolism; Brain - pathology; Brain targeting function; Disease Models, Animal; Humans; Inflammasomes - drug effects; Male; Mice; Mice, Inbred C57BL; MPTP Poisoning - etiology; MPTP Poisoning - metabolism; MPTP Poisoning - pathology; MPTP Poisoning - prevention & control; Neuroprotective Agents - pharmacology; Neurotoxins - toxicity; NF-E2-Related Factor 2 - metabolism; NLR Family, Pyrin Domain-Containing 3 Protein - antagonists & inhibitors; NLR Family, Pyrin Domain-Containing 3 Protein - genetics; NLR Family, Pyrin Domain-Containing 3 Protein - metabolism; NLRP3 inflammasome; Nrf2-ARE activator; Oxadiazoles - pharmacology; Oxidative stress; Oxidative Stress - drug effects; Parkinson Disease - etiology; Parkinson Disease - metabolism; Parkinson Disease - pathology; Parkinson Disease - prevention & control; Parkinson's disease; PC12 Cells; Rats
• ISSN: 0891-5849; 1873-4596
• DOI: 10.1016/j.freeradbiomed.2019.01.003

Parkinson's disease (PD) is the second most common aging-related neurodegenerative disease worldwide. Oxidative stress and neuroinflammation are critical events in the degeneration of dopaminergic neurons in PD. In this study, we found that DDO-7263, a novel Nrf2-ARE activator reported by us, has ideal therapeutic effects on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson's disease in mice. DDO-7263 improved the behavioral abnormalities induced by MPTP in mice, significantly attenuated chemically induced dopaminergic neuron loss of tyrosine hydroxylase (TH) in the substantia nigra (SN) and striatum of the mouse brain and inhibited the secretion of inflammatory factors. In addition, DDO-7263 protected PC12 neurons from H2O2-induced oxidative damage. The neuroprotective effects of DDO-7263 were confirmed both in vitro and in vivo models. Further studies showed that the neuroprotective effect of DDO-7263 was mediated by the activation of Nrf2-ARE signaling pathway and the inhibition of NLRP3 inflammasome activation. DDO-7263 induced NLRP3 inflammasome inhibition is dependent on Nrf2 activation. This conclusion was also verified in THP-1-derived macrophages (THP-Ms). DDO-7263 significantly inhibited NLRP3 activation, cleaved caspase-1 production and IL-1β protein expression in ATP-LPS-exposed THP-Ms cells. The pharmacokinetic parameters and tissue distribution results indicated that DDO-7263 has a brain tissue targeting function. All these lines of evidence show that DDO-7263 has ideal therapeutic effects on neurodegenerative diseases such as PD. [Display omitted] •Oxidative stress and neuroinflammation are critical events in Parkinson's disease.•DDO-7263, an Nrf2 activator, has ideal therapeutic effects on MPTP-induced PD in mice.•Neuroprotective effect of DDO-7263 was mediated by Nrf2 activation and NLRP3 inflammasome inhibition.•DDO-7263 induced NLRP3 inflammasome inhibition is dependent on Nrf2 activation.•Tissue distribution results of DDO-7263 explored its brain tissue targeting function.