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Free Radic Biol Med. 2019 Jan 4. pii: S0891-5849(18)32323-2. doi: 10.1016/j.freeradbiomed.2019.01.003. [Epub ahead of print]

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.

Author information

1
State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China; Key Laboratory on Protein Chemistry and Structural Biology, Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education, China Pharmaceutical University, Nanjing 210009, China.
2
Key Laboratory on Protein Chemistry and Structural Biology, Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education, China Pharmaceutical University, Nanjing 210009, China.
3
State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China. Electronic address: youqd@163.com.
4
State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China. Electronic address: jiangzhengyucpu@163.com.
5
Key Laboratory on Protein Chemistry and Structural Biology, Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education, China Pharmaceutical University, Nanjing 210009, China. Electronic address: dibin@cpu.edu.cn.

Abstract

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.

KEYWORDS:

Brain targeting function; NLRP3 inflammasome; Nrf2-ARE activator; Oxidative stress; Parkinson's disease

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