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Abstract Title:

Natural product piperine alleviates experimental allergic encephalomyelitis in mice by targeting dihydroorotate dehydrogenase.

Abstract Source:

Biochem Pharmacol. 2020 Jul ;177:114000. Epub 2020 Apr 28. PMID: 32353424

Abstract Author(s):

Zehui Liu, Qian Hu, Wanyan Wang, Sisi Lu, Dang Wu, Shuyin Ze, Jiacheng He, Ying Huang, Wuyan Chen, Yechun Xu, Weiqiang Lu, Jin Huang

Article Affiliation:

Zehui Liu

Abstract:

Multiple sclerosis (MS) is the most popular chronic and debilitating inflammatory disease of the central nervous system (CNS) that remains incurable. Dihydroorotate dehydrogenase (DHODH) is critical to the activity of T lymphocytes and represents a potential therapeutic target for MS. Here we identify piperine, a bioactive constituent of black pepper, as a potent inhibitor of DHODH with an ICvalue of 0.88 μM. Isothermal titration calorimetry and thermofluor assay demonstrate the directly interaction between piperine and DHODH. The co-complex crystal structure of DHODH and piperine at 1.98 Å resolution further reveal that Tyr356 residue of DHODH is crucial for piperine binding. Importantly, we show that piperine can inhibit T cell overactivation in a DHODH-dependent manner in concanavalin A-triggered T-cell assay and mixed lymphocyte reaction assay. Finally, piperine exhibits strong preventive and therapeutic effect in the MOG-induced experimental allergic encephalomyelitis (EAE), a usefulmodel for studying potential treatments for MS, by restricting inflammatory cells infiltration into the CNS and preventing myelin destruction and blood-brain barrier (BBB) disruption. Taken together, these findings highlight DHODH as a therapeutic target for autoimmune disease of the nervous system,and demonstrate a novel role for piperine in the treatment of MS.

Study Type : Animal Study

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