Leflunomide

Leflunomide (HWA486) is a pyrimidine biosynthesis inhibitor that acts by inhibiting dihydroorotate dehydrogenase (DHODH) and has anti-rheumatic effects^[1]. Leflunomide is a low molecular weight synthetic oral drug specifically developed for immunosuppression^[2]. Leflunomide is rapidly converted to its pharmacologically active metabolite A-771726 in vivo^[3].

In vitro, treatment of neuroblastoma cell lines (BE(2)-C, SK-N-DZ, and SK-N-F1 cells) with leflunomide (12.5-100µM) for 6 days reduced cell growth in a dose- and time-dependent manner. Treatment with 100µM leflunomide for 72h reduced cell number by more than 60% and induced S phase cell cycle arrest and apoptosis^[4]. Leflunomide (10µM) treatment of Jurkat cells for 2h blocked tumor necrosis factor (TNF)-induced I-κBα (NF-κB inhibitory subunit) phosphorylation and IκB kinase β (IKK-β) activation^[5].

In vivo, oral treatment of experimental autoimmune uveitis (EAU) rats with leflunomide (3, 6, 12mg/kg) for 2 weeks significantly prevented and treated EAU, reduced clinical and pathological scores, reduced serum IL17 and IFN-γ levels, and reduced the number of Th17 cells^[6]. Leflunomide (4, 20mg/kg) was orally treated in experimental autoimmune neuritis (EAN) rats, significantly preventing and treating EAN, protecting nerves from more extensive demyelination and axonal degeneration, and reducing the number of T cells and activated macrophages in the endoneurium^[7].

References:
[1] Kaur H, Sarma P, Bhattacharyya A, et al. Efficacy and safety of dihydroorotate dehydrogenase (DHODH) inhibitors “leflunomide” and “teriflunomide” in Covid-19: A narrative review[J]. European journal of pharmacology, 2021, 906: 174233.
[2] Cannon G W, Kremer J M. Leflunomide[J]. Rheumatic Disease Clinics, 2004, 30(2): 295-309.
[3] Herrmann M L, Schleyerbach R, Kirschbaum B J. Leflunomide: an immunomodulatory drug for the treatment of rheumatoid arthritis and other autoimmune diseases[J]. Immunopharmacology, 2000, 47(2-3): 273-289.
[4] Zhu S, Yan X, Xiang Z, et al. Leflunomide reduces proliferation and induces apoptosis in neuroblastoma cells in vitro and in vivo[J]. PloS one, 2013, 8(8): e71555.
[5] Manna S K, Mukhopadhyay A, Aggarwal B B. Leflunomide suppresses TNF-induced cellular responses: effects on NF-κB, activator protein-1, c-Jun N-terminal protein kinase, and apoptosis[J]. The Journal of Immunology, 2000, 165(10): 5962-5969.
[6] Fang C, Zhou D, Zhan S, et al. Amelioration of experimental autoimmune uveitis by leflunomide in Lewis rats[J]. PloS one, 2013, 8(4): e62071.
[7] Korn T, Toyka K, Hartung H P, et al. Suppression of experimental autoimmune neuritis by leflunomide[J]. Brain, 2001, 124(9): 1791-1802.

Leflunomide（来氟米特; HWA486）是一种嘧啶生物合成抑制剂，通过抑制二氢乳清酸脱氢酶 （DHODH）起作用，具有抗风湿的作用^[1]。Leflunomide是一种低分子量合成口服药物，专门开发用于免疫抑制^[2]。Leflunomide在体内迅速转化为其药理活性代谢物A-771726^[3]。

在体外，Leflunomide（12.5-100µM）处理神经母细胞瘤细胞系（BE(2)-C、SK-N-DZ和SK-N-F1细胞）6d，剂量和时间依赖性地减少了细胞生长，100µM Leflunomide处理72h使细胞数量均减少了60%以上，并诱导了S期细胞周期停滞和细胞凋亡^[4]。Leflunomide（10µM）处理Jurkat细胞2h，阻断了肿瘤坏死因子（TNF）诱导的I-κBα（NF-κB抑制亚基）磷酸化和IκB激酶β（IKK-β）激活^[5]。

在体内，Leflunomide（3、6、12mg/kg）通过口服治疗实验性自身免疫性葡萄膜炎（EAU）大鼠2周，显著预防和治疗了EAU，并降低了临床和病理评分，降低了血清IL17和IFN-γ水平，减少了Th17细胞数量^[6]。Leflunomide（4、20mg/kg）通过口服治疗实验性自身免疫性神经炎（EAN）大鼠，显著预防和治疗了EAN，保护神经免受更广泛的脱髓鞘和轴突变性，减少了神经内膜内T细胞和活化巨噬细胞的数量^[7]。