BAF312 (Siponimod) is a selective and orally active sphingosine-1-phosphate (S1P) receptor agonist, with the EC50 values of 0.39, 750, and 0.98nM for S1P1, S1P4, and S1P5 receptors, respectively [1]. BAF312 maintains the stability of the endothelial barrier by regulating the S1P receptors in microglia and enhances the endothelial barrier function of the blood-brain barrier (BBB)[2]. BAF312 has been widely used to improve the neurological function, repair GABAergic deficits in the striatum, and alleviate inflammatory responses in experimental autoimmune encephalomyelitis animal models [3].
In vitro, BAF312 treatment for 48 hours significantly inhibited the viability of mouse bone marrow macrophages (BMM), with an IC50 value of 45.38µM[4]. 1µM BAF312 treatment for 30 minutes significantly increased the phosphorylation of ERK and AKT in mouse astrocytes and induced the internalization of S1P1[5]. Treatment with 20µM BAF312 for 72 hours inhibited the G1-S phase transition of U118MG cells, significantly upregulated the expression level of pro-apoptotic protein Bax, and downregulated the expression level of anti-apoptotic protein Bcl-2, thereby inducing cell apoptosis[6].
In vivo, BAF312 treatment via oral administration at a dose of 10mg/kg/day for 7 days can protect the structure and function of the inner layer of the retina in mice from the damage caused by acute excitotoxicity of N-methyl-D-aspartate (NMDA) and diminish NMDA-induced activation of NLRP3 inflammasome and upregulation of neurotoxic inducible nitric oxide synthase (iNOS) [7]. For three consecutive days, a daily intraperitoneal injection of 0.3mg/kg dose of BAF312 was administered, which significantly reduced brain edema in the experimental mouse model of intracerebral hemorrhage (ICH), increased survival rate, and alleviated the sensory-motor dysfunction caused by ICH[8].
References:
[1] Gergely P, Nuesslein‐Hildesheim B, Guerini D, et al. The selective sphingosine 1‐phosphate receptor modulator BAF312 redirects lymphocyte distribution and has species‐specific effects on heart rate[J]. British journal of pharmacology, 2012, 167(5): 1035-1047.
[2] Spampinato S F, Costantino G, Merlo S, et al. Microglia contributes to baf-312 effects on blood–brain barrier stability[J]. Biomolecules, 2022, 12(9): 1174.
[3] Gentile A, Musella A, Bullitta S, et al. Effects of siponimod (BAF312) on inflammation-driven synaptopathy in experimental multiple sclerosis (P5. 311)[J]. Neurology, 2016, 86(16_supplement): P5. 311.
[4] Hu S, Hu Y, Tan Z, et al. Repurposing the multiple sclerosis drug Siponimod for osteoporosis treatment[J]. European Journal of Pharmacology, 2024, 974: 176630.
[5] O’Sullivan C, Schubart A, Mir A K, et al. The dual S1PR1/S1PR5 drug BAF312 (Siponimod) attenuates demyelination in organotypic slice cultures[J]. Journal of Neuroinflammation, 2016, 13(1): 31.
[6] Qin Q, Zhou Y, Feng M, et al. BAF312 Inhibits the Growth of Glioma and Promotes the Normalization of Tumor Blood Vessels[J]. The FASEB Journal, 2025, 39(16): e70941.
[7] Basavarajappa D, Gupta V, Chitranshi N, et al. Anti-inflammatory effects of siponimod in a mouse model of excitotoxicity-induced retinal injury[J]. Molecular Neurobiology, 2023, 60(12): 7222-7237.
[8] Bobinger T, Manaenko A, Burkardt P, et al. Siponimod (BAF-312) attenuates perihemorrhagic edema and improves survival in experimental intracerebral hemorrhage[J]. Stroke, 2019, 50(11): 3246-3254.
BAF312 (Siponimod)是一种选择性、口服有效的sphingosine-1-phosphate (S1P)受体激动剂，对S1P1、S1P4和S1P5受体的EC50值分别为0.39nM、750nM和0.98nM[1]。BAF312通过调节小胶质细胞中的S1P受体来维持内皮屏障的稳定性，并增强血脑屏障（BBB）的内皮屏障功能[2]。BAF312已被广泛用于改善实验性自身免疫性脑脊髓炎动物模型的神经功能，修复纹状体中的GABA能缺陷，并减轻炎症反应[3]。
在体外，BAF312处理48小时显著抑制了小鼠骨髓巨噬细胞的活力，IC50值为45.38µM[4]。1µM的BAF312处理小鼠星形胶质细胞30分钟，显著增加了ERK和AKT的磷酸化，并诱导了S1P1的内化[5]。用20µM的BAF312处理U118MG细胞72小时，抑制了细胞G1-S期转变，显著上调了促凋亡蛋白Bax的表达水平，并下调了抗凋亡蛋白Bcl-2的表达水平，从而诱导细胞凋亡[6]。
在体内，每日口服10mg/kg剂量的BAF312，连续7天，可保护小鼠视网膜内层结构和功能免受N-methyl-D-aspartate (NMDA)急性兴奋性毒性的损伤，并减少NMDA诱导的NLRP3炎症小体活化和神经毒性诱导型一氧化氮合酶(iNOS)的上调[7]。连续三天每日腹腔注射0.3mg/kg剂量的BAF312，可显著减轻实验性脑出血（ICH）小鼠模型的脑水肿，提高存活率，并减轻ICH引起的感觉运动功能障碍[8]。