PBT434 methanesulfonate

PBT434 methanesulfonate is a potent, orally active and cross the blood-brain barrier α-synuclein aggregation inhibitor. PBT434 methanesulfonate can be used as a iron chelator and modulates transcellular iron trafficking. PBT434 methanesulfonate inhibits iron-mediated redox activity and iron-mediated aggregation of α-synuclein. PBT434 methanesulfonate prevents the loss of substantia nigra pars compacta neurons (SNpc). PBT434 methanesulfonate has the potential for the research of Parkinson’s disease (PD)[1][2].

Research Areas >> Neurological Disease

PBT434 methanesulfonate (0-20 µM；3 小时) 显着抑制铁产生的 H2O2，并显着降低 Fe 介导的 α-突触核蛋白聚集速率[1]。 PBT434 methanesulfonate (0-100 µM; 24 h) 对脑微血管内皮细胞没有细胞毒性作用[2]。 PBT434 methanesulfonate (20 µM; 24 h) 增加 hBMVEC 中总 TfR、Cp 蛋白水平的表达[2]。 Cell Cytotoxicity Assay[2] Cell Line: hBMVEC Concentration: 1, 10, 20, 50, 100 µM Incubation Time: 24 h Result: Showed no cytotoxic effects on brain microvascular endothelial cells. Western Blot Analysis[2] Cell Line: hBMVEC Concentration: 20 μM Incubation Time: 24 h Result: Increased the expression of total TfR, Cp protein level.

PBT434 methanesulfonate (30 mg/kg；口服；每日一次，持续 21 天) 显着保留了 6-OHDA 毒模型中的神经元数量，并在 L-DOPA 模型中显示出明显更少的旋转，显着减少了 MPTP 模型中的 SNpc 神经元损失[ 1]。 Animal Model: 12 weeks, 25 g, Male C57BL/6 J mice (6-OHDA intoxication model)[1] Dosage: 30 mg/kg Administration: P.o.; daily for 21 days (commencing 3 days following induction of lesion) Result: Prevented neuronal loss following 6-OHDA, preserving up to 75% of the SNpc neurons remaining (both Nissl and tyrosine hydroxylase (TH) positive neurons) after the initial phase of cell death. Animal Model: 12 weeks, 25 g, Male C57BL/6 J mice (MPTP model)[1] Dosage: 1, 3, 10, 30, 80 mg/kg Administration: P.o.; daily for 21 days (commenced 24 h after induction of lesion) Result: Increased the proportion of SNpc cells rescued, increased there was a trend to improved turning behavior, significantly increased varicosity abundance, prevented the decline in levels of the presynaptic marker synaptophysin (SYNP) in a dose-dependent manner.

[1]. Finkelstein DI, et al. The novel compound PBT434 prevents iron mediated neurodegeneration and alpha-synuclein toxicity in multiple models of Parkinson's disease. Acta Neuropathol Commun. 2017 Jun 28;5(1):53.  

[2]. Bailey DK, Clark W, Kosman DJ. The iron chelator, PBT434, modulates transcellular iron trafficking in brain microvascular endothelial cells. PLoS One. 2021 Jul 26;16(7):e0254794.