JNJ-28583113 is an TRPM2 antagonist with brain permeability. JNJ-28583113 inhibits TRPM2 blocked phosphorylation of GSK3α and β subunits. JNJ-28583113 protects cells from oxidative stress induced cell death. JNJ-28583113 also suppresses cytokine release in response to pro-inflammatory stimuli in microglia[1].
JNJ-28583113 分别抑制不同物种中的 TRPM2，抑例如黑猩猩 (IC50=100 nM)、大鼠 (IC50=25 nM) 和人 (IC50=126 nM)[1]。
JNJ-28583113 (3 nM、30 nM 和 1 μM；200 秒) 在 hTRPM2-HEK 诱导细胞中记录的 ADPR 诱导电流中表现出电物理特性[1]。
JNJ-28583113 (10 μM；1 小时）防止细胞因 H2O2 诱导的细胞死亡，最高处理条件为 1mM H2O2。JNJ-28583113 (10 μM；1 小时) 还保护 HeLa 细胞免受 H2O2 (10 μM；1 小时) 诱导的形态变化[1]。
Western Blot Analysis[1]
| Cell Line: | hTRPM2-HEK cells |
| Concentration: | 10 μM |
| Incubation Time: | 30 min |
| Result: | Recovered phosphorylation of GSK3α and β subunits which inhibited by H2O2 (300 μM; 10 min). |
JNJ-28583113 (10 mg/kg，2?ml/kg；sc；单剂量) 具有脑穿透性，在脑室中可达 400?ng/mL[1]。
| Animal Model: | Harlan Sprague Dawley Rats (400 g)[1] |
| Dosage: | 10 mg/kg, 2?mL/kg |
| Administration: | SC; sampled at 0.5, 2, or 6?h post dosing |
| Result: | Quickly metabolized in the plasma, while it showed high levels in plasma and low levels in the brain. |
[1]. Fourgeaud L, et al. Pharmacology of JNJ-28583113: A novel TRPM2 antagonist. Eur J Pharmacol. 2019 Jun 15;853:299-307.