几种磷酸二酯酶4(PDE4)抑制剂已成为中枢神经系统(CNS)疾病的潜在治疗剂。这项研究调查了两种选择性PDE4抑制剂的药理作用,罗氟司特和扎托尔米尔斯特,对抗脂多糖诱导的神经炎症。
在BV-2细胞中,PDE4抑制剂罗氟司特通过抑制NF-κB磷酸化减少一氧化氮和肿瘤坏死因子-α(TNF-α)的产生。此外,小鼠服用罗氟司特有显著降低TNF-α,白细胞介素-1β(IL-1β),血浆和脑组织中的IL-6水平。相比之下,zatolmilast,PDE4D抑制剂,在体外或体内没有抗神经炎作用。接下来,进行了这些化合物在脑中的体外和体内药代动力学研究。3µM罗氟司特和扎托尔米司特的表观渗透系数高(>23×10-6cm/s)和中等(3.72-7.18×10-6cm/s),分别,并且在MDR1-MDCK单层中以浓度依赖性方式增加。流出比<1.92,表明这些化合物不是P-糖蛋白底物。口服后,罗氟司特和扎托尔米司特都被缓慢吸收和消除,药物的峰值浓度为2-2.3h,终末半衰期为7-20h。评估其脑分布显示,罗氟司特和扎托米司特的未结合脑-血浆分配系数分别为0.17和0.18。
这些发现表明罗氟司特,但不是Zatolmilast,具有用作针对神经炎症性疾病的治疗剂的潜力。
Several phosphodiesterase 4 (PDE4) inhibitors have emerged as potential therapeutics for central nervous system (CNS) diseases. This study investigated the pharmacological effects of two selective PDE4 inhibitors, roflumilast and
zatolmilast, against lipopolysaccharide-induced neuroinflammation.
In BV-2 cells, the PDE4 inhibitor roflumilast reduced the production of nitric oxide and tumor necrosis factor-α (TNF-α) by inhibiting NF-κB phosphorylation. Moreover, mice administered roflumilast had significantly reduced TNF-α, interleukin-1β (IL-1β), and IL-6 levels in plasma and brain tissues. By contrast,
zatolmilast, a PDE4D inhibitor, showed no anti-neuroinflammatory effects in vitro or in vivo. Next, in vitro and in vivo pharmacokinetic studies of these compounds in the brain were performed. The apparent permeability coefficients of 3 µM roflumilast and
zatolmilast were high (> 23 × 10-6 cm/s) and moderate (3.72-7.18 × 10-6 cm/s), respectively, and increased in a concentration-dependent manner in the MDR1-MDCK monolayer. The efflux ratios were < 1.92, suggesting that these compounds are not P-glycoprotein substrates. Following oral administration, both roflumilast and
zatolmilast were slowly absorbed and eliminated, with time-to-peak drug concentrations of 2-2.3 h and terminal half-lives of 7-20 h. Assessment of their brain dispositions revealed the unbound brain-to-plasma partition coefficients of roflumilast and zatolmilast to be 0.17 and 0.18, respectively.
These findings suggest that roflumilast, but not
zatolmilast, has the potential for use as a therapeutic agent against neuroinflammatory diseases.