Data Convergence Drug Research Center, Therapeutics & Biotechnology Division, Research Institute of Chemical Technology, 141 Gajeong-ro, Yuseong-gu, Daejeon, 34114, Korea.
College of Pharmacy, Chungnam National University, Daejeon, Korea.
BMC Neurosci. 2023 Jul 31;24(1):39. doi: 10.1186/s12868-023-00810-7.
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 cm/s) and moderate (3.72-7.18 × 10 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.
几种磷酸二酯酶 4（PDE4）抑制剂已成为治疗中枢神经系统（CNS）疾病的潜在治疗药物。本研究探讨了两种选择性 PDE4 抑制剂罗氟司特和扎托米司特对脂多糖诱导的神经炎症的药理作用。
在 BV-2 细胞中，PDE4 抑制剂罗氟司特通过抑制 NF-κB 磷酸化来减少一氧化氮和肿瘤坏死因子-α（TNF-α）的产生。此外，给予罗氟司特的小鼠的血浆和脑组织中的 TNF-α、白细胞介素-1β（IL-1β）和 IL-6 水平显著降低。相比之下，PDE4D 抑制剂扎托米司特在体外或体内均无抗神经炎症作用。接下来，对这些化合物在大脑中的体外和体内药代动力学进行了研究。3µM 罗氟司特和扎托米司特的表观渗透系数均较高（>23×10cm/s）且适中（3.72-7.18×10cm/s），并在 MDR1-MDCK 单层中呈浓度依赖性增加。外排比<1.92，表明这些化合物不是 P-糖蛋白的底物。口服给药后，罗氟司特和扎托米司特均缓慢吸收和消除，达峰时间为 2-2.3h，终末半衰期为 7-20h。评估它们的大脑分布情况发现，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，罗氟司特而非扎托米司特具有作为神经炎症性疾病治疗药物的潜力。
