Differential effects of two phosphodiesterase 4 inhibitors against lipopolysaccharide-induced neuroinflammation in mice

BMC Neuroscience

Research

Jung Woo Chae¹  Sunjoo Ahn²  Jin Sook Song²  Dong Ho Kang³ 

[1] College of Pharmacy, Chungnam National University, Daejeon, Korea;Data Convergence Drug Research Center, Therapeutics & Biotechnology Division, Research Institute of Chemical Technology, 141 Gajeong-ro, Yuseong-gu, 34114, Daejeon, Korea;Data Convergence Drug Research Center, Therapeutics & Biotechnology Division, Research Institute of Chemical Technology, 141 Gajeong-ro, Yuseong-gu, 34114, Daejeon, Korea;College of Pharmacy, Chungnam National University, Daejeon, Korea;

关键词: PDE4B;    PDE4D;    Neuroinflammation;    Roflumilast;    Zatolmilast;    Brain dispostion;   

DOI  :  10.1186/s12868-023-00810-7

 received in 2023-03-09, accepted in 2023-07-06,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundSeveral 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.ResultsIn 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.ConclusionsThese findings suggest that roflumilast, but not zatolmilast, has the potential for use as a therapeutic agent against neuroinflammatory diseases.

【 授权许可】

CC BY   
© The Author(s) 2023

【 图 表 】

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