Penehyclidine hydrochloride inhibits the LPS-induced inflammatory response in microglia

Background: Activated microglia play an important role in neuroinflammation, which contributes to the neuronal damage found in many neurodegenerative diseases. Penehyclidine hydrochloride (PHC) is an anesthetic used before surgical operations, but also exhibits anti-inflammatory effects on the respiratory and digestive system. In the present study, we investigated whether PHC produces similar anti-inflammatory effects in activated microglia in the central nervous system. Materials and methods: Microglial cells were incubated with lipopolysaccharide (LPS) in the presence or absence of various concentrations of PHC, SB203580 (p38 mitogen-activated protein kinase [MAPK] inhibitor), and pyrrolidine dithiocarbamate (nuclear factor-kappa B [NF-kappa B] inhibitor). Markers of inflammation and oxidative stress were measured using enzyme-linked immunosorbent assay and quantitative real-time polymerase chain reaction. The effect of PHC on NF-kappa B activity was assessed with a NF-kappa B p50/p65 transcription factor assay kit. The involvement of p38 MAPK phosphorylation in the anti-inflammatory effects of PHC was evaluated with a specific enzyme-linked immunosorbent assay kit for phospho-p38. Results: PHC significantly inhibited the release of nitric oxide, prostaglandin E-2, interleukin 1 beta, and tumor necrosis factor alpha while upregulating the expression of inducible nitric oxide synthase messenger RNA in LPS-activated microglia. Moreover, PHC effectively inhibited the translocation of NF-kappa B from the cytoplasm to the nucleus and the phosphorylation of p38 MAPK. The activities of NF-kappa B and p38 MAPK in LPS-treated microglia were significantly lowered after pretreatment of PHC. Conclusions: PHC inhibited the LPS-induced release of inflammatory mediators in microglia. These inhibitory effects of PHC may be mediated by blocking p38 MAPK and NF-kappa B pathways in microglia. These preclinical findings may offer a novel therapeutic option to confine microglial overactivation in neurodegenerative diseases. (C) 2014 Published by Elsevier Inc.