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.


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-κB] 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-κB activity was assessed with a NF-κB 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 E2, interleukin 1β, and tumor necrosis factor α while upregulating the expression of inducible nitric oxide synthase messenger RNA in LPS-activated microglia. Moreover, PHC effectively inhibited the translocation of NF-κB from the cytoplasm to the nucleus and the phosphorylation of p38 MAPK. The activities of NF-κB 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-κB pathways in microglia. These preclinical findings may offer a novel therapeutic option to confine microglial overactivation in neurodegenerative diseases.
Department of Anesthesia, First Hospital of Ningbo City, Ningbo, Zhejiang, China. Electronic address: changshunhuang666@outlook.com.
Changshun
C
Huang
Department of Anesthesia, First Hospital of Ningbo City, Ningbo, Zhejiang, China.
Jianguo
J
He
Department of Anesthesia, First Hospital of Ningbo City, Ningbo, Zhejiang, China.
Yijun
Y
Chen
Department of Anesthesia, First Hospital of Ningbo City, Ningbo, Zhejiang, China.
Yiwei
Y
Zhang
Department of Anesthesia, First Hospital of Ningbo City, Ningbo, Zhejiang, China.
Chunru
C
Chen
D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D015232:Dinoprostone / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D007249:Inflammation / Q000517:prevention & control*; D018836:Inflammation Mediators / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D008070:Lipopolysaccharides; D020935:MAP Kinase Signaling System; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D011812:Quinuclidines / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D018836:Inflammation Mediators; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D016328:NF-kappa B; D011812:Quinuclidines; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; C486140:penehyclidine; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D015232:Dinoprostone
Inflammation; Lipopolysaccharides; Microglia; NF-κB; Penehyclidine hydrochloride; p38 MAPK