Vinpocetine Suppresses Streptococcus pneumoniae–Induced Inflammation via Inhibition of ERK1 by CYLD

Abstract

Otitis media (OM) is the most common bacterial infection in children. It remains a major health problem and a substantial socioeconomic burden. Streptococcus pneumoniae (S. pneumoniae) is one of the most common bacterial pathogens causing OM. Innate inflammatory response plays a critical role in host defense against bacterial pathogens. However, if excessive, it has a detrimental impact on the middle ear, leading to middle ear inflammation, a hallmark of OM. Currently, there has been limited success in developing effective therapeutic agents to suppress inflammation without serious side effects. In this study, we show that vinpocetine, an antistroke drug, suppressed S. pneumoniae-induced inflammatory response in cultured middle ear epithelial cells as well as in the middle ear of mice. Interestingly, vinpocetine inhibited S. pneumoniae-induced inflammation via upregulating a key negative regulator cylindromatosis (CYLD). Moreover, CYLD suppressed S. pneumoniae-induced inflammation via inhibiting the activation of ERK. Importantly, the postinfection administration of vinpocetine markedly inhibited middle ear inflammation induced by S. pneumoniae in a well-established mouse OM model. These studies provide insights into the molecular mechanisms underlying the tight regulation of inflammation via inhibition of ERK by CYLD and identified vinpocetine as a potential therapeutic agent for suppressing the inflammatory response in the pathogenesis of OM via upregulating negative regulator CYLD expression.

The inhibitory effect of the deubiquitinase cylindromatosis (CYLD) on inflammatory responses in human gingival fibroblasts

“…Recent studies, including our own, have suggested that A20 participates in the pathogenesis of periodontitis (Crump et al., 2017; Hong et al., 2016; Mooney & Sahingur, 2020; Yan et al., 2020). Besides, A20, another negative regulator of NF‐κB signalling, is the CYLD protein, which functions as an important modulator of tumorigenesis and inflammatory responses, by inhibiting NF‐κB activation (Hrdinka et al., 2016; Komatsu et al., 2020; Lork et al., 2017; Mukherjee et al., 2020; Sato et al., 2015). Given the role of CYLD in restricting NF‐κB signalling and inflammation resolution, it is reasonable to speculate that CYLD may have an inhibitory effect on periodontal inflammatory responses.…”

Attenuated effects of topical vinpocetine in an imiquimod-induced mouse model of psoriasis

“…VNP's ability to increase cylindromatosis, a key inflammatory suppressor, and block MAPK and ERK activity, thereby decreasing S. pneumoniae -induced inflammation, clarifies these findings. 128 Likewise, Zhou and colleagues have found that VNP decreases levels of TNF-α and IL-6 cytokine peptides in murine microgliocytes challenged by LPS. 129 Notably, the medication suppresses the mRNA levels of TLR4 and TLR2 and their key signalling molecules, including the mitogen-activated protein kinase (MAPK) cascade and MYD88.…”

Dysregulation of immune response in otitis media

“…Another agent, vinpocetine, which suppresses inflammation induced by S. pneumoniae through inhibition of ERK (Ref. 99 ) reduces middle ear inflammation in a murine model of OM. To date, none of these have been trialled in human OM.…”