Memantine ameliorates pulmonary inflammation in a mice model of COPD induced by cigarette smoke combined with LPS

Biomed Pharmacother. 2019 Jan;109:2005-2013. doi: 10.1016/j.biopha.2018.11.002. Epub 2018 Nov 26.

Abstract

An enhanced chronic inflammatory response in the airways has been regarded as a critical characteristic of chronic obstructive pulmonary disease (COPD). Memantine, an N-methyl-d-aspartate (NMDA) receptors antagonist, has been reported to alleviate lung inflammation. In this study, we investigated the effect and mechanism of memantine on the COPD model induced by cigarette smoke (CS) combined with LPS. Mice and RAW264.7 cells were treated with LPS in the presence or absence of CS. We performed H&E staining to analysis the lung histopathological characteristics. Cytokines (IL-6, TNF-α, and IFN-γ) levels in bronchoalveolar lavage fluid (BALF), lung tissue homogenates and RAW264.7 cell culture medium were determined. Glutamate levels in plasma and culture medium of RAW264.7 were determined. The intracellular Ca2+ flux in RAW264.7 cells was measured by fluo-3 AM staining. The protein levels of NR-1, xCT, ERK1/2, and AKT signaling in the lung tissue and cells were investigated. The result showed that CS and LPS stimulation caused inflammation response, a significant increase in the release of cytokines, including TNF-α, IL-6, and IFN-γ, the elevated release of glutamate and protein levels of NR-1 and xCT, increased Ca2+ influx, and the activation of the ERK1/2 pathway in vitro and in vivo. The above effects of CS and LPS stimulation could be significantly attenuated by memantine treatment. In conclusion, memantine can effectively ameliorate pulmonary inflammation in CS + LPS-induced COPD in mice via reducing NR-1 and xCT expression, glutamate release, Ca2+ influx, and the phosphorylation of Erk1/2. We provided a possible mechanism by which memantine ameliorates COPD in mice.

Keywords: Chronic obstructive pulmonary disease (COPD); Cigarette smoke; Inflammation; Memantine.

MeSH terms

  • Animals
  • Disease Models, Animal
  • Excitatory Amino Acid Antagonists / therapeutic use
  • Lipopolysaccharides / toxicity*
  • Male
  • Memantine / therapeutic use*
  • Mice
  • Mice, Inbred C57BL
  • Pneumonia / chemically induced
  • Pneumonia / drug therapy*
  • Pneumonia / metabolism
  • Pulmonary Disease, Chronic Obstructive / chemically induced
  • Pulmonary Disease, Chronic Obstructive / drug therapy*
  • Pulmonary Disease, Chronic Obstructive / metabolism
  • RAW 264.7 Cells
  • Smoke / adverse effects*
  • Tobacco / adverse effects*

Substances

  • Excitatory Amino Acid Antagonists
  • Lipopolysaccharides
  • Smoke
  • Memantine