Neuroprotective effects of CysLT2R antagonist on Angiostrongylus cantonensis-induced edema and meningoencephalitis

Abstract

Abstract Background The pathogenesis of Angiostrongylus cantonensis-induced eosinophilic meningoencephalitis includes haemorrhage, brain edema formation, disrupting the blood–brain barrier (BBB), and induction of an inflammatory response. Cysteinyl leukotrienes (CysLTs) can induce a disruption of the BBB, and this reaction is mediated by cysteinyl-leukotriene receptors. In this study, we used A. cantonensis-induced eosinophilic meningoencephalitis as a model to investigate whether the CysLT2 receptor involved in the pathogenesis of angiostrongyliasis meningoencephalitis. Methods The brain edema was determined using the wet weight/dry weight method. Microglia polarization was detected by Flow cytometry and Enzyme-linked immunosorbent assay. Evans blue method was used to measure changes in the blood brain barrier, while western blotting was used to analyze BBB-related proteins. Gelatin zymography was used to assay matrix metalloproteinase-9 (MMP-9). MicroRNA expression was detected by Quantitative reverse transcription-PCR (qRT-PCR). Results The present study provides evidence that the CysLT2 receptor antagonist HAMI3379 reduced the number of infiltrated eosinophils and brain edema in eosinophilic meningoencephalitis. Additionally, we found that HAMI3379 significantly decreased the protein levels of M1 polarisation markers (CD80, iNOS, IL-5 and TNF-α), increased the expression of M2 polarisation markers (CD206, IL-10 and TGF-β) both in vivo and in vitro. Matrix metalloproteinase-9, S100B, GFAP, fibronectin, and claudin-5 were markedly lower after HAMI3379 treatment. Therefore, HAMI3379 reduced the BBB dysfunction in angiostrongyliasis meningoencephalitis. We have identified microRNA-155 as a BBB dysfunction marker in eosinophilic meningoencephalitis. The results showed that microRNA-155 was 15-fold upregulated in eosinophilic meningoencephalitis and 20-fold upregulated after HAMI3379 treatment. Conclusions Our results suggest that CysLT2R may be involved in A. cantonensis-induced brain edema and eosinophilic meningoencephalitis and that down-regulation of CysLT2R could be a novel and potential therapeutic strategy for the treatment of angiostrongyliasis meningoencephalitis.