Table_3_Trichostatin A, a Histone Deacetylase Inhibitor, Alleviates Eosinophilic Meningitis Induced by Angiostrongylus cantonensis Infection in Mice.DOCX

Histone deacetylase inhibitor (HDACi) has been used in the treatment of neurodegenerative or autoimmune diseases. Angiostrongyliasis cantonensis caused by Angiostrongylus cantonensis infection is an emerging zoonosis of human eosinophilic meningitis or meningoencephalitis. Progressive neuronal apoptosis is the pathological basis of behavioral dysfunctions in angiostrongyliasis cantonensis. Neurological defects after anthelmintic treatment for angiostrongyliasis cantonensis are still common. In this study, we examined the effects of trichostatin A (TSA), a HDACi, on eosinophilic meningitis induced by A. cantonensis in mice. Intragastric administration of TSA significantly ameliorated brain injury and decreased cognitive impairments in mice at 15 days post-infection. TSA administration effectively reduced the inflammatory factor levels of iNOS, TNF-α, IL-5, IL-6, and IL-13 in infected mice. TSA treatment counteracted apoptosis with reduced expression levels of cleaved caspase-3, -4, -6, and RIP3 in A. cantonensis infected mice. In addition, TSA administration reduced total HDAC activity and increased the acetylation of histone H3 and H4 in the brain tissue of infected mice. The underlying mechanism of TSA on eosinophilic meningitis might be associated with decreased NF-κB p65 nuclear accumulation by inhibiting IκB phosphorylation. Furthermore, a co-expressive network of NF-κB p65 with 22 other genes was constructed according to our previous transcriptomic data in infected mice. We identified the correlations in the gene expression of NF-κB p65 with Lrp10, Il12rb1, Nfkbia, Ube2n, and Ube2d1 in infected mice after TSA administration. Thus, TSA has a protective effect on the progression of eosinophilic meningitis induced by A. cantonensis in mice.

组蛋白去乙酰化酶抑制剂（HDACi）已被用于治疗神经退行性疾病或自身免疫性疾病。由钩口线虫（Angiostrongylus cantonensis）感染引起的嗜酸性脑膜炎或脑脊髓炎是一种新兴的人畜共患病。在钩口线虫感染中，神经元的渐进性凋亡是行为功能障碍的病理基础。在钩口线虫感染后的驱虫治疗中，神经缺陷仍然普遍存在。在本研究中，我们探讨了组蛋白去乙酰化酶抑制剂三尖杉酯碱（TSA）对由钩口线虫诱导的嗜酸性脑膜炎在小鼠中的影响。在感染后15天，TSA的胃内给药显著改善了小鼠的脑损伤并减轻了认知障碍。TSA给药有效降低了感染小鼠中炎症因子iNOS、TNF-α、IL-5、IL-6和IL-13的水平。TSA治疗通过降低裂解的caspase-3、-4、-6和RIP3的表达水平，对抗了凋亡。此外，TSA给药降低了感染小鼠大脑组织中总HDAC活性和组蛋白H3和H4的乙酰化水平。TSA对嗜酸性脑膜炎的作用机制可能与通过抑制IκB磷酸化而减少NF-κB p65在细胞核中的积累有关。进一步地，根据我们之前在感染小鼠中的转录组数据，构建了一个包含NF-κB p65与22个其他基因共表达的网络。我们发现，在TSA处理后，感染小鼠中NF-κB p65的基因表达与Lrp10、Il12rb1、Nfkbia、Ube2n和Ube2d1存在相关性。因此，TSA对由钩口线虫引起的嗜酸性脑膜炎在小鼠中的进展具有保护作用。