TGN020 application against aquaporin 4 improved multiple sclerosis by inhibiting astrocytes, microglia, and NLRP3 inflammasome in a cuprizone mouse model

IF 2.7 4区 医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Journal of chemical neuroanatomy Pub Date : 2023-10-01 DOI:10.1016/j.jchemneu.2023.102306
Yousef Mohamadi , Maryam Borhani-Haghighi
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引用次数: 2

Abstract

In multiple sclerosis (MS), activation of the astrocytes and microglia induces a cascading inflammatory response. Overexpression of the aquaporin 4 (AQP4) in the glia is a trigger for this reaction. This study aimed to block AQP4 by injecting TGN020 to alleviate the symptoms of MS. Total of 30 male mice were randomly divided into control (intact), cuprizone model of MS (fed with 0.2% cuprizone for 35 days), and TGN020-treated (received daily intraperitoneal injections of 200 mg/kg TGN020 with cuprizone intake) groups. Astrogliosis, M1-M2 microglia polarization, NLRP3 inflammasome activation, and demyelination were investigated in the corpus callosum by immunohistochemistry, real-time PCR, western blot, and luxol fast blue staining. The Rotarod test was performed for a behavior assessment. AQP4 inhibition caused a significant decrease in the expression of the astrocyte-specific marker, GFAP. It also changed the microglia polarization from M1 to M2 indicated by a significant downregulation of iNOS, CD86, MHC-ІІ, and upregulation of arginase1, CD206, and TREM-2. In addition, western blot data showed a significant decrease in the NLRP3, caspase1, and IL-1b proteins in the treatment group, which indicated inflammasome inactivation. The molecular changes following the TGN020 injection resulted in remyelination and motor recovery enhancement in the treatment group. In conclusion, the results draw the attention to the role of AQP4 in the cuprizone model of MS.

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在cuprizone小鼠模型中,TGN020抗水通道蛋白4通过抑制星形胶质细胞、小胶质细胞和NLRP3炎性体改善多发性硬化
在多发性硬化症(MS)中,星形胶质细胞和小胶质细胞的激活诱导级联炎症反应。水通道蛋白4(AQP4)在神经胶质中的过度表达是这种反应的触发因素。本研究旨在通过注射TGN020来阻断AQP4,以减轻MS的症状。将30只雄性小鼠随机分为对照组(完整)、多发性硬化症铜松模型组(用0.2%铜松喂养35天)和TGN020治疗组(每天腹膜内注射200mg/kg TGN020并摄入铜松)。通过免疫组织化学、实时PCR、蛋白质印迹和luxol快速蓝染色研究胼胝体中的星形胶质细胞增生、M1-M2小胶质细胞极化、NLRP3炎症小体激活和脱髓鞘。Rotarod测试是为了进行行为评估。AQP4的抑制导致星形胶质细胞特异性标志物GFAP的表达显著降低。它还通过iNOS、CD86、MHC-的显著下调和精氨酸酶1、CD206和TREM-2的上调,将小胶质细胞的极化从M1改变为M2。此外,蛋白质印迹数据显示,治疗组中NLRP3、胱天蛋白酶1和IL-1b蛋白显著降低,这表明炎症小体失活。TGN020注射后的分子变化导致治疗组髓鞘再生和运动恢复增强。总之,这些结果引起了人们对AQP4在铜腙MS模型中的作用的关注。
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来源期刊
Journal of chemical neuroanatomy
Journal of chemical neuroanatomy 医学-神经科学
CiteScore
4.50
自引率
3.60%
发文量
87
审稿时长
62 days
期刊介绍: The Journal of Chemical Neuroanatomy publishes scientific reports relating the functional and biochemical aspects of the nervous system with its microanatomical organization. The scope of the journal concentrates on reports which combine microanatomical, biochemical, pharmacological and behavioural approaches. Papers should offer original data correlating the morphology of the nervous system (the brain and spinal cord in particular) with its biochemistry. The Journal of Chemical Neuroanatomy is particularly interested in publishing important studies performed with up-to-date methodology utilizing sensitive chemical microassays, hybridoma technology, immunocytochemistry, in situ hybridization and receptor radioautography, to name a few examples. The Journal of Chemical Neuroanatomy is the natural vehicle for integrated studies utilizing these approaches. The articles will be selected by the editorial board and invited reviewers on the basis of their excellence and potential contribution to this field of neurosciences. Both in vivo and in vitro integrated studies in chemical neuroanatomy are appropriate subjects of interest to the journal. These studies should relate only to vertebrate species with particular emphasis on the mammalian and primate nervous systems.
期刊最新文献
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