Anti-inflammatory and immunomodulatory effects of valproate and carbamazepine involve distinct signaling in human peripheral blood mononuclear cells.

IF 2.9 4区 医学 Q3 IMMUNOLOGY
Goran Popović, Sara Rakočević, Miodrag Čolić, Ljiljana Kozić, Marija Drakul, Vanja Mališ, Dejan Bokonjić, Dušan Mihajlović
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引用次数: 0

Abstract

Objectives: Epilepsy is a chronic neurological condition with complex etiopathogenesis, treated with antiepileptics. In addition to their ability to regulate the activation threshold of neurons, antiepileptics have demonstrated a potential in shaping inflammation and the immune response. The main objective of our study was to analyze the effects of valproate, carbamazepine, and lamotrigine (commonly used antiepileptics) on viability, lymphocyte proliferation, and cytokine production by human peripheral blood mononuclear cells (PBMCs).

Methods: PBMCs were treated with different concentrations of antiepileptics, with or without phytohemagglutinin (PHA). Cytotoxicity, assessed by viability and apoptosis/necrosis assay, was determined by flow cytometry using the Annexin V/Propidium iodide (PI) staining method. Proliferation was determined using the MTT assay, whereas cytokine levels were assessed by the ELISA assay. A selective peroxisome proliferator-activated receptor gamma (PPAR-γ) antagonist (SR-202) was used to evaluate the involvement of PPAR-γ.

Results: Nontoxic concentrations of valproate and carbamazepine reduced the levels of three major proinflammatory cytokines (IL-1β, TNF-α, and IL-6) and impaired Th1 and Treg responses, without affecting the Th2 response. Lamotrigine did not exhibit immunomodulatory properties in this model. The effect of valproate on the production of proinflammatory and Th1 cytokines was significantly reversed by inhibiting PPAR-γ. In contrast, the blockade did not modify the effects of carbamazepine.

Conclusion: Our results demonstrated that valproate and carbamazepine, although similarly modulating the immune response in vitro, utilize different signaling mechanisms, in contrast to lamotrigine, which did not exhibit immunomodulatory effects.

丙戊酸和卡马西平的抗炎和免疫调节作用涉及人外周血单个核细胞的不同信号。
目的:癫痫是一种病因复杂的慢性神经系统疾病,常用抗癫痫药物治疗。除了调节神经元激活阈值的能力外,抗癫痫药还显示出在形成炎症和免疫反应方面的潜力。本研究的主要目的是分析丙戊酸、卡马西平和拉莫三嗪(常用的抗癫痫药)对人外周血单核细胞(PBMCs)的生存能力、淋巴细胞增殖和细胞因子产生的影响。方法:用不同浓度的抗癫痫药治疗pbmc,加或不加植物血凝素(PHA)。采用膜联蛋白V/碘化丙啶(PI)染色法,流式细胞术检测细胞毒性,通过活力和凋亡/坏死试验评估细胞毒性。增殖用MTT法测定,细胞因子水平用ELISA法测定。使用选择性过氧化物酶体增殖物激活受体γ (PPAR-γ)拮抗剂(SR-202)来评估PPAR-γ的参与。结果:无毒浓度的丙戊酸和卡马西平降低了三种主要的促炎细胞因子(IL-1β、TNF-α和IL-6)的水平,损害了Th1和Treg的反应,而不影响Th2的反应。拉莫三嗪在该模型中不表现出免疫调节特性。丙戊酸对促炎和Th1细胞因子产生的影响可通过抑制PPAR-γ而显著逆转。相反,阻断剂并没有改变卡马西平的作用。结论:我们的研究结果表明,丙戊酸钠和卡马西平虽然在体外调节免疫反应相似,但利用不同的信号机制,而拉莫三嗪不表现出免疫调节作用。
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来源期刊
CiteScore
5.40
自引率
0.00%
发文量
133
审稿时长
4-8 weeks
期刊介绍: The journal Immunopharmacology and Immunotoxicology is devoted to pre-clinical and clinical drug discovery and development targeting the immune system. Research related to the immunoregulatory effects of various compounds, including small-molecule drugs and biologics, on immunocompetent cells and immune responses, as well as the immunotoxicity exerted by xenobiotics and drugs. Only research that describe the mechanisms of specific compounds (not extracts) is of interest to the journal. The journal will prioritise preclinical and clinical studies on immunotherapy of disorders such as chronic inflammation, allergy, autoimmunity, cancer etc. The effects of small-drugs, vaccines and biologics against central immunological targets as well as cell-based therapy, including dendritic cell therapy, T cell adoptive transfer and stem cell therapy, are topics of particular interest. Publications pointing towards potential new drug targets within the immune system or novel technology for immunopharmacological drug development are also welcome. With an immunoscience focus on drug development, immunotherapy and toxicology, the journal will cover areas such as infection, allergy, inflammation, tumor immunology, degenerative disorders, immunodeficiencies, neurology, atherosclerosis and more. Immunopharmacology and Immunotoxicology will accept original manuscripts, brief communications, commentaries, mini-reviews, reviews, clinical trials and clinical cases, on the condition that the results reported are based on original, clinical, or basic research that has not been published elsewhere in any journal in any language (except in abstract form relating to paper communicated to scientific meetings and symposiums).
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