The neuroprotective and anti-neuroinflammatory effects of ramalin synthetic derivatives in BV2 and HT22 cells

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology Pub Date : 2024-11-23 DOI:10.1016/j.bcp.2024.116654

Zhiming Liu , Chi-Su Yoon , Hwan Lee , Eunae Kim , Joung Han Yim , Tai Kyoung Kim , Hyuncheol Oh , Dong-Sung Lee

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Abstract

Ramalin, a strong antioxidant isolated from Antarctic lichens, has been shown to have potential therapeutic effects in the treatment of Alzheimer’s disease. However, this compound is readily degraded in aqueous solutions, which restricts its development as a therapeutic agent. With a view toward addressing this problem, in this study, we modified the structure of ramalin to obtain more stable compounds and attempted to identify a derivative with the strongest neuroprotective properties. We synthesized a total of 20 ramalin derivatives, among which, RA-2 N was demonstrated to have the best neuroprotective effects, not only inhibiting inflammation in BV2 cells but also inhibiting inflammation-induced HT22 cell apoptosis in BV2–HT22 co-culture models. Moreover, we established that these effects were associated with an inhibition of the nuclear translocation of nuclear factor kappa-B (NF-κB). Our findings in this study revealed that the synthesis of ramalin derivatives is an effective approach for stabilizing this compound for therapeutic purposes. Given its modified structure, the RA-2 N derivative can inhibit inflammation and protect nerve cells, and thus indicate its potential application as a drug for treating neurodegenerative diseases.

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雷公藤苷合成衍生物在 BV2 和 HT22 细胞中的神经保护和抗神经炎症作用

拉玛琳是从南极地衣中分离出来的一种强抗氧化剂，已被证明对治疗阿尔茨海默氏症有潜在疗效。然而，这种化合物在水溶液中很容易降解，这限制了它作为治疗剂的发展。为了解决这一问题，在本研究中，我们改变了雷公藤苷的结构，以获得更稳定的化合物，并试图找出一种具有最强神经保护特性的衍生物。我们共合成了 20 种羊胎素衍生物，其中 RA-2 N 的神经保护效果最好，不仅能抑制 BV2 细胞的炎症反应，还能在 BV2-HT22 共培养模型中抑制炎症诱导的 HT22 细胞凋亡。此外，我们还证实这些作用与抑制核因子卡巴-B（NF-κB）的核转位有关。我们的研究结果表明，合成雷公藤苷衍生物是稳定这种化合物用于治疗目的的有效方法。鉴于 RA-2 N 衍生物的修饰结构，它可以抑制炎症和保护神经细胞，从而表明它有可能用作治疗神经退行性疾病的药物。

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来源期刊

Biochemical pharmacology 医学-药学

CiteScore

10.30

自引率

1.70%

发文量

420

审稿时长

17 days

期刊介绍： Biochemical Pharmacology publishes original research findings, Commentaries and review articles related to the elucidation of cellular and tissue function(s) at the biochemical and molecular levels, the modification of cellular phenotype(s) by genetic, transcriptional/translational or drug/compound-induced modifications, as well as the pharmacodynamics and pharmacokinetics of xenobiotics and drugs, the latter including both small molecules and biologics. The journal''s target audience includes scientists engaged in the identification and study of the mechanisms of action of xenobiotics, biologics and drugs and in the drug discovery and development process. All areas of cellular biology and cellular, tissue/organ and whole animal pharmacology fall within the scope of the journal. Drug classes covered include anti-infectives, anti-inflammatory agents, chemotherapeutics, cardiovascular, endocrinological, immunological, metabolic, neurological and psychiatric drugs, as well as research on drug metabolism and kinetics. While medicinal chemistry is a topic of complimentary interest, manuscripts in this area must contain sufficient biological data to characterize pharmacologically the compounds reported. Submissions describing work focused predominately on chemical synthesis and molecular modeling will not be considered for review. While particular emphasis is placed on reporting the results of molecular and biochemical studies, research involving the use of tissue and animal models of human pathophysiology and toxicology is of interest to the extent that it helps define drug mechanisms of action, safety and efficacy.