以及对毒扁豆碱类似物的探索，以了解Klotho与癫痫靶点之间的机制性相互作用。

and exploration of physostigmine analogues to understand the mechanistic crosstalk between Klotho and targets for epilepsy.

作者信息

Dahalia Mansi, Majid Haya, Khan Mohd Junaid, Rathi Akshat, Khan Mohd Ashif, Khan Imran Ahmd, Samim Mohammed, Rehman Sayeed Ur, Noorani Md Salik, Vohora Divya

机构信息

Department of Translational and Clinical Research, School of Chemical and Life Sciences, Jamia Hamdard, New Delhi, India.

Department of Pharmacology, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, India.

出版信息

Front Pharmacol. 2025 Apr 25;16:1580943. doi: 10.3389/fphar.2025.1580943. eCollection 2025.

DOI:10.3389/fphar.2025.1580943

PMID:40351444

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12062037/

Abstract

BACKGROUND

Epilepsy and seizures are characterized by neuronal hyperexcitability and damage, influenced by metabolic dysregulation, neuroinflammation, and oxidative stress. Despite available treatments, many patients remain resistant to therapy, necessitating novel therapeutic strategies. Klotho, a neuroprotective, anti-inflammatory, and antioxidative protein has emerged as a potential modulator of epilepsy-related pathways.

OBJECTIVE

This study investigates the therapeutic potential of novel physostigmine analogues in regulating Klotho expression and its downstream targets in epilepsy.

METHODS

An integrative and approach was employed in PTZ-induced kindled mice. Behavioral assessments, including the Morris Water Maze (MWM), Rota Rod, Black and White Box, and Tail Suspension tests were conducted. Biochemical analyses quantified serum glucose, lipid profiles, pro-inflammatory cytokines (TNF-α, FOXO1), and apoptotic proteins (caspase-3). Quantitative real-time PCR (qRT-PCR) was performed to assess Klotho and epilepsy-associated gene expression (STAT3, Bax, Bcl2).

RESULTS

The synthesized physostigmine analogues exhibited varying inhibitory effects on Klotho transcriptional activators, with Compound C (1,8-bis(phenylsulfonyl)-1,8-dihydropyrrolo [2,3-b] indole) showing the weakest inhibition (IC50 = 1.31 µM). , Compound C demonstrated anticonvulsant (p < 0.05), neuroprotective (5 mg/kg, p < 0.05, 10 mg/kg, p < 0.01, 20 mg/kg p < 0.0001), antidepressant (p < 0.05), and anti-inflammatory (p < 0.05) effects in PTZ-induced seizure models, improving motor function (p < 0.001), cognitive performance (p < 0.01), and reducing neuroinflammatory/metabolic markers (p < 0.05), while modulating STAT3 (p < 0.001), BAX (p < 0.001), Bcl2 (p < 0.05), and Klotho (p < 0.05) gene expression.

CONCLUSION

The therapeutic potential of 1,8-bis(phenylsulfonyl)-1,8-dihydropyrrolo [2,3-b] indole in epilepsy Klotho modulation was observed. Targeting metabolic, inflammatory, and apoptotic pathways presents a promising strategy for epilepsy management. Further research is required to optimize clinical translation and ensure long-term efficacy and safety.

摘要

背景

癫痫和癫痫发作的特征是神经元过度兴奋和损伤，受代谢失调、神经炎症和氧化应激影响。尽管有可用的治疗方法，但许多患者对治疗仍有抵抗性，因此需要新的治疗策略。α-klotho是一种具有神经保护、抗炎和抗氧化作用的蛋白质，已成为癫痫相关通路的潜在调节因子。

目的

本研究探讨新型毒扁豆碱类似物在调节癫痫中α-klotho表达及其下游靶点方面的治疗潜力。

方法

在戊四氮诱导的点燃小鼠中采用综合方法。进行了行为评估，包括莫里斯水迷宫（MWM）、转棒试验、黑白箱试验和悬尾试验。生化分析定量检测了血清葡萄糖、血脂谱、促炎细胞因子（TNF-α、FOXO1）和凋亡蛋白（caspase-3）。采用定量实时PCR（qRT-PCR）评估α-klotho和癫痫相关基因的表达（STAT3、Bax、Bcl2）。

结果

合成的毒扁豆碱类似物对α-klotho转录激活剂表现出不同程度的抑制作用，化合物C（1,8-双（苯磺酰基）-1,8-二氢吡咯并[2,3-b]吲哚）的抑制作用最弱（IC50 = 1.31 μM）。此外，在戊四氮诱导的癫痫模型中，化合物C表现出抗惊厥作用（p < 0.05）、神经保护作用（5 mg/kg，p < 0.05；10 mg/kg，p < 0.01；20 mg/kg，p < 0.0001）、抗抑郁作用（p < 0.05）和抗炎作用（p < 0.05），改善了运动功能（p < 0.001）、认知能力（p < 0.01），并降低了神经炎症/代谢标志物水平（p < 0.05），同时调节了STAT3（p < 0.001）、BAX（p < 0.001）、Bcl2（p < 0.05）和α-klotho（p < 0.05）的基因表达。