SG06, a Chalcone Derivative Targets PI3K/AKT1 Pathway for Neuroprotection and Cognitive Enhancement in an Alzheimer's Disease-Like Zebrafish Model.

IF 4.6 2区医学 Q1 NEUROSCIENCES

Molecular Neurobiology Pub Date : 2025-05-10 DOI:10.1007/s12035-025-05023-z

Santhanam Sanjai Dharshan, Meghana R, Shreya Madhankumar Rao, B Aswinanand, Karthikeyan Ramamurthy, Muthumareeswaran Muthuramamoorthy, M Valan Arasu, Kathiravan Muthu Kumaradoss, Ajay Guru, Senthilkumar Palaniappan, Jesu Arockiaraj

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引用次数: 0

Abstract

Alzheimer's disease (AD) and Alzheimer's dementia (ADM) are common neurodegenerative disorders marked by progressive cognitive decline, memory impairment, and behavioral deficits, which impose a significant burden on individuals and healthcare systems worldwide. Due to the complex nature of AD pathophysiology, effective treatment strategies may require targeting multiple pathways. This study explored the neuroprotective effects of the chalcone derivative SG06 in a scopolamine-induced AD-like zebrafish model using network pharmacology and molecular docking. SG06 showed strong binding to key targets such as AKT serine/threonine kinase 1 (AKT1), which are involved in processes like tau phosphorylation, amyloid-beta (Aβ) production, and inflammation. Behavioral assays indicated that SG06 improved cognitive function, reduced anxiety-like behavior, and restored social interactions. Additionally, sensory recovery was observed through better light/dark transitions and recovered olfactory function, likely due to improved neuronal communication and reduced oxidative stress. Mechanistically, SG06 appeared to activate the PI3K/AKT1 pathway, inhibiting Glycogen Synthase Kinase 3 beta (GSK3β) activity, which may help reduce tau hyperphosphorylation and amyloid processing. SG06 also restored antioxidant markers (CAT, GSH, GPx) and improved acetylcholinesterase (AChE) activity, reducing oxidative damage and cholinergic dysfunction. Histological analysis revealed improved cellular morphology and decreased Aβ plaque accumulation, while gene expression studies showed downregulation of pro-inflammatory markers and upregulation of neuroprotective genes. Additionally, SG06 helped improving neurotransmitter balance, particularly in Gamma-Aminobutyric Acid (GABA) and Dopamine (DPAN), contributing to improved synaptic plasticity and cognitive function. These findings suggest that SG06 may have potential as a multi-target therapeutic agent in addressing the complex pathology of AD.

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在阿尔茨海默病样斑马鱼模型中，查尔酮衍生物SG06靶向PI3K/AKT1通路的神经保护和认知增强。

阿尔茨海默病（AD）和阿尔茨海默氏痴呆（ADM）是一种常见的神经退行性疾病，其特征是进行性认知能力下降、记忆障碍和行为缺陷，给全世界的个人和医疗保健系统带来了沉重的负担。由于阿尔茨海默病病理生理的复杂性，有效的治疗策略可能需要针对多种途径。本研究利用网络药理学和分子对接技术，探讨查尔酮衍生物SG06在东莨菪碱诱导ad样斑马鱼模型中的神经保护作用。SG06与AKT丝氨酸/苏氨酸激酶1 （AKT1）等关键靶点有很强的结合，AKT丝氨酸/苏氨酸激酶1参与tau磷酸化、β淀粉样蛋白（Aβ）产生和炎症等过程。行为分析表明，SG06改善了认知功能，减少了焦虑样行为，恢复了社会互动。此外，通过更好的光/暗转换和嗅觉功能恢复，观察到感觉恢复，可能是由于神经元通信改善和氧化应激减少。机制上，SG06似乎激活PI3K/AKT1通路，抑制糖原合成酶激酶3β (GSK3β)活性，这可能有助于减少tau过度磷酸化和淀粉样蛋白加工。SG06还能恢复抗氧化标志物（CAT、GSH、GPx），提高乙酰胆碱酯酶（AChE）活性，减轻氧化损伤和胆碱能功能障碍。组织学分析显示细胞形态改善，Aβ斑块积累减少，基因表达研究显示促炎标志物下调，神经保护基因上调。此外，SG06有助于改善神经递质平衡，特别是γ -氨基丁酸（GABA）和多巴胺（DPAN），有助于改善突触可塑性和认知功能。这些发现表明SG06可能有潜力作为一种多靶点治疗药物来治疗AD的复杂病理。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Molecular Neurobiology 医学-神经科学

CiteScore

9.00

自引率

2.00%

发文量

480

审稿时长

1 months

期刊介绍： Molecular Neurobiology is an exciting journal for neuroscientists needing to stay in close touch with progress at the forefront of molecular brain research today. It is an especially important periodical for graduate students and "postdocs," specifically designed to synthesize and critically assess research trends for all neuroscientists hoping to stay active at the cutting edge of this dramatically developing area. This journal has proven to be crucial in departmental libraries, serving as essential reading for every committed neuroscientist who is striving to keep abreast of all rapid developments in a forefront field. Most recent significant advances in experimental and clinical neuroscience have been occurring at the molecular level. Until now, there has been no journal devoted to looking closely at this fragmented literature in a critical, coherent fashion. Each submission is thoroughly analyzed by scientists and clinicians internationally renowned for their special competence in the areas treated.