Dharshan Santhanam Sanjai, R Meghana, Rao Shreya Madhankumar, Aswinanand B, Ramamurthy Karthikeyan, Muthuramamoorthy Muthumareeswaran, Arasu M Valan, Kumaradoss Kathiravan Muthu, Guru Ajay, Palaniappan Senthilkumar, Arockiaraj Jesu
Toxicology and Pharmacology Laboratory, Department of Biotechnology, Faculty of Science and Humanities, SRM Institute of Science and Technology, Kattankulathur, 603203, Chengalpattu District, Tamil Nadu, India.
Faculty of Pharmacy, Karpagam Academy of Higher Education, Coimbatore, 641021, Tamil Nadu, India.
Mol Neurobiol. 2025 May 10. doi: 10.1007/s12035-025-05023-z.
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.
阿尔茨海默病（AD）和阿尔茨海默痴呆症（ADM）是常见的神经退行性疾病，其特征为进行性认知衰退、记忆障碍和行为缺陷，给全球个人和医疗保健系统带来了沉重负担。由于AD病理生理学的复杂性，有效的治疗策略可能需要针对多个途径。本研究使用网络药理学和分子对接，在东莨菪碱诱导的AD样斑马鱼模型中探索了查尔酮衍生物SG06的神经保护作用。SG06与关键靶点如AKT丝氨酸/苏氨酸激酶1（AKT1）有很强的结合，这些靶点参与tau蛋白磷酸化、淀粉样β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，减少了类似焦虑的行为，并恢复了社交互动。此外，通过更好的明/暗转换和恢复的嗅觉功能观察到感觉恢复，这可能是由于改善了神经元通讯和降低了氧化应激。从机制上讲，SG06似乎激活了PI3K/AKT1途径，抑制了糖原合酶激酶3β（GSK3β）的活性，这可能有助于减少tau蛋白过度磷酸化和淀粉样蛋白加工。SG06还恢复了抗氧化标志物（CAT、GSH、GPx）并改善了乙酰胆碱酯酶（AChE）活性，减少了氧化损伤和胆碱能功能障碍。组织学分析显示细胞形态得到改善，Aβ斑块积累减少，而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在解决AD的复杂病理方面可能具有作为多靶点治疗药物的潜力。
