Saleh Samar R, Khamiss Salma E, Aly Madhy Somaya, Khattab Sherine N, Sheta Eman, Elnozahy Fatma Y, Thabet Eman H, Ghareeb Doaa A, Awad Doaa, El-Bessoumy Ashraf A
Biochemistry Department, Faculty of Science, Alexandria University, Alexandria 21511, Egypt; Bio-Screening and Preclinical Trial Lab, Biochemistry Department, Faculty of Science, Alexandria University, Alexandria, Egypt.
Chemistry Department, Faculty of Science, Alexandria University, Alexandria, Egypt.
Int J Pharm. 2025 Jan 25;669:125021. doi: 10.1016/j.ijpharm.2024.125021. Epub 2024 Dec 2.
Ipriflavone (IPRI), an isoflavone derivative, is clinically used to prevent postmenopausal bone loss in addition to its antioxidant and cognitive benefits. However, its poor aqueous solubility retained its bioavailability. New strategies have been developed to improve the bioavailability and solubility of neurological medications to enhance their potency and limit adverse effects. This study aimed to prepare targeted IPRI-poly-lactic-co-glycolic acid (PLGA) nanoparticles coupled with Tet-1 peptide to increase the therapeutic potency of IPRI in a rat model of Alzheimer's disease (AD). Streptozotocin (STZ) exacerbates Alzheimer-related alterations by promoting central insulin resistance resulted from defective signaling pathways related to neuroinflammation and neurotoxicity. Bilateral intracerebroventricular (icv) injection of STZ was used to introduce the AD model. Icv-STZ injection significantly affected brain insulin, oxidative stress, inflammatory, and apoptotic indicators and caused behavioral abnormalities. STZ promoted the formation of amyloid β42 (Aβ42) by increasing BACE1 and reducing ADAM10 and ADAM17 expression levels. STZ also triggered the accumulation of neurofibrillary tangles and synaptic dysfunction, which are crucial for neurological impairments. Icv-STZ injection showed evident degenerative changes in the pyramidal cell layer and significantly reduced the count of viable cells in both CA1 and prefrontal cortex, indicating increased neuronal cell death. IPRI successfully ameliorated cognitive dysfunction by improving the phosphorylated forms of cAMP-response element-binding protein (pCREB) and extracellular signal-regulated kinase 1/2 (pERK1/2) related to synaptic plasticity. Targeted IPRI nanoparticles exceeded free IPRI potential in reducing oxidative stress, acetylcholinesterase/monoamine oxidase activities, Tau phosphorylation, and Aβ42 levels revealing less degenerative changes and increased viable neuron counts. IPRI-targeted nanoparticles improved the neuroprotective potential of free IPRI, making this strategy applicable to treat many neurodegenerative diseases. Finally, the in silico study predicted its ability to cross the BBB and to bind various protein targets in the brain.
依普黄酮（IPRI）是一种异黄酮衍生物，除了具有抗氧化和认知益处外，临床上还用于预防绝经后骨质流失。然而，其较差的水溶性限制了其生物利用度。人们已经开发出新策略来提高神经药物的生物利用度和溶解度，以增强其效力并限制不良反应。本研究旨在制备与Tet-1肽偶联的靶向依普黄酮-聚乳酸-羟基乙酸共聚物（PLGA）纳米颗粒，以提高依普黄酮在阿尔茨海默病（AD）大鼠模型中的治疗效力。链脲佐菌素（STZ）通过促进与神经炎症和神经毒性相关的信号通路缺陷导致的中枢胰岛素抵抗，加剧阿尔茨海默病相关改变。双侧脑室内（icv）注射STZ用于建立AD模型。icv-STZ注射显著影响脑胰岛素、氧化应激、炎症和凋亡指标，并导致行为异常。STZ通过增加β-分泌酶1（BACE1）并降低ADAM10和ADAM17表达水平促进淀粉样β42（Aβ42）的形成。STZ还引发神经原纤维缠结的积累和突触功能障碍，这对神经功能损害至关重要。icv-STZ注射显示锥体细胞层有明显的退行性变化，并且CA1区和前额叶皮层中活细胞数量显著减少，表明神经元细胞死亡增加。依普黄酮通过改善与突触可塑性相关的环磷酸腺苷反应元件结合蛋白（pCREB）和细胞外信号调节激酶1/2（pERK1/2）的磷酸化形式，成功改善了认知功能障碍。靶向依普黄酮纳米颗粒在降低氧化应激、乙酰胆碱酯酶/单胺氧化酶活性、Tau磷酸化和Aβ42水平方面超过了游离依普黄酮的潜力，显示出较少的退行性变化和增加的活神经元数量。依普黄酮靶向纳米颗粒提高了游离依普黄酮的神经保护潜力，使该策略适用于治疗许多神经退行性疾病。最后，计算机模拟研究预测了其穿过血脑屏障并与脑中各种蛋白质靶点结合的能力。
