Saleh Samar R, Abd-Elmegied Aml, Aly Madhy Somaya, Khattab Sherine N, Sheta Eman, Elnozahy Fatma Y, Mehanna Radwa A, Ghareeb Doaa A, Abd-Elmonem Nihad M
Biochemistry Department, Faculty of Science, Alexandria University, Alexandria, Egypt; Bio-Screening and Preclinical Trial Lab, Biochemistry Department, Faculty of Science, Alexandria University, Alexandria, Egypt.
Biochemistry Department, Faculty of Science, Alexandria University, Alexandria, Egypt; Bio-Screening and Preclinical Trial Lab, Biochemistry Department, Faculty of Science, Alexandria University, Alexandria, Egypt.
Int J Pharm. 2024 Jun 10;658:124218. doi: 10.1016/j.ijpharm.2024.124218. Epub 2024 May 9.
Alzheimer's disease (AD) is an age-related neurodegenerative disorder that causes severe dementia and memory loss. Surface functionalized poly(lactic-co-glycolic acid) nanoparticles have been reported for better transport through the blood-brain barrier for AD therapy. This study investigated the improved therapeutic potential of berberine-loaded poly(lactic-co-glycolic acid)/Tet-1 peptide nanoparticles (BBR/PLGA-Tet NPs) in a rat model of sporadic AD. BBR was loaded into the PLGA-Tet conjugate. BBR/PLGA-Tet NPs were physicochemically and morphologically characterized. AD was achieved by bilateral intracerebroventricular (ICV) injection of streptozotocin (STZ). Cognitively impaired rats were divided into STZ, STZ + BBR, STZ + BBR/PLGA-Tet NPs, and STZ + PLGA-Tet NPs groups. Cognitive improvement was assessed using the Morris Water Maze. Brain acetylcholinesterase and monoamine oxidase activities, amyloid β42 (Aβ42), and brain glycemic markers were estimated. Further, hippocampal neuroplasticity (BDNF, pCREB, and pERK/ERK), Tau pathogenesis (pGSK3β/GSK3β, Cdk5, and pTau), inflammatory, and apoptotic markers were evaluated. Finally, histopathological changes were monitored. ICV-STZ injection produces AD-like pathologies evidenced by Aβ42 deposition, Tau hyperphosphorylation, impaired insulin signaling and neuroplasticity, and neuroinflammation. BBR and BBR/PLGA-Tet NPs attenuated STZ-induced hippocampal damage, enhanced cognitive performance, and reduced Aβ42, Tau phosphorylation, and proinflammatory responses. BBR/PLGA-Tet NPs restored neuroplasticity, cholinergic, and monoaminergic function, which are critical for cognition and brain function. BBR/PLGA-Tet NPs may have superior therapeutic potential in alleviating sporadic AD than free BBR due to their bioavailability, absorption, and brain uptake.
阿尔茨海默病（AD）是一种与年龄相关的神经退行性疾病，会导致严重的痴呆和记忆丧失。据报道，表面功能化的聚乳酸-乙醇酸共聚物纳米颗粒可更好地穿过血脑屏障用于AD治疗。本研究在散发性AD大鼠模型中探究了载有小檗碱的聚乳酸-乙醇酸共聚物/Tet-1肽纳米颗粒（BBR/PLGA-Tet NPs）的治疗潜力是否得到改善。将BBR载入PLGA-Tet共轭物中。对BBR/PLGA-Tet NPs进行了物理化学和形态学表征。通过双侧脑室内（ICV）注射链脲佐菌素（STZ）诱导AD。将认知受损的大鼠分为STZ组、STZ + BBR组、STZ + BBR/PLGA-Tet NPs组和STZ + PLGA-Tet NPs组。使用莫里斯水迷宫评估认知改善情况。测定脑乙酰胆碱酯酶和单胺氧化酶活性、淀粉样β42（Aβ42）以及脑血糖标志物。此外，评估海马神经可塑性（脑源性神经营养因子、磷酸化环磷腺苷反应元件结合蛋白和磷酸化细胞外信号调节激酶/细胞外信号调节激酶）、Tau蛋白发病机制（磷酸化糖原合成酶激酶3β/糖原合成酶激酶3β、细胞周期蛋白依赖性激酶5和磷酸化Tau蛋白）、炎症和凋亡标志物。最后，监测组织病理学变化。ICV-STZ注射产生了类似AD的病理变化，表现为Aβ42沉积、Tau蛋白过度磷酸化、胰岛素信号传导和神经可塑性受损以及神经炎症。BBR和BBR/PLGA-Tet NPs减轻了STZ诱导的海马损伤，增强了认知能力，并减少了Aβ42、Tau蛋白磷酸化和促炎反应。BBR/PLGA-Tet NPs恢复了神经可塑性、胆碱能和单胺能功能，这些功能对认知和脑功能至关重要。由于其生物利用度、吸收和脑摄取情况，BBR/PLGA-Tet NPs在缓解散发性AD方面可能比游离BBR具有更好的治疗潜力。
