El-Marasy Salma A, AbouSamra Mona M, El-Mosallamy Aliaa E M K, Emam Ahmed N, Mabrok Hoda B, Galal Asmaa F, Ahmed-Farid Omar A, Abd El-Rahman Sahar S, Moustafa Passant E
Department of Pharmacology, Medical and clinical studies institute, National Research Centre, Giza, Egypt.
Pharmaceutical Technology Department, Pharmaceutical drug industries research institute, National Research Centre, Giza, Egypt.
Chem Biol Interact. 2023 Apr 25;375:110402. doi: 10.1016/j.cbi.2023.110402. Epub 2023 Feb 16.
Diabetic peripheral neuropathy (DPN) is a common diabetic complication. Chrysin (CHY) has many biological properties but poor oral bioavailability. This study investigates the effect of CHY and CHY-loaded nanovesicles (CHY-NVs) on streptozotocin (STZ)-induced DPN in rats. CHY-NVs were prepared by using film hydration method. The formula with the best entrapment efficiency%, lowest particle size, highest zeta potential, and highest in vitro CHY released profile was selected, characterized by Differential scanning calorimetry, Fourier transformation infrared spectroscopy analysis, and examined by Transmission electron microscope. Acute toxicity test, pharmacokinetic study and experimental model of diabetes mellitus were performed on the selected formulation. Wistar rats were considered diabetic by administration of a single intraperitoneal dose of STZ (50 mg/kg). 48 h after STZ administration, hyperglycemic rats were randomly assigned into four groups, one group of untreated hyperglycemic rats and the other three groups received daily oral doses of unloaded NVs, CHY-NVs (25 mg/kg), and CHY-NVs (50 mg/kg), respectively for 21 days. Moreover, five additional groups of healthy rats received: distilled water (control), free CHY, unloaded NVs, and CHY-NVs respectively for 21 days. CHY and CHY-NVs maintained body weight and reduced STZ-induced behavioral changes in rotarod, hind paw cold allodynia, tail cold allodynia, tail flick, and hot plate tests. CHY and CHY-NVs lowered blood glucose, glycated hemoglobin, elevated serum reduced glutathione (GSH), and reduced plasma malondialdehyde (MDA) levels. CHY-NVs elevated phosphatidylinositol 3-kinase (Pi3k), phosphorylated protein kinase B (p-AKT), and reduced nuclear factor kappa B (NF-κB), interleukin-6 (IL-6) in sciatic nerve homogenate. CHY and CHY-NVs increased nerve growth factor (NGF) and decreased glycogen synthase kinase-3β (GSK-3β) gene expressions in the sciatic nerve. In conclusion, CHY and CHY-NVs ameliorated STZ-induced DPN behavioral and histopathological changes via attenuating hyperglycemia, exerting anti-oxidant, anti-inflammatory effects, activating NGF/p-AKT/GSK-3β pathway, and its anti-apoptotic effect. The best pharmacokinetic profile and therapeutic effect was observed in rats treated with CHY-loaded NVs.
糖尿病周围神经病变（DPN）是一种常见的糖尿病并发症。白杨素（CHY）具有多种生物学特性，但口服生物利用度较差。本研究调查了CHY及载有CHY的纳米囊泡（CHY-NVs）对链脲佐菌素（STZ）诱导的大鼠DPN的影响。采用薄膜水化法制备CHY-NVs。选择包封率最高、粒径最小、zeta电位最高且体外CHY释放曲线最佳的配方，通过差示扫描量热法、傅里叶变换红外光谱分析进行表征，并通过透射电子显微镜进行检测。对所选制剂进行急性毒性试验、药代动力学研究及糖尿病实验模型研究。通过腹腔注射单剂量STZ（50 mg/kg）使Wistar大鼠患糖尿病。STZ给药48小时后，将高血糖大鼠随机分为四组，一组为未治疗的高血糖大鼠，其他三组分别每日口服空纳米囊泡、CHY-NVs（25 mg/kg）和CHY-NVs（50 mg/kg），持续21天。此外，另外五组健康大鼠分别接受：蒸馏水（对照）、游离CHY、空纳米囊泡和CHY-NVs，持续21天。CHY和CHY-NVs维持了体重，并减轻了STZ诱导的转棒试验、后爪冷痛觉过敏、尾冷痛觉过敏、甩尾试验和热板试验中的行为变化。CHY和CHY-NVs降低了血糖、糖化血红蛋白，提高了血清还原型谷胱甘肽（GSH）水平，并降低了血浆丙二醛（MDA）水平。CHY-NVs提高了坐骨神经匀浆中磷脂酰肌醇3-激酶（Pi3k）、磷酸化蛋白激酶B（p-AKT）的水平，并降低了核因子κB（NF-κB）、白细胞介素-6（IL-6）的水平。CHY和CHY-NVs增加了坐骨神经中神经生长因子（NGF）的表达，并降低了糖原合酶激酶-3β（GSK-3β）的基因表达。总之，CHY和CHY-NVs通过减轻高血糖、发挥抗氧化、抗炎作用、激活NGF/p-AKT/GSK-3β通路及其抗凋亡作用，改善了STZ诱导的DPN行为和组织病理学变化。在用载有CHY的纳米囊泡治疗的大鼠中观察到了最佳的药代动力学特征和治疗效果。
