Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan.
Riphah Institute of Pharmaceutical Sciences (RIPS), Islamabad, Pakistan.
Neurotoxicology. 2020 Jul;79:150-163. doi: 10.1016/j.neuro.2020.05.005. Epub 2020 May 23.
Epilepsy is a complex and multifactorial neurodegenerative disease described by recurrent seizures. Oxidative stress and dysregulation of brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF) are critical factors for the development of epilepsy. Daidzin is well-known for its effective anti-inflammatory and antioxidant potential for centuries. The present study was focused on exploring the anti-epileptic potential of daidzin in the pentylenetetrazole-induced mice model. Daidzin (1, 5, and 10 mg/kg) was administered in the acute study and the dose was optimized. Pretreatment with daidzin remarkably reduced the severity of epileptogenesis in a dose-dependent manner. Moreover, chronic epilepsy was induced in mice by administration of PTZ (35 mg/kg, i.p) every alternative day for 21 days. Results demonstrated that daidzin significantly prevented epileptogenesis and reversed histopathological changes in the hippocampus. It remarkably improved antioxidant (glutathione, glutathione sulfotransferase, superoxide dismutase, and catalase) levels while decreased MDA (malondialdehyde) and nitrite production in the brain. It remarkably improved the expressions of heme oxygenase-1 (HO-1) and BDNF while reduced the expression of VEGF. It remarkably prevented the neuronal apoptosis in the brain tissue. Additionally, spectroscopic analysis such as FTIR (Fourier transform infrared spectroscopy) and DSC (differential scanning calorimetry) revealed that daidzin remarkably prevented PTZ-induced protein damage. HPLC-UV spectrophotometry results demonstrated that there was no peak of aglycone daidzin (metabolite) in the brain sample which specify that the anticonvulsant effect of the compound is due to its direct entry into the brain tissue. Moreover, the molecular docking results showed that daidzin possesses a better binding affinity for ALDH2, estrogen receptor-β, P13k, AKT2, mTORC1, and HIF-1-α proteins. Taken together, the results of the present study showed that daidzin has remarkable neuroprotective and anti-epileptic properties through modulation of oxidative stress, BDNF/VEGF, and apoptotic signaling in the brain tissue of PTZ-kindled mice.
癫痫是一种复杂的、多因素的神经退行性疾病，表现为反复发作的癫痫发作。氧化应激和脑源性神经营养因子（BDNF）和血管内皮生长因子（VEGF）的失调是癫痫发生的关键因素。大豆苷元因其有效的抗炎和抗氧化作用而闻名数百年。本研究旨在探讨大豆苷元在戊四氮（PTZ）诱导的小鼠模型中的抗癫痫作用。大豆苷元（1、5 和 10mg/kg）在急性研究中给药，并优化了剂量。大豆苷元预处理可显著降低癫痫发作的严重程度，呈剂量依赖性。此外，通过每隔一天腹腔注射 PTZ（35mg/kg）连续 21 天诱导慢性癫痫。结果表明，大豆苷元可显著预防癫痫发生，并逆转海马的组织病理学变化。它显著提高了抗氧化（谷胱甘肽、谷胱甘肽硫转移酶、超氧化物歧化酶和过氧化氢酶）水平，同时降低了大脑中的 MDA（丙二醛）和亚硝酸盐生成。它显著提高血红素加氧酶-1（HO-1）和 BDNF 的表达，同时降低 VEGF 的表达。它显著防止了脑组织中的神经元凋亡。此外，傅里叶变换红外光谱（FTIR）和差示扫描量热法（DSC）等光谱分析表明，大豆苷元可显著防止 PTZ 诱导的蛋白质损伤。HPLC-UV 分光光度法结果表明，脑组织样本中没有苷元大豆苷元（代谢物）的峰，这表明该化合物的抗惊厥作用是由于其直接进入脑组织。此外，分子对接结果表明，大豆苷元对 ALDH2、雌激素受体-β、P13k、AKT2、mTORC1 和 HIF-1-α 蛋白具有更好的结合亲和力。综上所述，本研究结果表明，大豆苷元通过调节脑组织中氧化应激、BDNF/VEGF 和凋亡信号，对 PTZ 诱导的小鼠具有显著的神经保护和抗癫痫作用。
