Investigation of 1, 3, 4 Oxadiazole Derivative in PTZ-Induced Neurodegeneration: A Simulation and Molecular Approach.
Investigation of 1, 3, 4 Oxadiazole Derivative in PTZ-Induced Neurodegeneration: A Simulation and Molecular Approach.
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DOI：
10.2147/jir.s328609
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发表时间：
2021
影响因子：
4.5
通讯作者：
Ilyas U
中科院分区：
文献类型：
--
作者：
Faheem M;Althobaiti YS;Khan AW;Ullah A;Ali SH;Ilyas U
本研究观察了5-[（萘-2-基氧基）甲基]-1，3，4-恶二唑-2-硫醇（B3）对急性癫痫性休克动物模型的作用。通过SwissADME软件检查B3的药代动力学特征。通过Auto Dock和PyRx获得B3、地西泮和氟马西尼（FLZ）的结合亲和力。通过Discovery Studio Visualizer 2016进行对接后分析和氢键解释。利用Desmond软件包对三种配合物进行了分子动力学模拟。然后在PTZ诱导的急性癫痫模型中进行B3。在动物研究中使用氟马西尼以阐明B3的可能机制。行为学研究后，处死动物，分离脑组织样本并保存在4%福尔马林中进行分子研究，包括H和E染色、免疫组化染色和Elisa等。结果表明，20和40 mg/kg的B3延长了全身性癫痫发作的发作时间。B3能显著增加保护性谷胱甘肽S-转移酶和谷胱甘肽还原酶的表达，降低脂质过氧化反应和诱导型一氧化氮合酶（P < 0.001）。B3显著抑制（P < 0.01）炎性介质肿瘤坏死因子-α的过度表达，其在急性癫痫性休克中上调。因此，从上述结果可以得出结论，B3提供了PTZ诱导的急性癫痫模型的神经保护作用。FLZ预处理抑制B3的抗惊厥作用。B3具有抗惊厥作用，其机制可能与GABAA介导的抗癫痫通路有关。
The study investigated the effect 5-[(naphthalen-2-yloxy) methyl]-1,3,4-oxadiaszole2-thiol (B3) in animal model of acute epileptic shock. The pharmacokinetics profile of B3 was checked through SwissADME software. The binding affinities of B3, diazepam, and flumazenil (FLZ) were obtained through Auto Dock and PyRx. Post docking analysis and interpretation of hydrogen bonds were performed through Discovery Studio Visualizer 2016. Molecular dynamics simulations of three complexes were carried out through Desmond software package. B3 was then proceeded in PTZ-induced acute seizures models. Flumazenil was used in animal studies for elucidation of possible mechanism of B3. After behavioral studies, the animals were sacrificed, and the brain samples were isolated and stored in 4% formalin for molecular investigations including H and E staining, IHC staining and Elisa etc. The results demonstrate that B3 at 20 and 40 mg/kg prolonged the onset time of generalized seizures. B3 considerably increased the expression of protective glutathione S-transferase and glutathione reductase and reduced lipid peroxidation and inducible nitric oxide synthase (P < 0.001) in the cortex. B3 significantly suppressed (P < 0.01) the over expression of the inflammatory mediator tumor necrosis factor–α, whose up-regulation is reported in acute epileptic shocks. Hence, it is concluded from the aforementioned results that B3 provides neuroprotective effects PTZ-induced acute epileptic model. FLZ pretreatment resulted in inhibition of the anticonvulsant effect of B3. B3 possesses anticonvulsant effect which may be mediated through GABAA mediated antiepileptic pathway.