Investigation of 1, 3, 4 Oxadiazole Derivative in PTZ-Induced Neurodegeneration: A Simulation and Molecular Approach

Abstract

Objective

The study investigated the effect 5-[(naphthalen-2-yloxy) methyl]-1,3,4-oxadiaszole2-thiol (B3) in animal model of acute epileptic shock.

Methods

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.

Results

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.

Conclusion

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 GABA_A mediated antiepileptic pathway.

Keywords:

• docking
• molecular dynamic simulations
• gamma amino butyric acid A

Institutional Review Board Statement

This work was approved by ethical committee of Riphah Institute of Pharmaceutical Sciences, Riphah International University, Islamabad.

Data Sharing Statement

All the data is incorporated in the manuscript.

Acknowledgments

All the authors are grateful to Riphah International University, Islamabad for providing lab space and chemicals to conduct experiments and smoothly finish this research work. Yusuf S. Althobaiti was supported by Taif University Researchers Supporting Project number (TURSP-2020/78), Taif University, Taif, Saudi Arabia.

Author Contributions

All authors made a significant contribution to the work presented in the manuscript including conception, study design, execution, acquisition of data, analysis and interpretation. Took part in drafting and critically reviewing the article, gave final approval of the version to be published, and agree to be accountable for all aspects of the work.

Disclosure

The authors declare no conflicts of interest for this work.

Additional information

Funding

This research received no external funding.