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ORIGINAL RESEARCH article
Front. Pharmacol.
Sec. Neuropharmacology
Volume 15 - 2024 |
doi: 10.3389/fphar.2024.1446304
Nrf2/HO-1 and BDNF/VEGF signaling in stress-intensified PTZinduced epilepsy in mice
Provisionally accepted- 1 Quaid-i-Azam University, Islamabad, Islamabad, Pakistan
- 2 Prince Sattam Bin Abdulaziz University, Al-Kharj, Saudi Arabia
Stress is among the most common comorbid conditions with epilepsy and a strong factor in the pathophysiology of seizures. An imbalance in neuronal circuits causes recurrent unprovoked seizures in epilepsy. Dysregulation of BDNF/VEGF expression, oxidative stress, increased levels of neuroinflammatory cytokines, and increased expression of apoptotic genes contribute to the underlying cause of the seizure.Chrysophanol, an anthraquinone, has broad-spectrum therapeutic potential. This study evaluated the neuroprotective effect of chrysophanol with underlying pathways in PTZinduced epilepsy with stress as a comorbid condition.Male mice were given 35mg/kg of PTZ every other day to induce seizures. In addition, they were exposed to 120 minutes of daily restraint stress for 21 days to induce stress. Chrysophanol (0.1, 1, 10mg/kg) was administered to the mice 30 minutes before the PTZ in the acute study.The most effective dose (10mg/kg) was proceeded for the chronic epilepsy model. Following this, various tests were conducted, including behavioral assessments for memory impairment and stress, analysis of antioxidant levels, histopathological and immunohistochemistry examinations, measurement of cortisol levels using ELISA, and gene expression analysis using RT-PCR.Chrysophanol demonstrated a notable decrease in both the intensity and frequency of seizures.Additionally, it effectively boosted the levels of important antioxidants such as GSH, GST, and CAT, while simultaneously reducing the levels of MDA and NO. The histopathological analysis also showed improvement in overall morphology and survival of neurons.Chrysophanol treatment effectively showed an increase in the expression of BCL-2, and Nrf-2 with a decrease in BAX expression confirmed by immunohistochemistry. Dysregulation of vascular permeability factor, production of inflammatory cytokines, and apoptotic gene expression was successfully reversed after chrysophanol treatment analyzed through RT-PCR.Cortisol concentration was decreased in treatment groups analyzed through ELISA. Molecular docking of chrysophanol with different proteins declared the binding affinity of the ligands with the target sites of proteins.In conclusion, chrysophanol demonstrated remarkable neuroprotective and antiepileptic effects at a dose of 10mg/kg in stress-exacerbated PTZ-induced epilepsy following the TLR4/ NFκB -Nrf2/HO-1 and BDNF/VEGF pathways.
Keywords: Chrysophanol, stress, Pentylenetetrazole, Epilepsy, Neuroinflammation, Oxidative Stress, neurodegeneration
Received: 09 Jun 2024; Accepted: 31 Oct 2024.
Copyright: © 2024 Khan, Zainab, Rehman, Rehman, Shah and Tipu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Fawad Shah, Prince Sattam Bin Abdulaziz University, Al-Kharj, Saudi Arabia
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