1,3,4, Oxadiazole Compound A3 Provides Robust Protection Against PTZ-Induced Neuroinflammation and Oxidative Stress by Regulating -Pathway

Overview

Journal J Inflamm Res

Publisher Dove Medical Press

Date 2022 Jan 10

PMID 35002275

Authors

Arooj Mohsin Alvi

Fawad Ali Shah

Asmaa Jan Muhammad

Jinxing Feng

Shupeng Li

Affiliations

Soon will be listed here.

Abstract

Background: Epilepsy is a common neurological disorder that is characterized by recurrent episodes of seizures. Various studies have demonstrated a direct association between oxidative stress and inflammation in several neurological disorders including epilepsy. This study aimed to investigate the neuroprotective effects of a synthetic 1,3,4, oxadiazole compound A3 against pentylenetetrazole (PTZ)-induced kindling and seizure model.

Methodology: PTZ was administered in a sub-convulsive dose of 40 mg/kg for 15 days, at 48-hour intervals to male Swiss-Albino mice until animals were fully kindled. Two different doses of A3 (10 mg/kg and 30 mg/kg) were administered to find out the effective dose of A3 and to further demonstrate the relative role of nuclear factor E2-related factor () in the PTZ-induced kindled model.

Results: Our results demonstrated a compromised antioxidant capacity associated with a low level of catalase (CAT), superoxide dismutase (SOD), glutathione (GST), and glutathione S-transferase (GSH) in the kindled group. However, the PTZ-induced group demonstrated an elevated level of lipid peroxidation (LPO) level parallel to pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), mediators as cyclooxygenase (COX-2), and nuclear factor kappa B (NFκB). Furthermore, the A3 treatment reversed these changes and overexpressed the antioxidant gene and its downstream . To further investigate the involvement of , we employed an -inhibitor, ie, all-trans retinoic acid (ATRA), that further aggravated the PTZ toxicity. Moreover, vascular endothelial growth factor (VEGF) expression was evaluated to assess the extent of BBB disruption.

Conclusion: The findings of this study suggest that A3 could mediate neuroprotection possibly by activating dependent downregulation of inflammatory cascades.

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References

Waldbaum S, Patel M . Mitochondrial dysfunction and oxidative stress: a contributing link to acquired epilepsy?. J Bioenerg Biomembr. 2010; 42(6):449-55. PMC: 3102435. DOI: 10.1007/s10863-010-9320-9. View

Ali A, Shah F, Zeb A, Malik I, Alvi A, Alkury L . NF-κB Inhibitors Attenuate MCAO Induced Neurodegeneration and Oxidative Stress-A Reprofiling Approach. Front Mol Neurosci. 2020; 13:33. PMC: 7121334. DOI: 10.3389/fnmol.2020.00033. View

Karikas G, Schulpis K, Bartzeliotou A, Regoutas S, Thanopoulou C, Papaevangelou V . Early effects of sodium valproate monotherapy on serum paraoxonase/arylesterase activities. Scand J Clin Lab Invest. 2008; 69(1):31-5. DOI: 10.1080/00365510802248051. View

Ho Y, Lin Y, Wu C, Chao Y, Chang A, Chan J . Peripheral inflammation increases seizure susceptibility via the induction of neuroinflammation and oxidative stress in the hippocampus. J Biomed Sci. 2015; 22:46. PMC: 4477313. DOI: 10.1186/s12929-015-0157-8. View

Iqbal S, Shah F, Naeem K, Nadeem H, Sarwar S, Ashraf Z . Succinamide Derivatives Ameliorate Neuroinflammation and Oxidative Stress in Scopolamine-Induced Neurodegeneration. Biomolecules. 2020; 10(3). PMC: 7175202. DOI: 10.3390/biom10030443. View

Bhat A, Dar K, Anees S, Zargar M, Masood A, Sofi M . Oxidative stress, mitochondrial dysfunction and neurodegenerative diseases; a mechanistic insight. Biomed Pharmacother. 2015; 74:101-10. DOI: 10.1016/j.biopha.2015.07.025. View

Cardoso A, Lukoyanova E, Madeira M, Lukoyanov N . Seizure-induced structural and functional changes in the rat hippocampal formation: comparison between brief seizures and status epilepticus. Behav Brain Res. 2011; 225(2):538-46. DOI: 10.1016/j.bbr.2011.07.057. View

Loscher W . Critical review of current animal models of seizures and epilepsy used in the discovery and development of new antiepileptic drugs. Seizure. 2011; 20(5):359-68. DOI: 10.1016/j.seizure.2011.01.003. View

Alvi A, Al Kury L, Alattar A, Ullah I, Muhammad A, Alshaman R . Carveol Attenuates Seizure Severity and Neuroinflammation in Pentylenetetrazole-Kindled Epileptic Rats by Regulating the Signaling Pathway. Oxid Med Cell Longev. 2021; 2021:9966663. PMC: 8376446. DOI: 10.1155/2021/9966663. View

10.

Kensler T, Wakabayashi N, Biswal S . Cell survival responses to environmental stresses via the Keap1-Nrf2-ARE pathway. Annu Rev Pharmacol Toxicol. 2006; 47:89-116. DOI: 10.1146/annurev.pharmtox.46.120604.141046. View

11.

Minami M, Kuraishi Y, Satoh M . Effects of kainic acid on messenger RNA levels of IL-1 beta, IL-6, TNF alpha and LIF in the rat brain. Biochem Biophys Res Commun. 1991; 176(2):593-8. DOI: 10.1016/s0006-291x(05)80225-6. View

12.

Irshad N, Khan A, Shah F, Nadeem H, Ashraf Z, Tipu M . Antihyperlipidemic effect of selected pyrimidine derivatives mediated through multiple pathways. Fundam Clin Pharmacol. 2021; 35(6):1119-1132. DOI: 10.1111/fcp.12682. View

13.

Malik I, Shah F, Ali T, Tan Z, Alattar A, Ullah N . Potent Natural Antioxidant Carveol Attenuates MCAO-Stress Induced Oxidative, Neurodegeneration by Regulating the Nrf-2 Pathway. Front Neurosci. 2020; 14:659. PMC: 7344277. DOI: 10.3389/fnins.2020.00659. View

14.

Walsh S, Donnan J, Fortin Y, Sikora L, Morrissey A, Collins K . A systematic review of the risks factors associated with the onset and natural progression of epilepsy. Neurotoxicology. 2016; 61:64-77. DOI: 10.1016/j.neuro.2016.03.011. View

15.

Lim J, Wilhelmus M, de Vries H, Drukarch B, Hoozemans J, van Horssen J . Antioxidative defense mechanisms controlled by Nrf2: state-of-the-art and clinical perspectives in neurodegenerative diseases. Arch Toxicol. 2014; 88(10):1773-86. DOI: 10.1007/s00204-014-1338-z. View

16.

Naeem K, Al Kury L, Nasar F, Alattar A, Alshaman R, Shah F . Natural Dietary Supplement, Carvacrol, Alleviates LPS-Induced Oxidative Stress, Neurodegeneration, and Depressive-Like Behaviors via the Nrf2/HO-1 Pathway. J Inflamm Res. 2021; 14:1313-1329. PMC: 8041651. DOI: 10.2147/JIR.S294413. View

17.

Ambrogini P, Torquato P, Bartolini D, Albertini M, Lattanzi D, Di Palma M . Excitotoxicity, neuroinflammation and oxidant stress as molecular bases of epileptogenesis and epilepsy-derived neurodegeneration: The role of vitamin E. Biochim Biophys Acta Mol Basis Dis. 2019; 1865(6):1098-1112. DOI: 10.1016/j.bbadis.2019.01.026. View

18.

Imran M, Al Kury L, Nadeem H, Shah F, Abbas M, Naz S . Benzimidazole Containing Acetamide Derivatives Attenuate Neuroinflammation and Oxidative Stress in Ethanol-Induced Neurodegeneration. Biomolecules. 2020; 10(1). PMC: 7023260. DOI: 10.3390/biom10010108. View

19.

Bellezza I, Tucci A, Galli F, Grottelli S, Mierla A, Pilolli F . Inhibition of NF-κB nuclear translocation via HO-1 activation underlies α-tocopheryl succinate toxicity. J Nutr Biochem. 2012; 23(12):1583-91. DOI: 10.1016/j.jnutbio.2011.10.012. View

20.

Kilinc E, Ankarali S, Ayhan D, Ankarali H, Torun I, Cetinkaya A . Protective effects of long-term probiotic mixture supplementation against pentylenetetrazole-induced seizures, inflammation and oxidative stress in rats. J Nutr Biochem. 2021; 98:108830. DOI: 10.1016/j.jnutbio.2021.108830. View