Abstract
There is substantial evidence that anti-inflammatory agents and antioxidants have neuroprotective properties and may be useful in the treatment of neurodegenerative disorders. In this regard, the effects of oxaprozin (OXP) (a nonsteroidal anti-inflammatory drug) on the experimental model of seizure and memory impairment caused by seizures in rats were investigated in the present study. Seizures in male Wistar rats (200–250 g, 8 weeks) were induced by pentylenetetrazol (PTZ, 60 mg/kg). The anticonvulsant effects of OXP (100, 200, and 400 mg/kg, administered intraperitoneally) were evaluated in the seizure model. The effect on memory was assessed using the passive avoidance (PA) test. After behavioral tests, the animals underwent deep anesthesia and were euthanized painlessly. Animal serum was isolated for antioxidant assays (MDA and GPx). The animals' brains (hippocampus) were also isolated to gauge the relative expression of genes in the oxidative stress pathway (Nrf2/HO-1). Intraperitoneal injection of OXP decreased the mean score on the Racine scale compared to the PTZ group. Moreover, in the PA test, OXP caused a significant increase in retention latency (RL) and total time spent in the light compartment (TLC) compared to the PTZ group. Biochemical tests showed that OXP was able to significantly increase GPx serum levels and significantly reduce MDA serum levels compared to the PTZ group. Quantitative polymerase chain reaction (qPCR) results also revealed that OXP counteracted the negative effects of PTZ by significantly increasing the expression of the Nrf2 and Hmox1 genes. Overall, this study suggests the potential neuroprotective effects of the nonsteroidal anti-inflammatory drug OXP in a model of memory impairment caused by seizures via inhibition of the oxidative stress pathway.
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Data Availability
The analyzed data sets generated during the study are available from the corresponding author on reasonable request.
References
Aghaie F, Shemshaki A, Rajabi M, Khatami P, Hosseini A (2021) Rapamycin alleviates memory deficit against pentylenetetrazole-induced neural toxicity in Wistar male rats. Mol Biol Rep 48:5083–5091. https://doi.org/10.1007/s11033-021-06504-9
Calvo-Rodriguez M, García-Rodríguez C, Villalobos C, Núñez L (2020) Role of toll like receptor 4 in Alzheimer's Disease. Front Immunol 11:1588. https://doi.org/10.3389/fimmu.2020.01588
Costa D, Gomes A, Reis S, Lima JL, Fernandes E (2005) Hydrogen peroxide scavenging activity by non-steroidal anti-inflammatory drugs. Life Sci 76:2841–2848. https://doi.org/10.1016/j.lfs.2004.10.052
Dallegri F, Bertolotto M, Ottonello L (2005) A review of the emerging profile of the anti-inflammatory drug oxaprozin. Expert Opin Pharmacother 6:777–785. https://doi.org/10.1517/14656566.6.5.777
Demiryilmaz I, Turan MI, Kisaoglu A, Gulapoglu M, Yilmaz I, Suleyman H (2014) Protective effect of nimesulide against hepatic ischemia/reperfusion injury in rats: effects on oxidant/antioxidants, DNA mutation and COX-1/COX-2 levels. Pharmacol Rep 66:647–652. https://doi.org/10.1016/j.pharep.2014.02.015
Dhir A, Padi SS, Naidu PS, Kulkarni SK (2006) Protective effect of naproxen (non-selective COX-inhibitor) or rofecoxib (selective COX-2 inhibitor) on immobilization stress-induced behavioral and biochemical alterations in mice. Eur J Pharmacol 535:192–198. https://doi.org/10.1016/j.ejphar.2006.01.064
Duman B et al (2019) Risk factors for valproic acid induced hyperammonemia and its association with cognitive functions. Gen Hosp Psychiatry 59:67–72. https://doi.org/10.1016/j.genhosppsych.2019.05.005
Fattorusso A, Matricardi S, Mencaroni E, Dell’Isola GB, Di Cara G, Striano P, Verrotti A (2021) The Pharmacoresistant Epilepsy: an overview on existant and new emerging therapies. Front Neurol 12
Holley AJ, Lugo JN (2016) Effects of an acute seizure on associative learning and memory. Epilepsy Behav 54:51–57. https://doi.org/10.1016/j.yebeh.2015.11.001
Holmes GL (2015) Cognitive impairment in epilepsy: the role of network abnormalities. Epileptic Disord 17:101–116. https://doi.org/10.1684/epd.2015.0739
Hosseini A, Allahyari F, Azizi V (2021) Effects of Tanacetum Polycephalum on Passive Avoidance Learning and Oxidative Stress in Epileptic Model of Memory Impairment in the Male Wistar Rats. Adv Tradit Med 21:545–552. https://doi.org/10.1007/s13596-020-00464-4
Ilari S et al (2020) Protective Effect of antioxidants in Nitric Oxide/COX-2 Interaction during inflammatory pain: The Role of Nitration Antioxidants (Basel) 9. https://doi.org/10.3390/antiox9121284
Jara-Gutiérrez Á, Baladrón V (2021) The role of prostaglandins in different types of cancer. Cells 10. https://doi.org/10.3390/cells10061487
Katyal J, Kumar H, Gupta YK (2015) Anticonvulsant activity of the cyclooxygenase-2 (COX-2) inhibitor etoricoxib in pentylenetetrazole-kindled rats is associated with memory impairment. Epilepsy Behav 44:98–103. https://doi.org/10.1016/j.yebeh.2014.12.032
Katyayan A, Diaz-Medina G (2021) Epilepsy: Epileptic syndromes and treatment. Neurol Clin 39:779–795. https://doi.org/10.1016/j.ncl.2021.04.002
Kumar R, Arora R, Agarwal A, Gupta YK (2018) Protective effect of Terminalia chebula against seizures, seizure-induced cognitive impairment and oxidative stress in experimental models of seizures in rats. J Ethnopharmacol 215:124–131. https://doi.org/10.1016/j.jep.2017.12.008
Mekala S, Nelson G, Li YM (2020) Recent developments of small molecule γ-secretase modulators for Alzheimer’s disease RSC. Med Chem 11:1003–1022. https://doi.org/10.1039/d0md00196a
Munguía-Martínez MF, Nava-Ruíz C, Ruíz-Díaz A, Díaz-Ruíz A, Yescas-Gómez P, Méndez-Armenta M (2019) Immunohistochemical study of antioxidant enzymes regulated by Nrf2 in the models of epileptic seizures (KA and PTZ). Oxid Med Cell Longev 1327986. https://doi.org/10.1155/2019/1327986
Muralidharan A, Rahman J, Banerjee D, Hakim Mohammed AR, Malik BH (2020) Parkinsonism: A rare adverse effect of valproic acid. Cureus 12:e8782. https://doi.org/10.7759/cureus.8782
Nagib MM, Tadros MG, Al-Khalek HAA, Rahmo RM, Sabri NA, Khalifa AE, Masoud SI (2018) Molecular mechanisms of neuroprotective effect of adjuvant therapy with phenytoin in pentylenetetrazole-induced seizures: Impact on Sirt1/NRF2 signaling pathways. Neurotoxicology 68:47–65. https://doi.org/10.1016/j.neuro.2018.07.006
Olowe R, Sandouka S, Saadi A, Shekh-Ahmad T (2020) Approaches for reactive oxygen species and oxidative stress quantification in epilepsy. Antioxidants (Basel) 9. https://doi.org/10.3390/antiox9100990
Pahuja M, Mehla J, Reeta KH, Tripathi M, Gupta YK (2013) Effect of Anacyclus pyrethrum on pentylenetetrazole-induced kindling, spatial memory, oxidative stress and rho-kinase II expression in mice. Neurochem Res 38:547–556. https://doi.org/10.1007/s11064-012-0947-2
Rainsford KD (1988) Comparative irritancy of oxaprozin on the gastrointestinal tract of rats and mice: relationship to drug uptake and effects in vivo on eicosanoid metabolism. Aliment Pharmacol Ther 2:439–450. https://doi.org/10.1111/j.1365-2036.1988.tb00717.x
Rao X, Huang X, Zhou Z, Lin X (2013) An improvement of the 2ˆ(-delta delta CT) method for quantitative real-time polymerase chain reaction data analysis. Biostat Bioinforma Biomath 3:71–85
Suleymanova EM (2021) Behavioral comorbidities of epilepsy and neuroinflammation: Evidence from experimental and clinical studies. Epilepsy Behav 117:107869. https://doi.org/10.1016/j.yebeh.2021.107869
Wang Z, Xiao S, Huang J, Liu S, Xue M, Lu F (2021) Chemoprotective Effect of Boeravinone B against DMBA/Croton Oil Induced Skin Cancer via Reduction of Inflammation. J Oleo Sci 70:955–964. https://doi.org/10.5650/jos.ess21055
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This study is financially supported by Islamic Azad University.
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PK: Data curation, Formal analysis, Investigation, Methodology, Software, Validation, Visualization, Writing–original draft, Writing–review & editing. NM: Conceptualization, Funding acquisition, Methodology, Project administration, Resources, Supervision, Validation, Visualization, Writing–original draft, Writing-review & editing. MK: Conceptualization, Funding acquisition, Methodology, Project administration, Supervision, Writing–original draft, Writing–review & editing. MB: Project administration, Resources, Writing–original draft, Writing–review & editing. All authors read and approved the final manuscript.
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Khatami, P., Mirazi, N., Khosravi, M. et al. Nonsteroidal Anti-inflammatory Drug Oxaprozin is Beneficial Against Seizure-induced Memory Impairment in an Experimental Model of Seizures in Rats: Impact On Oxidative Stress and Nrf2/HO-1 Signaling Pathway. J Mol Neurosci 72, 880–887 (2022). https://doi.org/10.1007/s12031-022-01967-2
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DOI: https://doi.org/10.1007/s12031-022-01967-2