Quercetin Exerts Anticonvulsant Effect through Mitigation of Neuroinflammatory Response in Pentylenetetrazole-induced Seizure in Mice
DOI:
https://doi.org/10.54548/njps.v38i2.7Keywords:
Epilepsy., neuro-inflammation, kindling., Neurodegeneration, epileptogenesis.Abstract
Epilepsy is a chronic disease of the brain characterized by seizures. The currently available anticonvulsants only treat symptoms with serious adverse drug reactions. Therefore, there is need for new therapeutic intervention that will prevent epileptogenesis with greater therapeutic success. Quercetin (QT) is a flavonoid with known neuroprotective and anti-inflammatory properties. The study aimed to investigate its effects against pentylenetetrazole (PTZ)-induced seizures. Animals were divided into four groups (n = 10). Group 1(control) only received vehicle (10 mL/kg), group 2 received vehicle, groups 3 and 4 received QT 12.5 mg/kg and 25 mg/kg respectively. Sixty minutes after treatments, animals in groups 2 to 4 were injected with sub-convulsive dose of pentylenetetrazole (35 mg/kg, i.p.) on every alternate day (48±2h) for 21 days. The mice were observed for 30 minutes after each PTZ injection for seizure activity. Brain samples were collected for biochemical assays. Administration of PTZ caused significant increase in the intensity of seizures, neuronal degeneration and level of proinflammatory cytokines in animals compared to control. These behavioural alterations were attenuated significantly by QT (12.5 and 25 mg/kg). The PTZ-induced increase in IL-12, TNF-α and IFN-ɣ were significantly reduced by pre-treatment with the QT (12.5 and 25 mg/kg, p.o). Quercetin also reduced neuronal loss compared to control. Quercetin attenuates seizures in kindled mice and reduces neuroinflammation and neurodegeneration. This neuroprotective effect may be attributed to its ability to inhibit inflammatory mediators in the brain
References
AHMADIAN, S. R., GHASEMI-KASMAN, M., POURAMIR, M. & SADEGHI, F. 2019. Arbutin attenuates cognitive impairment and inflammatory response in pentylenetetrazol-induced kindling model of epilepsy. Neuropharmacology, 146, 117-127.
AKYUZ, E., PAUDEL, Y. N., POLAT, A. K., DUNDAR, H. E. & ANGELOPOULOU, E. 2021. Enlightening the neuroprotective effect of quercetin in epilepsy: From mechanism to therapeutic opportunities. Epilepsy & Behavior, 115, 107701.
AMIRI, S., HAJ-MIRZAIAN, A., AMINI-KHOEI, H., SHIRZADIAN, A., RAHIMI-BALAEI, M., RAZMI, A., BERGEN, H., RASTEGAR, M., KORDJAZY, N. & HAJ-MIRZAIAN, A. 2016. Lithium attenuates the proconvulsant effect of adolescent social isolation stress via involvement of the nitrergic system. Epilepsy & Behavior, 61, 6-13.
BIEN, C., URBACH, H., SCHRAMM, J., SOEDER, B., BECKER, A., VOLTZ, R., VINCENT, A. & ELGER, C. 2007. Limbic encephalitis as a precipitating event in adult-onset temporal lobe epilepsy. Neurology, 69, 1236-1244.
CAN, Ö. D. & ÖZKAY, Ü. D. 2012. Effects of Hypericum montbretti extract on the central nervous system and involvement of GABA (A)/benzodiazepine receptors in its pharmacological activity. Phytotherapy Research, 26, 1695-1700.
CERRI, C., CALEO, M. & BOZZI, Y. 2017. Chemokines as new inflammatory players in the pathogenesis of epilepsy. Epilepsy Research, 136, 77-83.
CHAKRABORTY, J., SINGH, R., DUTTA, D., NASKAR, A., RAJAMMA, U. & MOHANAKUMAR, K. P. 2014. Quercetin improves behavioral deficiencies, restores astrocytes and microglia, and reduces serotonin metabolism in 3‐nitropropionic acid‐induced rat model of Huntington's disease. CNS neuroscience & therapeutics, 20, 10-19.
CHEN, Z., DUAN, R.-S., CONCHA, Q. H., WU, Q., MIX, E., WINBLAD, B., LJUNGGREN, H.-G. & ZHU, J. 2004. IL-12p35 deficiency alleviates kainic acid-induced hippocampal neurodegeneration in C57BL/6 mice. Neurobiology of disease, 17, 171-178.
CHOI, J., NORDLI, D. R., ALDEN, T. D., DIPATRI, A., LAUX, L., KELLEY, K., ROSENOW, J., SCHUELE, S. U., RAJARAM, V. & KOH, S. 2009. Cellular injury and neuroinflammation in children with chronic intractable epilepsy. Journal of neuroinflammation, 6, 1-14.
CHOUDHARY, N., BIJJEM, K. R. V. & KALIA, A. N. 2011. Antiepileptic potential of flavonoids fraction from the leaves of Anisomeles malabarica. Journal of Ethnopharmacology, 135, 238-242.
DALMAU, J., GLEICHMAN, A. J., HUGHES, E. G., ROSSI, J. E., PENG, X., LAI, M., DESSAIN, S. K., ROSENFELD, M. R., BALICE-GORDON, R. & LYNCH, D. R. 2008. Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies. The Lancet Neurology, 7, 1091-1098.
DE SOUZA, A. G., CHAVES FILHO, A. J. M., OLIVEIRA, J. V. S., DE SOUZA, D. A. A., LOPES, I. S., DE CARVALHO, M. A. J., DE LIMA, K. A., SOUSA, F. C. F., VASCONCELOS, S. M. M. & MACEDO, D. 2019. Prevention of pentylenetetrazole-induced kindling and behavioral comorbidities in mice by levetiracetam combined with the GLP-1 agonist liraglutide: involvement of brain antioxidant and BDNF upregulating properties. Biomedicine & Pharmacotherapy, 109, 429-439.
DEHKORDI, H. T., BIJAD, E., SAGHAEI, E., KORRANI, M. S. & AMINI-KHOEI, H. 2023. Chronic stress but not acute stress decreases the seizure threshold in PTZ-induced seizure in mice: role of inflammatory response and oxidative stress. Naunyn-Schmiedeberg's Archives of Pharmacology, 396, 973-982.
DHIR, A. 2012. Pentylenetetrazol (PTZ) kindling model of epilepsy. Current protocols in neuroscience, 58, 9.37. 1-9.37. 12.
DINARELLO, C. A. 2004. Infection, fever, and exogenous and endogenous pyrogens: some concepts have changed. Journal of endotoxin research, 10, 201-222.
GALES, J. M. & PRAYSON, R. A. 2017. Chronic inflammation in refractory hippocampal sclerosis-related temporal lobe epilepsy. Annals of Diagnostic Pathology, 30, 12-16.
GALIC, M. A., RIAZI, K. & PITTMAN, Q. J. 2012. Cytokines and brain excitability. Frontiers in neuroendocrinology, 33, 116-125.
GUO, J., XUE, C., DUAN, J.-A., QIAN, D., TANG, Y. & YOU, Y. 2011. Anticonvulsant, antidepressant-like activity of Abelmoschus manihot ethanol extract and its potential active components in vivo. Phytomedicine, 18, 1250-1254.
GUPTA, Y., KUMAR, M. V. & SRIVASTAVA, A. 2003. Effect of Centella asiatica on pentylenetetrazole-induced kindling, cognition and oxidative stress in rats. Pharmacology Biochemistry and Behavior, 74, 579-585.
HAJ-MIRZAIAN, A., RAMEZANZADEH, K., TAFAZOLIMOGHADAM, A., KAZEMI, K., NIKBAKHSH, R., NIKBAKHSH, R., AMINI-KHOEI, H., AFSHARI, K., HADDADI, N.-S. & SHAKIBA, S. 2019. Protective effect of minocycline on LPS-induced mitochondrial dysfunction and decreased seizure threshold through nitric oxide pathway. European journal of pharmacology, 858, 172446.
JEON, G. S., PARK, S. K., PARK, S. W., KIM, D. W., CHUNG, C. K. & CHO, S. S. 2008. Glial expression of interleukin-18 and its receptor after excitotoxic damage in the mouse hippocampus. Neurochemical research, 33, 179-184.
KAUR, D., PAHWA, P. & GOEL, R. K. 2016. Protective effect of nerolidol against pentylenetetrazol-induced kindling, oxidative stress and associated behavioral comorbidities in mice. Neurochemical research, 41, 2859-2867.
KIASALARI, Z., KHALILI, M., ROGHANI, M., HEIDARI, H. & AZIZI, Y. 2013. Antiepileptic and antioxidant effect of hydroalcoholic extract of ferula assa foetida gum on pentylentetrazole-induced kindling in male mice. Basic and clinical neuroscience, 4, 299.
LACH, P., KLUS, W., ZAJDEL, K., SZELESZCZUK, A., KOMOROWSKA, E., BURDA, K. & KUROWSKI, P. 2022. Neuroinflammation in Epilepsy—Diagnostics and Therapeutic Perspectives. Current Pharmacology Reports, 8, 31-35.
LAXER, K. D., TRINKA, E., HIRSCH, L. J., CENDES, F., LANGFITT, J., DELANTY, N., RESNICK, T. & BENBADIS, S. R. 2014. The consequences of refractory epilepsy and its treatment. Epilepsy & behavior, 37, 59-70.
LI, YAO, HAN, YANG, J., CHAUDHRY, M. T., WANG, S., LIU, H. & YIN, Y. 2016a. Quercetin, inflammation and immunity. Nutrients, 8, 167.
LI, X., WANG, H., GAO, Y., LI, L., TANG, C., WEN, G., ZHOU, Y., ZHOU, M., MAO, L. & FAN, Y. 2016b. Protective effects of quercetin on mitochondrial biogenesis in experimental traumatic brain injury via the Nrf2 signaling pathway. PloS one, 11, e0164237.
MALHOTRA, J. & GUPTA, Y. K. 1997. Effect of adenosine receptor modulation on pentylenetetrazole‐induced seizures in rats. British journal of pharmacology, 120, 282-288.
MANIGAUHA, A. & PATEL, S. 2010. Pentylenetetrazole induced convulsion in RATS. International journal of pharma and bio sciences, 1, 2.
MCNAMARA, J. O. 1984. Kindling: an animal model of complex partial epilepsy. Annals of Neurology: Official Journal of the American Neurological Association and the Child Neurology Society, 16, S72-S76.
MEHLA, J., REETA, K., GUPTA, P. & GUPTA, Y. K. 2010. Protective effect of curcumin against seizures and cognitive impairment in a pentylenetetrazole-kindled epileptic rat model. Life sciences, 87, 596-603.
MENG, F. & YAO, L. 2020. The role of inflammation in epileptogenesis. Acta Epileptologica, 2, 1-19.
MUKE, S., KAIKINI, A., PESHATTIWAR, V., BAGLE, S., DIGHE, V. & SATHAYE, S. 2018. Neuroprotective effect of coumarin nasal formulation: kindling model assessment of epilepsy. Frontiers in pharmacology, 9, 992.
NASSIRI-ASL, M., HAJIALI, F., TAGHILOO, M., ABBASI, E., MOHSENI, F. & YOUSEFI, F. 2016. Comparison between the effects of quercetin on seizure threshold in acute and chronic seizure models. Toxicology and industrial health, 32, 936-944.
NIEOCZYM, D., SOCAŁA, K., RASZEWSKI, G. & WLAŹ, P. 2014. Effect of quercetin and rutin in some acute seizure models in mice. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 54, 50-58.
PEARSON-SMITH, J. N. & PATEL, M. 2017. Metabolic dysfunction and oxidative stress in epilepsy. International Journal of Molecular Sciences, 18, 2365.
POURMOTABBED, A., NEDAEI, S., CHERAGHI, M., MORADIAN, S., TOUHIDI, A., AEINFAR, M., SEYFI, Z. & POURMOTABBED, T. 2011. Effect of prenatal pentylenetetrazol-induced kindling on learning and memory of male offspring. Neuroscience, 172, 205-211.
RACINE, R. J. 1972. Modification of seizure activity by electrical stimulation: II. Motor seizure. Electroencephalography and clinical neurophysiology, 32, 281-294.
RANA, A. & MUSTO, A. E. 2018. The role of inflammation in the development of epilepsy. Journal of neuroinflammation, 15, 1-12.
RAWAT, C., KUKAL, S., DAHIYA, U. R. & KUKRETI, R. 2019. Cyclooxygenase-2 (COX-2) inhibitors: future therapeutic strategies for epilepsy management. Journal of neuroinflammation, 16, 1-15.
RIAZI, K., GALIC, M. A. & PITTMAN, Q. J. 2010. Contributions of peripheral inflammation to seizure susceptibility: cytokines and brain excitability. Epilepsy research, 89, 34-42.
RIIKONEN, R. 2004. Topical review: infantile spasms: therapy and outcome. Journal of child neurology, 19, 401-404.
RISHITHA, N. & MUTHURAMAN, A. 2018. Therapeutic evaluation of solid lipid nanoparticle of quercetin in pentylenetetrazole induced cognitive impairment of zebrafish. Life sciences, 199, 80-87.
SALGADO, P. R. R., DA FONSÊCA, D. V., DE MELO, C. G. F., LEITE, F. C., ALVES, A. F., FERREIRA, P. B., PIUVEZAM, M. R., DE SOUSA, D. P. & DE ALMEIDA, R. N. 2018. Comparison of behavioral, neuroprotective, and proinflammatory cytokine modulating effects exercised by (+)‐cis‐EC and (−)‐cis‐EC stereoisomers in a PTZ‐induced kindling test in mice. Fundamental & Clinical Pharmacology, 32, 507-515.
SAMOKHINA, E. & SAMOKHIN, A. 2018. Neuropathological profile of the pentylenetetrazol (PTZ) kindling model. International Journal of Neuroscience, 128, 1086-1096.
SANKARANENI, R. & LACHHWANI, D. 2015. Antiepileptic drugs—a review. Pediatric annals, 44, e36-e42.
SCHIPPER, S., AALBERS, M., RIJKERS, K., SWIJSEN, A., RIGO, J., HOOGLAND, G. & VLES, J. 2016. Tonic GABAA receptors as potential target for the treatment of temporal lobe epilepsy. Molecular neurobiology, 53, 5252-5265.
SEFIL, F., KAHRAMAN, I., DOKUYUCU, R., GOKCE, H., OZTURK, A., TUTUK, O., AYDIN, M., OZKAN, U. & PINAR, N. 2014. Ameliorating effect of quercetin on acute pentylenetetrazole induced seizures in rats. International Journal of Clinical and Experimental Medicine, 7, 2471.
SEMPLE, B. D., DILL, L. K. & O'BRIEN, T. J. 2020. Immune challenges and seizures: how do early life insults influence epileptogenesis? Frontiers in Pharmacology, 11, 2.
SHIMADA, T., TAKEMIYA, T., SUGIURA, H. & YAMAGATA, K. 2014. Role of inflammatory mediators in the pathogenesis of epilepsy. Mediators of inflammation, 2014.
SHIMADA, T. & YAMAGATA, K. 2018. Pentylenetetrazole-induced kindling mouse model. JoVE (Journal of Visualized Experiments), e56573.
SINGH, A. & TREVICK, S. 2016. The epidemiology of global epilepsy. Neurologic clinics, 34, 837-847.
STELLWAGEN, D., BEATTIE, E. C., SEO, J. Y. & MALENKA, R. C. 2005. Differential regulation of AMPA receptor and GABA receptor trafficking by tumor necrosis factor-α. Journal of Neuroscience, 25, 3219-3228.
SUBASH, S. & SUBRAMANIAN, P. 2009. Morin a flavonoid exerts antioxidant potential in chronic hyperammonemic rats: a biochemical and histopathological study. Molecular and cellular biochemistry, 327, 153-161.
TAIWE, G. S., TCHOYA, T. B., MENANGA, J. R., DABOLE, B. & DE WAARD, M. 2016. Anticonvulsant activity of an active fraction extracted from Crinum jagus L.(Amaryllidaceae), and its possible effects on fully kindled seizures, depression-like behaviour and oxidative stress in experimental rodent models. Journal of ethnopharmacology, 194, 421-433.
TAKEUCHI, H., JIN, S., WANG, J., ZHANG, G., KAWANOKUCHI, J., KUNO, R., SONOBE, Y., MIZUNO, T. & SUZUMURA, A. 2006. Tumor necrosis factor-α induces neurotoxicity via glutamate release from hemichannels of activated microglia in an autocrine manner. Journal of Biological Chemistry, 281, 21362-21368.
TAVAKOLI, Z., DEHKORDI, H. T., LORIGOOINI, Z., RAHIMI-MADISEH, M., KORANI, M. S. & AMINI-KHOEI, H. 2023. Anticonvulsant effect of quercetin in pentylenetetrazole (PTZ)-induced seizures in male mice: The role of anti-neuroinflammatory and anti-oxidative stress. International Immunopharmacology, 116, 109772.
THOMPSON, C., GARY, D., MATTSON, M., MACKENZIE, A. & ROBERTSON, G. S. 2004. Kainic acid-induced naip expression in the hippocampus is blocked in mice lacking TNF receptors. Molecular brain research, 123, 126-131.
VEZZANI, A. & BARAM, T. Z. 2007. New roles for interleukin-1 Beta in the mechanisms of epilepsy. Epilepsy currents, 7, 45-50.
VEZZANI, A., FRENCH, J., BARTFAI, T. & BARAM, T. Z. 2011. The role of inflammation in epilepsy. Nature reviews neurology, 7, 31-40.
VINCENT, A. & BIEN, C. G. 2008. Anti-NMDA-receptor encephalitis: a cause of psychiatric, seizure, and movement disorders in young adults. The Lancet Neurology, 7, 1074-1075.
WATANABE, M., MIYAI, A., DANJO, S., NAKAMURA, Y. & ITOH, K. 2013. The threshold of pentylenetetrazole-induced convulsive seizures, but not that of nonconvulsive seizures, is controlled by the nitric oxide levels in murine brains. Experimental neurology, 247, 645-652.
WHELESS, J. W., CLARKE, D. F., ARZIMANOGLOU, A. & CARPENTER, D. 2007. Treatment of pediatric epilepsy: European expert opinion, 2007. Epileptic disorders, 9, 353-412.
WIRRELL, E., FARRELL, K. & WHITING, S. 2005. The epileptic encephalopathies of infancy and childhood. Canadian journal of neurological sciences, 32, 409-418.
WU, D., ZHENG, Z., FAN, S., WEN, X., HAN, X., WANG, S., WANG, Y., ZHANG, Z., SHAN, Q. & LI, M. 2020. Ameliorating effect of quercetin on epilepsy by inhibition of inflammation in glial cells. Experimental and Therapeutic Medicine, 20, 854-859.
ZHENG, J., WU, J., CHEN, J., LIU, J., LU, Y., HUANG, C., HU, G., WANG, X. & ZENG, Y. 2016. Therapeutic effects of quercetin on early inflammation in hypertriglyceridemia-related acute pancreatitis and its mechanism. Pancreatology, 16, 200-210.
Downloads
Published
Issue
Section
License
Copyright (c) 2024 Nigerian Journal of Physiological Sciences
This work is licensed under a Creative Commons Attribution 4.0 International License.