Russian Journal of PhysiologyRussian Journal of PhysiologyРоссийский физиологический журнал им. И.М. Сеченова0869-81392658-655XThe Russian Academy of Sciences65168710.31857/S0869813924010096WJDRNOEXPERIMENTAL ARTICLESЭКСПЕРИМЕНТАЛЬНЫЕ СТАТЬИResearch ArticleCardarin effect on the formation of histopathological and behavioral abnormalities in the lithium-pilocarpine model of temporal lobe epilepsy in ratsДействие кардарина на формирование гистопатологических и поведенческих нарушений в литий-пилокарпиновой модели височной эпилепсии у крысSubkhankulovM. R.СубханкуловМ. Р.
Russian Federation
ZubarevaOE@mail.ruSinyakD. S.СинякД. С.
Russian Federation
ZubarevaOE@mail.ruGukV. A.ГукВ. А.
Russian Federation
ZubarevaOE@mail.ruPostnikovaT. Yu.ПостниковаТ. Ю.
Russian Federation
ZubarevaOE@mail.ruRoginskayaA. I.РогинскаяА. И.
Russian Federation
ZubarevaOE@mail.ruZubarevaO. E.ЗубареваО. Е.
Russian Federation
ZubarevaOE@mail.ruSechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of SciencesИнститут эволюционной физиологии и биохимии им. И.М. Сеченова РАН15012024110113615401022025Copyright ©; 2024, Russian Academy of SciencesCopyright ©; 2024, Российская академия наук2024Russian Academy of SciencesРоссийская академия наукhttps://journals.eco-vector.com/0869-8139/article/view/651687

Epilepsy is a severe neuropsychological disease accompanied by the development of spontaneous recurrent seizures (SRS) and associated behavioral disorders that are difficult to treat. In recent years, the neuroprotective properties of agonists of peroxisome proliferator-activated receptors (PPAR α, β/δ, γ), nuclear transcription factors involved in the regulation of lipid and carbohydrate metabolism, as well as inflammatory signaling pathways involved in the pathogenesis of epilepsy, have been actively investigated. The neuroprotective properties of PPARγ agonists have been repeatedly described in models of epilepsy; the effects of PPARβ/δ agonists in these models have not been sufficiently investigated. The aim of this work was to study the effects of administering the PPARβ/δ agonist cardarin on the formation of histopathological and behavioral abnormalities in the lithium-pilocarpine model of temporal lobe epilepsy (TLE). The lithium-pilocarpine model is one of the best experimental models of chronic temporal lobe epilepsy. In this study, epilepsy was induced by administration of pilocarpine to male Wistar rats at the age of 7 weeks one day after LiCl injection. Cardarin (2.5 mg/kg) was administered daily for 7 days after pilocarpine, with the first injection one day after pilocarpine injection. Behavioral testing was performed 2‒3 months after induction of the model in the following tests: Open Field, Resident Stranger, New Object Exploration, Y Maze Spontaneous Alternation and Morris Water Maze. Brain sampling for histological studies (assessment of neuronal death, Nissl staining) was performed after the end of behavioral experiments, 95 days after TLE induction. It was shown that untreated rats with TLE exhibited significant hippocampal neuron death and behavioral disorders: increased motor activity, anxiety, memory disorders, research and communicative behavior. Caradrin did not affect the survival rate of hippocampal neurons, but reduced the manifestation of almost all the above-mentioned behavioral disorders, except for hyperactivity. Thus, this study demonstrated the promising use of PPARβ/δ agonists to attenuate the development of behavioral disorders characteristic of epilepsy.

Эпилепсия – тяжелое нервно-психическое заболевание, сопровождающееся развитием спонтанных рецидивирующих судорог и сопутствующих нарушений поведения, трудно поддающихся лечению. В последние годы активно исследуются нейропротекторные свойства агонистов рецепторов, активируемых пролифератором пероксисом (PPAR α, β/δ, γ) – ядерных транскрипционных факторов, участвующих в регуляции липидного и углеводного обмена, а также воспалительных сигнальных путей, вовлеченных в патогенез эпилепсии. Нейропротекторные свойства агонистов PPARγ неоднократно описаны в моделях эпилепсии, эффекты агонистов PPARβ/δ в этих моделях исследованы недостаточно. Целью работы являлось изучение эффектов введений агониста PPARβ/δ кардарина (GW 501516) на формирование гистопатологических и поведенческих нарушений крыс в литий-пилокарпиновой модели височной эпилепсии (TLE). Литий-пилокарпиновая модель – одна из лучших экспериментальных моделей хронической височной эпилепсии. В данной работе эпилепсию индуцировали введением пилокарпина крысам самцам Вистар в возрасте 7 недель через сутки после инъекции LiCl. Кардарин (2.5 мг/кг) вводили ежедневно в течение 7 дней после пилокарпина, первая инъекция – через сутки после введения пилокарпина. Тестирование поведения проводили через 2–3 месяца после индукции модели в тестах: Открытое поле, Чужак-резидент, Обследование новых предметов, спонтанное чередование в Y-образном лабиринте и Водный лабиринт Морриса. Забор мозга для гистологических исследований (оценка гибели нейронов, окраска по Нисcлю) производили после окончания поведенческих экспериментов, через 95 дней после индукции TLE. Показано, что у нелеченых крыс с TLE отмечается значительная гибель нейронов в гиппокампе и нарушения поведения: повышенная двигательная активность, тревожность, нарушения памяти, исследовательского и коммуникативного поведения. Кардарин не влиял на выживаемость нейронов гиппокампа, однако уменьшал проявление практически всех названных поведенческих нарушений за исключением гиперактивности. Таким образом, проведенное исследование показало перспективность использования агонистов PPARβ/δ для ослабления развития характерных для эпилепсии нарушений поведения.

Temporal lobe epilepsylithium-pilocarpine modelperoxisome proliferator-activated receptor agonistscardarin (GW 501516)behaviormemoryneuronal death in the hippocampusвисочная эпилепсиялитий-пилокарпиновая модельагонисты рецепторов, активируемых пролифератором пероксисомкардарин (GW 501516)поведениепамятьгибель нейронов в гиппокампеРоссийский научный фонд (проект)Russian Science Foundation (project)23-25-00480Beghi E (2020) The Epidemiology of Epilepsy. Neuroepidemiology 54: 185–191. https://doi.org/10.1159/000503831Kahane P, Barba C, Rheims S, Job-Chapron AS, Minotti L, Ryvlin P (2015) The concept of temporal ‘plus’ epilepsy. Rev Neurol (Paris) 171: 267–272. https://doi.org/10.1016/j.neurol.2015.01.562Tellez-Zenteno JF, Dhar R, Hernandez-Ronquillo L, Wiebe S (2007) Long-term outcomes in epilepsy surgery: antiepileptic drugs, mortality, cognitive and psychosocial aspects. Brain 130: 334–345. https://doi.org/10.1093/brain/awl316Willment KC, Golby A (2013) Hemispheric Lateralization Interrupted: Material-Specific Memory Deficits in Temporal Lobe Epilepsy. Front Hum Neurosci 7. https://doi.org/10.3389/fnhum.2013.00546Bonora A, Benuzzi F, Monti G, Mirandola L, Pugnaghi M, Nichelli P, Meletti S (2011) Recognition of emotions from faces and voices in medial temporal lobe epilepsy. Epilepsy & Behavior 20: 648–654. https://doi.org/10.1016/j.yebeh.2011.01.027Swinkels WAM, Kuyk J, Dyck R van, Spinhoven Ph (2005) Psychiatric comorbidity in epilepsy. Epilepsy & Behavior 7: 37–50. https://doi.org/10.1016/j.yebeh.2005.04.012Chen B, Choi H, Hirsch LJ, Katz A, Legge A, Buchsbaum R, Detyniecki K (2017) Psychiatric and behavioral side effects of antiepileptic drugs in adults with epilepsy. Epilepsy & Behavior 76: 24–31. https://doi.org/10.1016/j.yebeh.2017.08.039Soltani Khaboushan A, Yazdanpanah N, Rezaei N (2022) Neuroinflammation and Proinflammatory Cytokines in Epileptogenesis. Mol Neurobiol 59: 1724–1743. https://doi.org/10.1007/s12035-022-02725-6Wójtowicz S, Strosznajder AK, Jeżyna M, Strosznajder JB (2020) The Novel Role of PPAR Alpha in the Brain: Promising Target in Therapy of Alzheimer’s Disease and Other Neurodegenerative Disorders. Neurochem Res 45: 972–988. https://doi.org/10.1007/s11064-020-02993-5Mirza AZ, Althagafi II, Shamshad H (2019) Role of PPAR receptor in different diseases and their ligands: Physiological importance and clinical implications. Eur J Med Chem 166: 502–513. https://doi.org/10.1016/j.ejmech.2019.01.067Warden A, Truitt J, Merriman M, Ponomareva O, Jameson K, Ferguson LB, Mayfield RD, Harris RA (2016) Localization of PPAR isotypes in the adult mouse and human brain. Sci Rep 6. https://doi.org/10.1038/srep27618Bernardo A, Minghetti L (2006) PPAR -gamma agonists as Regulators of Microglial Activation and Brain Inflammation. Curr Pharm Des 12: 93–109. https://doi.org/10.2174/138161206780574579Storer PD, Xu J, Chavis J, Drew PD (2005) Peroxisome proliferator-activated receptor-gamma agonists inhibit the activation of microglia and astrocytes: Implications for multiple sclerosis. J Neuroimmunol 161: 113–122. https://doi.org/10.1016/j.jneuroim.2004.12.015Zhao Y, Patzer A, Gohlke P, Herdegen T, Culman J (2005) The intracerebral application of the PPARγ-ligand pioglitazone confers neuroprotection against focal ischaemia in the rat brain. Eur J Neurosci 22: 278–282. https://doi.org/10.1111/j.1460-9568.2005.04200.xAdabi Mohazab R, Javadi-Paydar M, Delfan B, Dehpour AR (2012) Possible involvement of PPAR-gamma receptor and nitric oxide pathway in the anticonvulsant effect of acute pioglitazone on pentylenetetrazole-induced seizures in mice. Epilepsy Res 101: 28–35. https://doi.org/10.1016/j.eplepsyres.2012.02.015Yu X, Shao X-G, Sun H, Li Y-N, Yang J, Deng Y-C, Huang Y-G (2008) Activation of cerebral peroxisome proliferator-activated receptors gamma exerts neuroprotection by inhibiting oxidative stress following pilocarpine-induced status epilepticus. Brain Res 1200: 146–158. https://doi.org/10.1016/j.brainres.2008.01.047Strosznajder AK, Wójtowicz S, Jeżyna MJ, Sun GY, Strosznajder JB (2021) Recent Insights on the Role of PPAR-β/δ in Neuroinflammation and Neurodegeneration, and Its Potential Target for Therapy. Neuromol Med 23: 86–98. https://doi.org/10.1007/s12017-020-08629-9Esmaeili MA, Yadav S, Gupta RKr, Waggoner GR, Deloach A, Calingasan NY, Beal MF, Kiaei M (2016) Preferential PPAR-α activation reduces neuroinflammation, and blocks neurodegeneration in vivo. Hum Mol Genet 25: 317–327. https://doi.org/10.1093/hmg/ddv477Leite JP, Garcia-Cairasco N, Cavalheiro EA (2002) New insights from the use of pilocarpine and kainate models. Epilepsy Res 50: 93–103. https://doi.org/10.1016/S0920-1211(02)00072-4Juvale IIA, Che Has ATC (2020) The evolution of the pilocarpine animal model of status epilepticus. Heliyon 6: e04557. https://doi.org/10.1016/j.heliyon.2020.e04557Phelan KD, Shwe UT, Williams DK, Greenfield LJ, Zheng F (2015) Pilocarpine-induced status epilepticus in mice: A comparison of spectral analysis of electroencephalogram and behavioral grading using the Racine scale. Epilepsy Res 117: 90–96. https://doi.org/10.1016/j.eplepsyres.2015.09.008Dyomina AV, Zubareva OE, Smolensky IV, Vasilev DS, Zakharova MV, Kovalenko AA, Schwarz AP, Ischenko AM, Zaitsev AV (2020) Anakinra Reduces Epileptogenesis, Provides Neuroprotection, and Attenuates Behavioral Impairments in Rats in the Lithium–Pilocarpine Model of Epilepsy. Pharmaceuticals 13: 340. https://doi.org/10.3390/ph13110340Gould TD, Dao DT, Kovacsics CE (2009) The Open Field Test. Neuromethods (42): 1-20. https://doi.org/10.1007/978-1-60761-303-9_1Steinbach JM, Garza ET, Ryan BC (2016) Novel Object Exploration as a Potential Assay for Higher Order Repetitive Behaviors in Mice. J Vis Exp 20(114): 54324. https://doi.org/10.3791/54324File SE, Hyde JRG (1978) Can social interaction be used to measure anxiety? Br J Pharmacol 62: 19–24. https://doi.org/10.1111/j.1476-5381.1978.tb07001.xBlanchard RJ, Caroline Blanchard D (1977) Aggressive behavior in the rat. Behav Biol 21: 197–224. https://doi.org/10.1016/S0091-6773(77)90308-XKim J, Kang H, Lee Y-B, Lee B, Lee D (2023) A quantitative analysis of spontaneous alternation behaviors on a Y-maze reveals adverse effects of acute social isolation on spatial working memory. Sci Rep 13: 14722. https://doi.org/10.1038/s41598-023-41996-4Wolfer DP, Stagljar-Bozicevic M, Errington ML, Lipp H-P (1998) Spatial Memory and Learning in Transgenic Mice: Fact or Artifact? Physiology 13: 118–123. https://doi.org/10.1152/physiologyonline.1998.13.3.118Postnikova TY, Diespirov GP, Amakhin DV, Vylekzhanina EN, Soboleva EB, Zaitsev AV (2021) Impairments of Long-Term Synaptic Plasticity in the Hippocampus of Young Rats during the Latent Phase of the Lithium-Pilocarpine Model of Temporal Lobe Epilepsy. Int J Mol Sci 22: 13355. https://doi.org/10.3390/ijms222413355Heneka M, Landreth G (2007) PPARs in the brain. Biochim Biophys Acta (BBA) - Mol and Cell Biol of Lipids 1771: 1031–1045. https://doi.org/10.1016/j.bbalip.2007.04.016Moreno S, Farioli-Vecchioli S, Cerù MP (2004) Immunolocalization of peroxisome proliferator-activated receptors and retinoid x receptors in the adult rat CNS. Neuroscience 123. https://doi.org/10.1016/j.neuroscience.2003.08.064Basu-Modak S, Braissant O, Escher P, Desvergne B, Honegger P, Wahli W (1999) Peroxisome Proliferator-activated Receptor β Regulates Acyl-CoA Synthetase 2 in Reaggregated Rat Brain Cell Cultures. J Biol Chem 274: 35881–35888. https://doi.org/10.1074/jbc.274.50.35881Wang Y, Nakajima T, Gonzalez FJ, Tanaka N (2020) PPARs as Metabolic Regulators in the Liver: Lessons from Liver-Specific PPAR-Null Mice. Int J Mol Sci 21: 2061. https://doi.org/10.3390/ijms21062061Han L, Shen W-J, Bittner S, Kraemer FB, Azhar S (2017) PPARs: regulators of metabolism and as therapeutic targets in cardiovascular disease. Part II: PPAR-β/δ and PPAR-γ. Future Cardiol 13: 279–296. https://doi.org/10.2217/fca-2017-0019Han L, Shen W-J, Bittner S, Kraemer FB, Azhar S (2017) PPARs: regulators of metabolism and as therapeutic targets in cardiovascular disease. Part I: PPAR-α. Future Cardiol 13: 259–278. https://doi.org/10.2217/fca-2016-0059Christofides A, Konstantinidou E, Jani C, Boussiotis VA (2021) The role of peroxisome proliferator-activated receptors (PPAR) in immune responses. Metabolism 114: 154338. https://doi.org/10.1016/j.metabol.2020.154338Zolezzi JM, Santos MJ, Bastías-Candia S, Pinto C, Godoy JA, Inestrosa NC (2017) PPARs in the central nervous system: roles in neurodegeneration and neuroinflammation. Biol Rev 92: 2046–2069. https://doi.org/10.1111/brv.12320Thakur S, Dhapola R, Sarma P, Medhi B, Reddy DH (2023) Neuroinflammation in Alzheimer’s Disease: Current Progress in Molecular Signaling and Therapeutics. Inflammation 46: 1–17. https://doi.org/10.1007/s10753-022-01721-1Chen Y, Nagib MM, Yasmen N, Sluter MN, Littlejohn TL, Yu Y, Jiang J (2023) Neuroinflammatory mediators in acquired epilepsy: an update. Inflammat Res 72: 683–701. https://doi.org/10.1007/s00011-023-01700-8Suleymanova EM (2021) Behavioral comorbidities of epilepsy and neuroinflammation: Evidence from experimental and clinical studies. Epilepsy & Behavior 117: 107869. https://doi.org/10.1016/j.yebeh.2021.107869Kuang G, He Q, Zhang Y, Zhuang R, Xiang A, Jiang Q, Luo Y, Yang J (2012) Modulation of Preactivation of PPAR- β on Memory and Learning Dysfunction and Inflammatory Response in the Hippocampus in Rats Exposed to Global Cerebral Ischemia/Reperfusion. PPAR Res 2012: 1–11. https://doi.org/10.1155/2012/209794Chehaibi K, le Maire L, Bradoni S, Escola JC, Blanco-Vaca F, Slimane MN (2017) Effect of PPAR-β/δ agonist GW0742 treatment in the acute phase response and blood–brain barrier permeability following brain injury. Translat Res 182: 27–48. https://doi.org/10.1016/j.trsl.2016.10.004Senn L, Costa A-M, Avallone R, Socała K, Wlaź P, Biagini G (2023) Is the peroxisome proliferator-activated receptor gamma a putative target for epilepsy treatment? Current evidence and future perspectives. Pharmacol Ther 241: 108316. https://doi.org/10.1016/j.pharmthera.2022.108316Hung T-Y, Chu F-L, Wu DC, Wu S-N, Huang C-W (2019) The Protective Role of Peroxisome Proliferator-Activated Receptor-Gamma in Seizure and Neuronal Excitotoxicity. Mol Neurobiol 56: 5497–5506. https://doi.org/10.1007/s12035-018-1457-2Peng J, Wang K, Xiang W, Li Y, Hao Y, Guan Y (2019) Rosiglitazone polarizes microglia and protects against pilocarpine-induced status epilepticus. CNS Neurosci Ther 25: 1363–1372. https://doi.org/10.1111/cns.13265Hong S, Xin Y, HaiQin W, GuiLian Z, Ru Z, ShuQin Z, HuQing W, Li Y, Yun D (2012) The PPARγ agonist rosiglitazone prevents cognitive impairment by inhibiting astrocyte activation and oxidative stress following pilocarpine-induced status epilepticus. Neurol Sci 33: 559–566. https://doi.org/10.1007/s10072-011-0774-2Oliver WR, Shenk JL, Snaith MR, Russell CS, Plunket KD, Bodkin NL, Lewis MC, Winegar DA, Sznaidman ML, Lambert MH, Xu HE, Sternbach DD, Kliewer SA, Hansen BC, Willson TM (2001) A selective peroxisome proliferator-activated receptor δ agonist promotes reverse cholesterol transport. Proc Natl Acad Sci U S A 98: 5306–5311. https://doi.org/10.1073/pnas.091021198Schmeiser B, Li J, Brandt A, Zentner J, Doostkam S, Freiman TM (2017) Different mossy fiber sprouting patterns in ILAE hippocampal sclerosis types. Epilepsy Res 136: 115–122. https://doi.org/10.1016/j.eplepsyres.2017.08.002Zubareva OE, Dyomina AV, Kovalenko AA, Roginskaya AI, Melik-Kasumov TB, Korneeva MA, Chuprina AV, Zhabinskaya AA, Kolyhan SA, Zakharova MV, Gryaznova MO, Zaitsev AV (2023) Beneficial Effects of Probiotic Bifidobacterium longum in a Lithium–Pilocarpine Model of Temporal Lobe Epilepsy in Rats. Int J Mol Sci 24: 8451. https://doi.org/10.3390/ijms24098451Smolensky IV, Zubareva OE, Kalemenev SV, Lavrentyeva VV, Dyomina AV, Karepanov AA, Zaitsev AV (2019) Impairments in cognitive functions and emotional and social behaviors in a rat lithium-pilocarpine model of temporal lobe epilepsy. Behav Brain Res 372. https://doi.org/10.1016/j.bbr.2019.112044Müller CJ, Gröticke I, Bankstahl M, Löscher W (2009) Behavioral and cognitive alterations, spontaneous seizures, and neuropathology developing after a pilocarpine-induced status epilepticus in C57BL/6 mice. Exp Neurol 219: 284–297. https://doi.org/10.1016/j.expneurol.2009.05.035