Endogenous and exogenous serotonin, but not sumatriptan, ameliorate seizures and neuroinflammation in the pentylenetetrazole-induced seizure model in rats

ABSTRACT

Background: Epilepsy has neuropsychiatric comorbidities such as depression, bipolar disorder, and anxiety. Drugs that target epilepsy may also be useful for its neuropsychiatric comorbidities. Objective: To investigate the effects of serotonergic modulation on pro-inflammatory cytokines and the seizures in pentylenetetrazole (PTZ)-induced seizure model in rats. Methods: Male Wistar rats were injected intraperitoneally with serotonin, selective serotonin reuptake inhibitor fluoxetine, 5-HT1B/D receptor agonist sumatriptan, or saline 30 min prior to PTZ treatment. Behavioral seizures were assessed by the Racine's scale. Concentrations of IL-1β, IL-6, and TNF-α in serum and brain tissue were determined by ELISA. Results: Serotonin and fluoxetine, but not sumatriptan, alleviated PTZ-induced seizures by prolonging onset times of myoclonic-jerk and generalized tonic-clonic seizures. The anti-seizure effect of fluoxetine was greater than that of serotonin. Likewise, serotonin and fluoxetine, but not sumatriptan, reduced PTZ-induced increases in the levels of IL-1β and IL-6 in both serum and brain tissue. None of the administered drugs including PTZ affected TNF-α concentrations. Conclusions: Our findings suggest that endogenous and exogenous serotonin exhibits anticonvulsant effects by suppressing the neuroinflammation. It seems that 5-HT1B/D receptors do not mediate anticonvulsant and anti-neuroinflammatory effects of serotonin.

RESUMO

Antecedentes: A epilepsia apresenta comorbidades neuropsiquiátricas como depressão, transtorno bipolar e ansiedade. Os medicamentos que visam o tratamento da epilepsia podem ser úteis para a epilepsia e suas comorbidades neuropsiquiátricas. Objetivo: Investigar os efeitos da modulação serotonérgica em citocinas pró-inflamatórias e as convulsões no modelo de convulsão induzida por pentilenotetrazol (PTZ) em ratos. Métodos: Ratos Wistar machos foram injetados intraperitonealmente com serotonina, inibidor seletivo da recaptação da serotonina fluoxetina, sumatriptano agonista do receptor 5-HT1B / D ou solução salina 30 min antes do tratamento com PTZ. As crises comportamentais foram avaliadas pela escala de Racine. As concentrações de IL-1β, IL-6 e TNF-α no soro e tecido cerebral foram determinadas por ELISA. Resultados: A serotonina e a fluoxetina, mas não o sumatriptano, aliviaram as convulsões induzidas por PTZ ao prolongar os tempos de início das convulsões mioclônicas e tônico-clônicas generalizadas. O efeito anticonvulsivo da fluoxetina foi maior do que o da serotonina. Da mesma forma, a serotonina e a fluoxetina, mas não o sumatriptano, reduziram os aumentos induzidos por PTZ nos níveis de IL-1β e IL-6 no soro e no tecido cerebral. Nenhum dos medicamentos administrados, incluindo PTZ, alterou as concentrações de TNF-α. Conclusões: Nossos achados sugerem que a serotonina endógena e exógena exibe efeitos anticonvulsivantes por suprimir a neuroinflamação. Aparentemente, os receptores 5-HT1B / D não medeiam os efeitos anticonvulsivantes e anti-neuroinflamatórios da serotonina.

Keywords:

Serotonin 5-HT1 Receptor Agonists - Fluoxetine - Seizures - Epilepsy - Inflammation

Palavras-chave:

Agonistas do Receptor 5-HT1 de Serotonina - Fluoxetina - Convulsões - Epilepsia - Inflamação

Authors’ contributions:

EK: contributed to the idea and design of the study; IET, YBK: carried out the experiments and the analysis of the samples; EK: contributed to the writing of the article. All authors contributed to the revision of the article.

Support

The study has been funded by the Bolu Abant Izzet Baysal University Scientific Research Fund (Grant numbers: 2016.08.02.1082 and 2018.08.02.1370).

Publication History

Received: 23 March 2021

Accepted: 12 May 2021

Article published online:
30 January 2023

• References

• 1 Thijs RD, Surges R, O'Brien TJ, Sander JW. Epilepsy in adults. Lancet 2019; 393 10172 689-701 https://doi.org/10.1016/S0140-6736(18)32596-0
• 2 Kilinc E, Gunes H. Modulatory effects of neuropeptides on pentylenetetrazol-induced epileptic seizures and neuroinflammation in rats. Rev Assoc Med Bras (1992) 2019; 65 (09) 1188-1192 https://doi.org/10.1590/1806-9282.65.9.1188
• 3 Rana A, Musto AE. The role of inflammation in the development of epilepsy. J Neuroinflammation 2018; 15 (01) 144 https://doi.org/10.1186/s12974-018-1192-7
• 4 Vezzani A, French J, Bartfai T, Baram TZ. The role of inflammation in epilepsy. Nat Rev Neurol 2011; 7 (01) 31-40 https://doi.org/10.1038/nrneurol.2010.178
• 5 Hendriksen E, van Bergeijk D, Oosting RS, Redegeld FA. Mast cells in neuroinflammation and brain disorders. Neurosci Biobehav Rev 2017; 79: 119-133 https://doi.org/10.1016/j.neubiorev.2017.05.001
• 6 Musto AE, Rosencrans RF, Walker CP, Bhattacharjee S, Raulji CM, Belayev L. et al. Dysfunctional epileptic neuronal circuits and dysmorphic dendritic spines are mitigated by platelet-activating factor receptor antagonism. Sci Rep 2016; 6: 30298 https://doi.org/10.1038/srep30298
• 7 Gidal BE. Serotonin and epilepsy: the story continues. Epilepsy Curr 2013; 13 (06) 289-290 https://doi.org/10.5698/1535-7597-13.6.289
• 8 Kilinc E, Torun IE, Cetinkaya A, Tore F. Mast cell activation ameliorates pentylenetetrazole-induced seizures in rats: the potential role for serotonin. Eur J Neurosci 2021; Epub ahead of print
• 9 Kanner AM. Is depression associated with an increased risk of treatment-resistant epilepsy? Research strategies to investigate this question. Epilepsy Behav 2014; 38: P3-P7 https://doi.org/10.1016/j.yebeh.2014.06.027
• 10 Hamid H, Kanner AM. Should antidepressant drugs of the selective serotonin reuptake inhibitor family be tested as antiepileptic drugs?. Epilepsy Behav 2013; 26 (03) P261-P265 https://doi.org/10.1016/j.yebeh.2012.10.009
• 11 Maia GH, Brazete CS, Soares JI, Luz LL, Lukoyanov NV. Serotonin depletion increases seizure susceptibility and worsens neuropathological outcomes in kainate model of epilepsy. Brain Res Bull 2017; 134: 109-120 https://doi.org/10.1016/j.brainresbull.2017.07.009
• 12 da Fonseca NC, Joaquim HPG, Talib LL, de Vincentiis S, Gattaz WF, Valente KD. Hippocampal serotonin depletion is related to the presence of generalized tonic-clonic seizures, but not to psychiatric disorders in patients with temporal lobe epilepsy. Epilepsy Res 2015; 111: 18-25 https://doi.org/10.1016/j.eplepsyres.2014.12.013
• 13 Rocha L, Alonso-Vanegas M, Orozco-Suárez S, Alcántara-González D, Cruzblanca H, Castro E. Do certain signal transduction mechanisms explain the comorbidity of epilepsy and mood disorders?. Epilepsy Behav 2014; 38: P25-P31 https://doi.org/10.1016/j.yebeh.2014.01.001
• 14 Conley RK, Hutson PH. Effects of acute and chronic treatment with fluoxetine on stress-induced hyperthermia in telemetered rats and mice. Eur J Pharmacol 2007; 564 1-3 138-145 https://doi.org/10.1016/j.ejphar.2007.02.063
• 15 Bates EA, Nikai T, Brennan KC, Fu Y-H, Charles AC, Basbaum AI. et al. Sumatriptan alleviates nitroglycerin-induced mechanical and thermal allodynia in mice. Cephalalgia 2010; 30 (02) 170-178 https://doi.org/10.1111/j.1468-2982.2009.01864.x
• 16 Taskiran AS, Tastemur Y. The role of nitric oxide in anticonvulsant effects of lycopene supplementation on pentylenetetrazole-induced epileptic seizures in rats. Exp Brain Res 2021; 239 (02) 591-599 https://doi.org/10.1007/s00221-020-06012-5
• 17 Sefil F, Kahraman I, Dokuyucu R, Gokce H, Ozturk A, Tutuk O. et al. Ameliorating effect of quercetin on acute pentylenetetrazole induced seizures in rats. Int J Clin Exp Med 2014; 7 (09) 2471-2477
• 18 Hernandez EJ, Williams PA, Dudek FE. Effects of fluoxetine and TFMPP on spontaneous seizures in rats with pilocarpine-induced epilepsy. Epilepsia 2002; 43 (11) 1337-1345 https://doi.org/10.1046/j.1528-1157.2002.48701.x
• 19 Mazarati A, Siddarth P, Baldwin RA, Shin D, Caplan R, Sankar R. Depression after status epilepticus: behavioural and biochemical deficits and effects of fluoxetine. Brain 2008; 131 (08) 2071-2083 https://doi.org/10.1093/brain/awn117
• 20 Clinckers R, Smolders I, Meurs A, Ebinger G, Michotte Y. Anticonvulsant action of hippocampal dopamine and serotonin is independently mediated by D and 5-HT receptors. J Neurochem 2004; 89 (04) 834-843 https://doi.org/10.1111/j.1471-4159.2004.02355.x
• 21 Albano C, Cupello A, Mainardi P, Scarrone S, Favale E. Successful treatment of epilepsy with serotonin reuptake inhibitors: proposed mechanism. Neurochem Res 2006; 31 (04) 509-514 https://doi.org/10.1007/s11064-006-9045-7
• 22 Zhao H, Lin Y, Chen S, Li X, Huo H. 5-HT3 Receptors: a potential therapeutic target for epilepsy. Curr Neuropharmacol 2018; 16 (01) 29-36 https://doi.org/10.2174/1570159X15666170508170412
• 23 López-Meraz M-L, González-Trujano M-E, Neri-Bazán L, Hong E, Rocha LL. 5-HT1A receptor agonists modify epileptic seizures in three experimental models in rats. Neuropharmacology 2005; 49 (03) 367-375 https://doi.org/10.1016/j.neuropharm.2005.03.020
• 24 Gharedaghi MH, Seyedabadi M, Ghia J-E, Dehpour AR, Rahimian R. The role of different serotonin receptor subtypes in seizure susceptibility. Exp Brain Res 2014; 232 (02) 347-367 https://doi.org/10.1007/s00221-013-3757-0
• 25 Gooshe M, Ghasemi K, Rohani MM, Tafakhori A, Amiri S, Aghamollaii V. et al. Biphasic effect of sumatriptan on PTZ-induced seizures in mice: Modulation by 5-HT1B/D receptors and NOS/NO pathway. Eur J Pharmacol 2018; 824: 140-147 https://doi.org/10.1016/j.ejphar.2018.01.025
• 26 Alyu F, Dikmen M. Inflammatory aspects of epileptogenesis: contribution of molecular inflammatory mechanisms. Acta Neuropsychiatr 2017; 29 (01) 1-16 https://doi.org/10.1017/neu.2016.47
• 27 Kalueff AV, Lehtimaki KA, Ylinen A, Honkaniemi J, Peltola J. Intranasal administration of human IL-6 increases the severity of chemically induced seizures in rats. Neurosci Lett 2004; 365 (02) 106-110
• 28 Stellwagen D, Beattie EC, Seo JY, Malenka RC. Differential regulation of AMPA receptor and GABA receptor trafficking by tumor necrosis factor-alpha. J Neurosci 2005; 25 (12) 3219-3228 https://doi.org/10.1523/JNEUROSCI.4486-04.2005
• 29 Ichiyama T, Nishikawa M, Yoshitomi T, Hayashi T, Furukawa S. Tumor necrosis factor-alpha, interleukin-1 beta, and interleukin-6 in cerebrospinal fluid from children with prolonged febrile seizures. Comparison with acute encephalitis/encephalopathy. Neurology 1998; 50 (02) 407-411 https://doi.org/10.1212/WNL.50.2.407
• 30 Roseti C, van Vliet EA, Cifelli P, Ruffolo G, Baayen JC, Di Castro MA. et al. GABAA currents are decreased by IL-1β in epileptogenic tissue of patients with temporal lobe epilepsy: implications for ictogenesis. Neurobiol Dis 2015; 82: 311-320 https://doi.org/10.1016/j.nbd.2015.07.003
• 31 Kilinc E, Guerrero-Toro C, Zakharov A, Vitale C, Gubert-Olive M, Koroleva K. et al. Serotonergic mechanisms of trigeminal meningeal nociception: implications for migraine pain. Neuropharmacology 2017; 116: 160-173 https://doi.org/10.1016/j.neuropharm.2016.12.024
• 32 Kilinc E, Tore F, Dagistan Y, Bugdayci G. Thymoquinone inhibits neurogenic inflammation underlying migraine through modulation of calcitonin gene-related peptide release and stabilization of meningeal mast cells in glyceryltrinitrate-induced migraine model in rats. Inflammation 2020; 43 (01) 264-273 https://doi.org/10.1007/s10753-019-01115-w
• 33 Gharishvandi F, Abdollahi A, Shafaroodi H, Jafari RM, Pasalar P, Dehpour AR. Involvement of 5-HT1B/1D receptors in the inflammatory response and oxidative stress in intestinal ischemia/reperfusion in rats. Eur J Pharmacol 2020; 882: 173265 https://doi.org/10.1016/j.ejphar.2020.173265
• 34 Herr N, Bode C, Duerschmied D. The effects of serotonin in immune cells. Front Cardiovasc Med 2017; 4: 48 https://doi.org/10.3389/fcvm.2017.00048
• 35 Domínguez-Soto Á, Usategui A, de Las Casas-Engel ML, Simón-Fuentes M, Nieto C, Cuevas VD. et al. Serotonin drives the acquisition of a profibrotic and anti-inflammatory gene profile through the 5-HT7R-PKA signaling axis. Sci Rep 2017; 7 (01) 14761 https://doi.org/10.1038/s41598-017-15348-y
• 36 Sitges M, Gómez CD, Aldana BI. Sertraline reduces IL-1β and TNF-α mRNA expression and overcomes their rise induced by seizures in the rat hippocampus. PLoS One 2014; 9 (11) e111665 https://doi.org/10.1371/journal.pone.0111665