Perfil de estrés oxidativo y de modulación del sistema de adenosina: Relación con la epileptogenicidad y el riesgo de Muerte Súbita Inesperada en Epilepsia (SUDEP)
DOI:
https://doi.org/10.47924/neurotarget2025478Palabras clave:
epilepsia focal farmacorresistente, stress oxidativo, adenosina, SUDEPResumen
Objetivo. Determinar la relación del perfil de estrés oxidativo y de modulación del sistema de adenosina con la epileptogenicidad y la estratificación del riesgo de muerte súbita inesperada en la epilepsia (SUDEP, por sus siglas en inglés) en pacientes con epilepsia focal farmacorresistentes (EFFR) temporal y extratemporal.
Método. Se evaluaron muestras de suero obtenidas de 21 pacientes con EFFR. Se estudiaron además controles sanos pareados en edad y sexo. Se determinaron las concentraciones séricas de adenosina de la peroxidación lipídica del malondialdehido (MDA), de la producción de óxido nítrico (NOx), productos avanzados de oxidación a proteínas y glicación (AGE), así como vitamina C. Se empleó un análisis de regresión múltiple para delinear los marcadores significativos asociados con las variables clínicas y el riesgo de SUDEP. Se realizó un análisis de clúster utilizando técnicas de validación basados en Bootstrap.
Resultados. Los valores de adenosina (t(33)=1.87, p<0.05) y las concentraciones séricas de los productos de estrés oxidativo fueron significativamente mayores en los pacientes que en los controles; AGE: t(38)=2.577 p<0.01, NOx: t(37)=2.03, p<0.04, MDA: t(38)=3.62, p<0.0008, VitC: t(37)=2.52, p<0.016. Existió una correlación directamente proporcional entre la edad de inicio de las crisis y las concentraciones séricas de AGE. (t(5.12)=2.22, p<0.118. La prueba de hipótesis univariada t-test mostró una tendencia a concentraciones más alta de adenosina en los pacientes con alto riesgo de SUDEP; 126.81 vs 95.58 t(16)=1.758, p=0.097.
Conclusiones. En pacientes con EFFR existen perfiles incrementados de adenosina y de toxicidad por estrés oxidativo, más relevante en los pacientes con epilepsia del lóbulo temporal. Estos perfiles se relacionan con la epileptogenicidad, y resultan independientes de la medicación anticrisis. En pacientes con EFFR con alto riesgo de SUDEP existe una tendencia a mayores concentraciones de adenosina, lo que sustenta la hipótesis de la adenosina en la fisiopatología de la SUDEP.
Métricas
Citas
Beghi E. The Epidemiology of Epilepsy. Neuroepide-miology. 2020;54(2):185-91. doi:10.1159/000503831. Epub 2019 Dec 18.
Morales Chacón LM, Garcia Maeso I, Baez Martin MM, Bender Del Busto JE, García Navarro ME, Quintanal Cordero N, et al. Long-Term Electroclinical and Employment Follow up in Temporal Lobe Epilepsy Surgery. A Cuban Comprehensive Epilepsy Surgery Program. Behav Sci (Basel). 2018;8(2):19. doi:0.3390/bs8020019.
Brodie MJ. Diagnosing and predicting refractory epilepsy. Acta Neurol Scand Suppl. 2005;181:36-9. doi:10.1111/j.6000404.2005.00507.x.
Morales Chacón LM, González González J, Ríos Castillo M, Berrillo Batista S, Batista García-Ramo K, Santos Santos A, et al. Surgical Outcome in Extratemporal Epilepsies Based on Multimodal Pre-Surgical Evaluation and Sequential Intraoperative Electrocorticography. Behav Sci (Basel). 2021;11(3):30. doi:10.3390/bs11030030.
Alqarni F, Eweis HS, Ali A, Alrafiah A, Alsieni M, Karim S, et al. Mitochondrial dysfunction in neurodege-nerative disorders. Biomedicines. 2022;10(1):168. doi:10.3390/biomedicines10010168.
Aguiar CC, Almeida AB, Araújo PV, de Abreu RN, Chaves EM, do Vale OC, et al. Oxidative stress and epilepsy: literature review. Oxid Med Cell Longev. 2012;2012:795259. doi:10.1155/2012/795259.
Lorigados Pedre L, Morales Chacón LM, Orozco Suárez S, Pavón Fuentes N, Estupiñán Díaz B, Serrano Sánchez T, et al. Inflammatory mediators in epilepsy. Curr Pharm Des. 2013;19(38):6766-72. doi: 10.2174/1381612811319380009.
Vishnoi S, Raisuddin S, Parvez S. Glutamate Excitotoxicity and Oxidative Stress in Epilepsy: Modulatory Role of Melatonin. J Environ Pathol Toxicol Oncol. 2016;35(4):365-74. doi:10.1615/JEnvironPatholToxicolOncol.2016016399.
Ambrogini P, Torquato P, Bartolini D, Albertini MC, Lattanzi D, Di Palma M, et al. Excitotoxicity, neuroin-flammation 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):1098-112. doi: 10.16/j.bbadis.2019.01.026.
Fabisiak T, Patel M. Crosstalk between neuroinflam-mation and oxidative stress in epilepsy. Front Cell Dev Biol. 2022;10:976953. doi:10.3389/fcell.2022.976953. eCollection 2022.
Chen TS, Lai MC, Huang HI, Wu SN, Huang CW. Immunity, Ion Channels and Epilepsy. Int J Mol Sci. 2022;23(12):6446. doi:10.3390/ijms23126446.
Lu W, Wu Z, Zhang C, Gao T, Ling X, Xu M, et al. The Interconnected Mechanisms of Oxidative Stress and Neuroinflammation in Epilepsy. Evid Based Complement Alternat Med. 2022;2022:7792791. doi:10.1155/2022/7792791. eCollection 2022.
Dal-Pizzol F, Klamt F, Vianna MM, Schröder N, Quevedo J, Benfato MS, et al. Lipid peroxidation in hippocampus early and late after status epilepticus induced by pilocarpine or kainic acid in Wistar rats. Neurosci Lett. 2000;291(3):179-82. doi: 10.1016/s0304 3940(00)01409-9.
Rosendahl S, Anturaniemi J, Kukko-Lukjanov TK, Vuori KA, Moore R, Hemida M, et al. Increased Superoxide Dismutase 2 by Allopregnanolone Ameliorates ROS-Mediated Neuronal Death in Mice with Pilocarpine-Induced Status Epilepticus. J Vet Intern Med. 2023;37(3):1100-10. doi: 10.11/jvim.16698.
Bhuyan P, Patel DC, Wilcox KS, Patel M. Oxidative stress in murine Theiler's virus-induced temporal lobe epilepsy. Exp Neurol. 2015;271:329-34. doi:10.1016/j.expneurol.2015.06.012. Epub Jun 14.
Shakeel S, Rehman MU, Tabassum N, Amin U, Mir MUR. SIRT5 Deficiency Enhances Susceptibility to Kainate-Induced Seizures and Exacerbates Hippocampal Neurodegeneration not through Mitochondrial Antioxi-dant Enzyme SOD2. Pharmacogn Mag. 2017;13(Suppl 1):S154-S60. doi:10.4103/0973-1296.203977. Epub 2017 Apr 7.
Kiasalari Z, Khalili M, Shafiee S, Roghani M. The effect of Vitamin E on learning and memory deficits in intrahippocampal kainate-induced temporal lobe epilepsy in rats. Indian J Pharmacol. 2016;48(1):11-4. doi: 0.4103/0253-7613.174394.
Khamse S, Sadr SS, Roghani M, Hasanzadeh G, Mohammadian M. Rosmarinic acid exerts a neuroprotective effect in the kainate rat model of temporal lobe epilepsy: Underlying mechanisms. Pharm Biol. 2015;53(12):1818-25. doi:10.3109/13880209.2015.1010738. Epub 2015 Apr 15
Dariani S, Baluchnejadmojarad T, Roghani M. Thymoquinone attenuates astrogliosis, neurodegenera-tion, mossy fiber sprouting, and oxidative stress in a model of temporal lobe epilepsy. J Mol Neurosci. 2013;51(3):679-86. doi:10.1007/s12031-013-0043-3. Epub 2013 Jun 23.
Peternel S, Pilipović K, Zupan G. Seizure susceptibility and the brain regional sensitivity to oxidative stress in male and female rats in the lithium-pilocarpine model of temporal lobe epilepsy. Prog Neuropsychopharmacol Biol Psychiatry. 2009;33(3):456-62. doi:10.1016/j.pnpbp.2009.01.005. Epub Jan 21.
Pearson-Smith JN, Patel M. Metabolic Dysfunction and Oxidative Stress in Epilepsy. Int J Mol Sci. 2017;18(11):2365. doi:10.3390/ijms18112365.
Patel M. Mitochondrial dysfunction and oxidative stress: cause and consequence of epileptic seizures. Free Radic Biol Med. 2004;37(12):1951-62. doi:10.016/j.freeradbiomed.2004.08.021.
Hong H, Lu X, Wu C, Chen J, Chen C, Zhang J, et al. Adenosine dysfunction in epilepsy. Front Pharmacol. 2022;13:898955. doi:10.3389/fphar.2022.898955. eCollection 2022.
Tescarollo FC, Rombo DM, DeLiberto LK, Fedele DE, Alharfoush E, Tomé Â R, et al. Role of Adenosine in Epilepsy and Seizures. J Caffeine Adenosine Res. 2020;10(2):45-60. doi:10.1089/caff.2019.0022. Epub 2020 Jun 4.
Ashraf O, Huynh T, Purnell BS, Murugan M, Fedele DE, Chitravanshi V, et al. Reducing the Risk of Sudden Unexpected Death in Epilepsy (SUDEP). Neuropharm. 2021;184:108405. doi:10.1016/j.neuropharm.2020.108405. Epub 2020 Nov 16.
Tescarollo FC, Rombo DM, DeLiberto LK, Fedele DE, Alharfoush E, Tomé ÂR, et al. Role of Adenosine in Epilepsy and Seizures. J Neurophysiol. 2016;115(5):2286-93. doi:10.1152/jn.00011.2016. Epub 2016 Feb 17.
Patodia S, Paradiso B, Garcia M, Ellis M, Diehl B, Thom M, et al. Adenosine kinase and adenosine receptors A(1) R and A(2A) R in temporal lobe epilepsy and hippocampal sclerosis and association with risk factors for SUDEP. Epilepsia. 2020;61(4):787-97. doi:10.1111/epi.16487. Epub 2020 Apr 3.
King-Stephens D. Biomarkers for SUDEP: Are We There Yet? Front Neurosci. 2021;15:708304. doi:10.3389/fnins.2021.708304. eCollection 2021.
Zhao H, Long L, Xiao B. Advances in sudden unexpected death in epilepsy. Acta Neurol Scand. 2022;146(6):716-22. doi:10.1111/ane.13715. Epub 2022 Nov 10.
Tupal S, Faingold CL. Evidence supporting a role of serotonin in modulation of sudden death induced by seizures in DBA/2 mice. Epilepsia. 2006;47(1):21-6. doi:10.1111/j.528-67.2006.00365.x.
Purnell B, Murugan M, Jani R, Boison D. The Good, the Bad, and the Deadly: Adenosinergic Mechanisms Underlying Sudden Unexpected Death in Epilepsy. Neuron. 2014;83(5):996-8. doi:10.1016/j.neuron.2014.08.026.
Patodia S, Paradiso B, Ellis M, Somani A, Sisodiya SM, Devinsky O, et al. Characterisation of medullary astrocytic populations in respiratory nuclei and alterations in sudden unexpected death in epilepsy. Epilepsy Res. 2019;157:106213. doi:10.1016/j.eplepsyres.2019.106213. Epub 2019 Oct 1.
Boison D. Adenosine and epilepsy: from therapeutic rationale to new therapeutic strategies. Neuroscientist. 2005;11(1):25-36. doi:10.1177/1073858404269112.
Jacobson KA, Gao ZG. Adenosine receptors as therapeutic targets. Nat Rev Drug Discov. 2006;5(3):247-64. doi:10.1038/nrd983.
Wade CR, van Rij AM. Plasma thiobarbituric acid reactivity: reaction conditions and the role of iron, antioxidants and lipid peroxy radicals on the quantitation of plasma lipid peroxides. Life Sci. 1988;43(13):1085-93. doi:10.16/0024-3205(88)90204-4.
Green LC, Wagner DA, Glogowski J, Skipper PL, Wishnok JS, Tannenbaum SR. Analysis of nitrate, nitrite, and [15N] nitrate in biological fluids. Anal Biochem. 1982;126(1):131-8. doi:10.1016/0003-2697(82)90118-x.
Henle T, Deppisch R, Beck W, Hergesell O, Hänsch GM, Ritz E. Advanced glycated end-products (AGE) during haemodialysis treatment: discrepant results with different methodologies reflecting the heterogeneity of AGE compounds. Nephrol Dial Transplant. 1999;14(8):1968-75. doi:10.093/ndt/14.8.
Prieto P, Pineda M, Aguilar M. Spectrophotometric quantitation of antioxidant capacity through the formation of a phosphomolybdenum complex: specific application to the determination of vitamin E. Anal Biochem. 1999;269(2):337-41. doi:10.1006/abio.999.4019.
Lorigados Pedre L, Gallardo JM, Morales Chacón LM, Vega García A, Flores-Mendoza M, Neri-Gómez T, et al. Oxidative Stress in Patients with Drug Resistant Partial Complex Seizure. Behav Sci (Basel). 2018;8(6):59. doi:10.3390/bs8060059.
Chuang YC. Mitochondrial dysfunction and oxidative stress in seizure-induced neuronal cell death. Acta Neurol Taiwan. 2010;19(1):3-15.
Akünal Türel C, Yunusoğlu O. Mitochondrial diseases and status epilepticus. Int J Environ Health Res. 2023; 33(5):529-40. doi:10.1080/09603123.2023.2167947.
Palmieri B, Sblendorio V. Oxidative stress tests: overview on reliability and use. Part II. Eur Rev Med Pharmacol Sci. 2007;11(6):383-99.
Dotan Y, Lichtenberg D, Pinchuk I. Lipid peroxidation cannot be used as a universal criterion of oxidative stress. Prog Lipid Res. 2004;43(3):200-27. doi:10.1016/j.plipres.2003.10.001.
López J, González ME, Lorigados L, Morales L, Riverón G, Bauzá JY. Oxidative stress markers in surgically treated patients with refractory epilepsy. Clin Biochem. 2007;40(5-6):292-8. doi: 10.1016/j.clinbiochem.2006.11.019. Epub 7 Jan 5.
Ho YH, Lin YT, Wu CW, Chao YM, Chang AY, Chan JY. Peripheral inflammation increases seizure susceptibility via the induction of neuroinflammation and oxidative stress in the hippocampus. J Biomed Sci. 2015;22(1):46. doi:10.1186/s12929-015-0157-8.
Ben-Menachem E, Kyllerman M, Marklund S. Superoxide dismutase and glutathione peroxidase function in progressive myoclonus epilepsies. Epilepsy Res. 2000;40(1):33-9. doi:10.1016/s0920-1211(00)00096-6.
Ayala A, Muñoz MF, Argüelles S. Lipid peroxidation: production, metabolism, and signaling mechanisms of malondialdehyde and 4-hydroxy-2-nonenal. Oxid Med Cell Longev. 2014;2014:360438. doi:10.1155/2014/360438. Epub 2014 May 8.
Münch G, Keis R, Wessels A, Riederer P, Bahner U, Heidland A, et al. Determination of advanced glycation end products in serum by fluorescence spectroscopy and competitive ELISA. Eur J Clin Chem Clin Biochem. 1997;35(9):669-77. doi:10.1515/cclm.997.35.9.669.
Maes M, Landucci Bonifacio K, Morelli NR, Vargas HO, Barbosa DS, Carvalho AF, et al. Major Differences in Neurooxidative and Neuronitrosative Stress Pathways Between Major Depressive Disorder and Types I and II Bipolar Disorder. Mol Neurobiol. 2019;56(1):141-56. doi:10.1007/s12035-018-1051-7. Epub 2018 Apr 21.
Rowley S, Liang LP, Fulton R, Shimizu T, Day B, Patel M. Mitochondrial respiration deficits driven by reactive oxygen species in experimental temporal lobe epilepsy. Neurobiol Dis. 2015;75:151-8. doi:10.1016/j.nbd.2014.12.025. Epub 5 Jan 17.
Thom M. Review: Hippocampal sclerosis in epilepsy: a neuropathology review. Neuropathol Appl Neurobiol. 2014;40(5):520-43. doi:10.1111/nan.12150.
Hamed SA, Abdellah MM, El-Melegy N. Blood levels of trace elements, electrolytes, and oxidative stress/ antioxidant systems in epileptic patients. J Pharmacol Sci. 2004;96(4):465-73. doi:10.1254/jphs.fpj04032x. Epub 2004 Dec 10.
Peker E, Oktar S, Ari M, Kozan R, Doğan M, Cağan E, et al. Nitric oxide, lipid peroxidation, and antioxidant enzyme levels in epileptic children using valproic acid. Brain Res. 2009;1297:194-7. doi:10.1016/j.brainres.2009.08.048. Epub Aug 21.
Arhan E, Kurt ANC, Neselioglu S, Yerel O, Uçar HK, Aydin K, et al. Effects of antiepileptic drugs on dynamic thiol/disulphide homeostasis in children with idiopathic epilepsy. Seizure. 2019;65:89-93. doi:10.1016/j.seizure.2018.12.019. Epub Dec 26.
Menon B, Ramalingam K, Kumar RV. Oxidative stress in patients with epilepsy is independent of antiepileptic drugs. Seizure. 2012;21(10):780-4. doi: 10.1016/j.seizure.2012.09.003. Epub Sep 30.
Liu CS, Wu HM, Kao SH, Wei YH. Phenytoin-mediated oxidative stress in serum of female epileptics: a possible pathogenesis in the fetal hydantoin syndrome. Hum Exp Toxicol. 1997;16(3):177-81. doi: 10.1177/096032719701600308.
Maes M, Supasitthumrong T, Limotai C, Michelin AP, Matsumoto AK, de Oliveira Semão L, et al. Increased Oxidative Stress Toxicity and Lowered Antioxidant Defenses in Temporal Lobe Epilepsy and Mesial Temporal Sclerosis: Associations with Psychiatric Comorbidities. Mol Neurobiol. 2020;57(8):3334-48. doi: 10.1007/s12035-020-01949-8. Epub 2020 Jun 9.
Weltha L, Reemmer J, Boison D. The role of adenosine in epilepsy. Brain Res Bull. 2019;151:46-54. doi:10.1016/j.brainresbull.2018.11.008. Epub Nov 20.
Beamer E, Kuchukulla M, Boison D, Engel T. ATP and adenosine-Two players in the control of seizures and epilepsy development. Prog Neurobiol. 2021;204:102105 doi:10.1016/j.pneurobio.2021.102105. Epub 2021 Jun 16.
Pignataro G, Simon RP, Boison D. Transgenic overexpression of adenosine kinase aggravates cell death in ischemia. J Cereb Blood Flow Metab. 2007;27(1):1-5. doi: 10.1038/sj.jcbfm.9600334. Epub 2006 May 10.
Cunha RA. Adenosine A1 and A2A Receptors in the Brain: Current Research and Their Role in Neurodegeneration. J Neurochem. 2016;139(6):1019-55. doi:10.111/jnc.13724. Epub 2016 Aug 16.
Baltos JA, Casillas-Espinosa PM, Rollo B, Gregory KJ, White PJ, Christopoulos A, et al. The role of the adenosine system in epilepsy and its comorbidities. Br J Pharmacol. 2023;19(10):16094.
Descargas
Publicado
Cómo citar
Número
Sección
Licencia
Derechos de autor 2025 Lilia Morales Chacón, Sandra Orozco Suarez, Lídice Galán García, Nancy Pavón Fuentes, Juan Manuel Gallardo, Nelson Ernesto Quintanal Cordero, Antoni Camins Espuny, Luisa Rocha Arrieta
Esta obra está bajo una licencia internacional Creative Commons Atribución 4.0.
Este artículo se distribuye bajo la licencia Creative Commons Attribution 4.0 License. A menos que se indique lo contrario, el material publicado asociado se distribuye bajo la misma licencia.
