Pretratamiento con enoxaparina alivia las crisis epilépticas inducidas por pentilentetrazol en ratas Wistar

• Huseyin Gungor Sivas Cumhuriyet University, Faculty of Veterinary Medicine, Department of Pharmacology and Toxicology. Sivas, Türkiye
• Nergiz Hacer Turgut Izmir Katip Celebi University, Faculty of Pharmacy, Department of Pharmacology. Izmir, Türkiye

DOI: https://doi.org/10.52973/rcfcv-e34399

Palabras clave: Enoxaparina, epilepsia, antioxidante, antiinflamatorio, antiapoptótico

Resumen

La epilepsia, un trastorno neurológico prevalente caracterizado por convulsiones recurrentes, que centran la atención sobre las propiedades multifacéticas de la enoxaparina, una heparina de bajo peso molecular. Además de su actividad anticoagulante, la enoxaparina ha demostrado efectos antiinflamatorios, antioxidantes y antiapoptóticos. En consecuencia, el propósito de este estudio fue evaluar el efecto protector de la enoxaparina contra las convulsiones, el estrés oxidativo, las citoquinas proinflamatorias, la apoptosis, las concentraciones del factor neurotrópico derivado del cerebro (BDNF) y el deterioro cognitivo en el encendido inducido por pentilentetrazol (PTZ) en ratas Wistar. Se utilizaron veinticuatro ratas divididas en 4 grupos (Control, PTZ, ENX₂₅₀+PTZ, ENX₅₀₀+PTZ). Se administró a ratas enoxaparina (250 y 500 UI·kg^-1,intraperitoneal –ip–) o vehículo (solución salina) durante 5 días. El quinto día, 30 min después de la administración del fármaco, se administró PTZ (45 mg·kg^-1, ip) para provocar convulsiones. Los parámetros conductuales de las convulsiones se evaluaron mediante grabación de vídeo. Se realizó una prueba conductual, prueba de evitación pasiva. La administración de PTZ disminuyó el estado antioxidante total (TAS) mientras que aumentó el estado oxidante total (TOS) tanto en el hipocampo como en la corteza. Además, PTZ indujo niveles elevados de factor de necrosis tumoral alfa (TNF–α), interleucina–1β (IL–1β), BDNF, caspasa–3 y caspasa–9. El pretratamiento con enoxaparina disminuyó los niveles de estos parámetros y TOS, mientras que aumentó TAS. El pretratamiento con enoxaparina disminuyó significativamente las puntuaciones de las crisis epilépticas según la escala de Racine, aumentó el tiempo del primer tirón mioclónico (FMJ) y el tiempo de prueba en la prueba de evitación pasiva. Estos resultados indican que la enoxaparina (250 y 500 UI·kg^-1) en ambas dosis tiene un efecto protector prometedor contra la epilepsia inducida por PTZ al mejorar el deterioro de la memoria, la inflamación, el estrés oxidativo y la apoptosis. Este efecto positivo fue más prominente con una dosis de 500 UI·kg^-1 de enoxaparina.

Citas

Zupec‐Kania BA, Spellman E. An overview of the ketogenic diet for pediatric epilepsy. Nutr. Clin. Pract. [Internet]. 2008; 23(6):589–596. doi: https://doi.org/bhnjc5

Koutroumanidis M, Arzimanoglou A, Caraballo R, Goyal S, Kaminska A, Laoprasert P, Oguni H, Rubboli G, Tatum W, Thomas P. The role of EEG in the diagnosis and classification of the epilepsy syndromes: a tool for clinical practice by the ILAE Neurophysiology Task Force (Part 2). Epileptic Disord. [Internet]. 2017; 19(4):385–437. doi: https://doi.org/gt7bjx

Dhir A. Pentylenetetrazol (PTZ) kindling model of epilepsy. Curr. Protoc. Neurosci. [Internet]. 2012; 58:9.37.1–9.37. 12. doi: https://doi.org/fzszjp

Singh T, Mishra A, Goel RK. PTZ kindling model for epileptogenesis, refractory epilepsy, and associated comorbidities: relevance and reliability. Metab. Brain. Dis. [Internet]. 2021; 36(7):1573–1590. doi: https://doi.org/gqr6rk

Speckmann EJ, Walden J, Bingmann D. Die funktionelle Bedeutung von Calcium–Ionen bei epileptischen Anfällen. Antiepileptische Wirkung organischer Calcium–Antagonisten [Functional implication of calcium ions in epileptic seizures. Antiepileptic effects of organic calcium antagonists]. Arzneimittelforschung. 1989; 39(1A):149–156. German. PMID: 2655613

Rumelt S, Stolovich C, Segal ZI, Rehany U. Intraoperative enoxaparin minimizes inflammatory reaction after pediatric cataract surgery. Am. J. Ophthalmol. [Internet]. 2006; 141(3):433–437. doi: https://doi.org/dxsg4h

Nasiripour S, Gholami K, Mousavi S, Mohagheghi A, Radfar M, Abdollahi M, Khazaeipour Z, Mojtahedzadeh M. Comparison of the effects of enoxaparin and heparin on inflammatory biomarkers in patients with ST–segment elevated myocardial infarction: a prospective open label pilot clinical trial. Iran J. Pharm Res. [Internet]. 2014 [cited 10 Jan. 2024]; 13(2):583. PMID: 2523735. Available in: https://goo.su/anurf

Baram D, Rashkovsky M, Hershkoviz R, Drucker I, Reshef T, Ben–Shitrit S, Mekori YA. Inhibitory effects of low molecular weight heparin on mediator release by mast cells: preferential inhibition of cytokine production and mast cell–dependent cutaneous inflammation. Clin. Exp. Immunol. [Internet]. 1997; 110(3):485–491. doi: https://doi.org/ctfpt9

Shastri MD, Stewart N, Horne J, Zaidi STR, Sohal SS, Peterson GM, Korner H, Gueven N, Patel RP. Non–anticoagulant fractions of enoxaparin suppress inflammatory cytokine release from peripheral blood mononuclear cells of allergic asthmatic individuals. PLoS One [Internet]. 2015; 10(6):e0128803. doi: https://doi.org/gt7bjz

Lean QY, Eri RD, Randall–Demllo S, Sohal SS, Stewart N, Peterson GM, Gueven N, Patel RP. Orally administered enoxaparin ameliorates acute colitis by reducing macrophage–associated inflammatory responses. PLoS One [Internet]. 2015; 10(7):e0134259. doi: https://doi.org/gt7bj2

Assy N, Hussein O, Khalil A, Luder A, Szvalb S, Paizi M, Spira G. The beneficial effect of aspirin and enoxaparin on fibrosis progression and regenerative activity in a rat model of cirrhosis. Dig. Dis. Sci. [Internet]. 2007; 52:1187–1193. doi: https://doi.org/dbc93t

Kukner A, Tore F, Firat T, Terzi EH, Oner H, Balaban YH, Ozogul C. The preventive effect of low molecular weight heparin on CCL4–induced necrosis and apoptosis in rat liver. Ann. Hepatol. 2010; 9(4):445–454. PMID: 21057164

Lee JH, Lee H, Joung YK, Jung KH, Choi JH, Lee DH, Park KD, Hong SS. The use of low molecular weight heparin–pluronic nanogels to impede liver fibrosis by inhibition the TGF–β/Smad signaling pathway. Biomaterials [Internet]. 2011; 32(5):1438–1445. doi: https://doi.org/cnwdqj

Seidensticker M, Seidensticker R, Damm R, Mohnike K, Pech M, Sangro B, Hass P, Wust P, Kropf S, Gademann G. Prospective randomized trial of enoxaparin, pentoxifylline and ursodeoxycholic acid for prevention of radiation–induced liver toxicity. PloS One [Internet]. 2014; 9(11):e112731. doi: https://doi.org/gkpjh4

Abdel–Salam OM, Baiuomy AR, Ameen A, Hassan NS. A study of unfractionated and low molecular weight heparins in a model of cholestatic liver injury in the rat. Pharmacol. Res. [Internet]. 2005; 51(1):59–67. doi: https://doi.org/fd2b62

Koyuncuoğlu T, Vızdıklar C, Üren D, Yılmaz H, Yıldırım Ç, Atal SS, Akakın D, Demirci EK, Yüksel M, Yeğen BÇ. Obestatin improves oxidative brain damage and memory dysfunction in rats induced with an epileptic seizure. Peptides [Internet]. 2017; 90:37–47. doi: https://doi.org/f9475w

Kobbi Z, Kraiem H, Benlasfar Z, Marouani A, Massoud T, Boubaker S, Bouhaouala–Zahar B, Fenina N: Comparative subcutaneous repeated toxicity study of enoxaparin products in rats. Regul. Toxicol. Pharmacol. [Internet]. 2017; 84:9–17. doi: https://doi.org/f9xd55

Sandri ASS, Rodriguez R, Costa MM, Porto SM, Schwingel D, Vieira MIB. High–dose enoxaparin in the treatment of abdominal angiostrongyliasis in Swiss mice. J. Helminthol. [Internet]. 2018; 92(6):662–667. doi: https://doi.org/gbzs59

Shaker RA, Abboud SH, Assad HC, Hadi N. Enoxaparin attenuates doxorubicin induced cardiotoxicity in rats via interfering with oxidative stress, inflammation and apoptosis. BMC Pharmacol. Toxicol. [Internet]. 2018; 19:3. doi: https://doi.org/nc8d

Aboyoussef AM, Abdel–Sattar AR, Abdel–Bakky MS, Messiha BA. Enoxaparin prevents CXCL16/ADAM10–mediated cisplatin renal toxicity: Role of the coagulation system and the transcriptional factor NF–κβ. Life Sci. [Internet]. 2021; 270:119120. doi: https://doi.org/gt7bj3

Erdogan MA, Yusuf D, Christy J, Solmaz V, Erdogan A, Taskiran E, Erbas O. Highly selective SGLT2 inhibitor dapagliflozin reduces seizure activity in pentylenetetrazol–induced murine model of epilepsy. BMC Neurology [Internet]. 2018; 18(81):1–8. doi: https://doi.org/gdqx3b

Erdogan MA, Yusuf D, Erdogan A, Erbas O. Levodropropizine suppresses seizure activity in rats with pentylenetetrazol–induced epilepsy. Epilepsy Res. [Internet]. 2019; 150:32–37. doi: https://doi.org/gt7bj4

Bradford MM. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein–dye binding. Anal. Biochem. 1976; 72(1–2):248–254. doi: https://doi.org/bv9drn

Salim S. Oxidative stress and the central nervous system. Journal of Pharmacology and Experimental Therapeutics. J. Pharmacol. Exp. Ther. [Internet]. 2017; 360(1):201–205. doi: https://doi.org/gjfxcr

Hayashi M, Miyata R, Tanuma N. Oxidative stress in developmental brain disorders. In: Ahmad SI, editor. Neurodegenerative Diseases. Vol. 724 [Internet]. New York: Springer; 2012. p. 278–290. (Advances in Experimental Medicine and Biology Series). doi: https://doi.org/gt7bj5

Trist BG, Hare DJ, Double KL. Oxidative stress in the aging substantia nigra and the etiology of Parkinson’s disease. Aging Cell [Internet]. 2019; 18(6):e13031. doi: https://doi.org/gn6fn2

Eastman CL, D’Ambrosio R, Ganesh T. Modulating neuroinflammation and oxidative stress to prevent epilepsy and improve outcomes after traumatic brain injury. Neuropharmacology [Internet]. 2020; 172:107907. doi: https://doi.org/ggqgrd

Xiong L, McCoy M, Komuro H, West XZ, Yakubenko V, Gao D, Dudiki T, Milo A, Chen J, Podrez EA, Trapp B, Byzova TV. Inflammation–dependent oxidative stress metabolites as a hallmark of amyotrophic lateral sclerosis. Free Radic. Biol. Med. [Internet]. 2022; 178:125–133. doi: https://doi.org/gt7bj6

Parsons ALM, Bucknor EMV, Castroflorio E, Soares TR, Oliver PL, Rial D. The Interconnected Mechanisms of Oxidative Stress and Neuroinflammation in Epilepsy. Antioxidants [Internet]. 2022; 11(1):157. doi: https://doi.org/gt7bj7

Amin F, Tabassum S, Sarwar S, Qureshi R, Sohaib Khalid M, Riaz N, Al–Qahtani WH, Murtaza I. Neuroprotective Effect of Otostegia limbata Against PTZ–Induced Mice Model of Epilepsy by Attenuated Expression of p–NFκB and TNF–α. Front. Neurosci. [Internet]. 2022; 16:779681. doi: https://doi.org/gt7bj8

Köksoy FN, Yankol Y, Şen Oran E, Özkan Gürdal S, Yüksel M, Akyildiz Iğdem A, Yildirim Yazgan N, Soybir GR. Preventive effects of enoxaparin and hesperidin in cerulein–induced acute pancreatitis in rats. Turk. J. Gastroenterol. [Internet]. 2013; 24(6):495–501. doi: https://doi.org/gt7bj9

Ozcil MD, Ozcan O, Hakverdi S, Bayraktar H, Dirican E, Kacmaz F. Impact of Enoxaparin +α Lipoic acid combination on oxidative stress, follicle development and apoptotic damage in ovarian ischemia reperfusion model. Eur. Rev. Med. Pharmacol. Sci. [Internet]. 2022; 26(18):6583–6592. doi: https://doi.org/gt7bkb

Kamali AN, Zian Z, Bautista JM, Hamedifar H, Hossein–Khannazer N, Hosseinzadeh R, Yazdani R, Azizi G. The potential role of pro–inflammatory and anti–inflammatory cytokines in epilepsy pathogenesis. Endocr. Metab. Immune. Disord. Drug. Targets. [Internet]. 2021; 21(10):1760–1774. doi: https://doi.org/gt7bkc

Ethemoglu O, Ay H, Koyuncu I, Gönel A. Comparison of cytokines and prooxidants/antioxidants markers among adults with refractory versus well–controlled epilepsy: A cross–sectional study. Seizure [Internet]. 2018; 60:105–109. doi: https://doi.org/gfcbhd

Grosskopf I, Shaish A, Ray A, Harats D, Kamari Y. Low molecular weight heparin–induced increase in chylomicron–remnants clearance, is associated with decreased plasma TNF–α level and increased hepatic lipase activity. Thromb. Res. [Internet]. 2014; 133(4):688–692. doi: https://doi.org/f5vzcw

Berkowitz S, Gofrit SG, Aharoni SA, Golderman V, Qassim L, Goldberg Z, Dori A, Maggio N, Chapman J, Shavit–Stein E. LPS–Induced Coagulation and Neuronal Damage in a Mice Model Is Attenuated by Enoxaparin. Int. J. Mol. Sci. [Internet]. 2022; 23(18):10472. doi: https://doi.org/gt7bkd

Lei J, Feng F, Duan Y, Xu F, Liu Z, Lian L, Liang Q, Zhang N, Wang F. Intranasal nerve growth factor attenuating the seizure onset via p75R/Caspase pathway in the experimental epilepsy. Brain Res. Bull. [Internet]. 2017; 134:79–84. doi: https://doi.org/gb2qs2

Vega–García A, Orozco–Suárez S, Villa A, Rocha L, Feria–Romero I, Vanegas MA, Alonso–Vanegas MA, Guevara–Guzmán R. Cortical expression of IL1–β, Bcl–2, Caspase–3 and 9, SEMA–3a, NT–3 and P–glycoprotein as biological markers of intrinsic severity in drug–resistant temporal lobe epilepsy. Brain. Res. [Internet]. 2021; 1758:147303. doi: https://doi.org/gt7bkf

Zhao Q, Yin C, Yuan Y, Zhang H, Teng L. Down–regulation of Mir–145 improves learning and memory abilities in epileptic rats by regulating hippocampal neuron apoptosis. World Neurosurg. [Internet]. 2019; 122:e1432–e1438. doi: https://doi.org/gt7bkg

Findik O, Yilmaz MY, Yazir Y, Rençber SF, Sarihan KK, Kunt AT. Investigation of the protective effect of enoxaparin and ticagrelor pretreatment against ischemia–reperfusion injury in rat lung tissue. Rev. Assoc. Med. Bras. [Internet]. 2019; 65(9):1193–1200. doi: https://doi.org/ghhdzc

Findik O, Baris O, Yazir Y, Yilmaz MY, Rencber SF, Sarihan KK, Kunt AT. Changes in cardiac cells due to ticagrelor and enoxaparin in a rat ischemia/reperfusion model. Rev. Assoc. Med. Bras. [Internet]. 2021; 67(12):1764–1770. doi: https://doi.org/gt7bkh

Koshal P, Kumar P. Neurochemical modulation involved in the beneficial effect of liraglutide, GLP–1 agonist on PTZ kindling epilepsy–induced comorbidities in mice. Mol. Cell. Biochem. [Internet]. 2016; 415:77–87. doi: https://doi.org/f8g2b7

Karabulut S, Filiz AK, Akkaya R: Thiamine alleviates cognitive impairment and epileptogenesis by relieving brain inflammation in PTZ–induced kindling rat model. Neurol. Res. [Internet]. 2022; 44(10):902–909. doi: https://doi.org/gt7bkj

Timmer NM, van Dijk L, van der Zee CEEM, Kiliaan A, de Waal RMW, Verbeek MM. Enoxaparin treatment administered at both early and late stages of amyloid β deposition improves cognition of APPswe/PS1dE9 mice with differential effects on brain Aβ levels. Neurobiol. Dis. [Internet]. 2010; 40(1):340–347. doi: https://doi.org/cvhd8r

Stutzmann JM, Mary V, Wahl F, Grosjean‐Piot O, Uzan A, Pratt J. Neuroprotective profile of enoxaparin, a low molecular weight heparin, in in vivo models of cerebral ischemia or traumatic brain injury in rats: a review. CNS Drug Rev. [Internet]. 2002; 8(1):1–30. doi: https://doi.org/bx63vf

Hao F, Jia LH, Li XW, Zhang YR, Liu XW. Garcinol upregulates GABAA and GAD65 expression, modulates BDNF–TrkB pathway to reduce seizures in pentylenetetrazole (PTZ)–induced epilepsy. Med Sci. Monit. [Internet]. 2016; 22:4415. doi: https://doi.org/f9cfbc

Binder DK, Scharfman HE. Brain–derived neurotrophic factor. Growth factors [Internet]. 2004; 22(3):123–131. doi: https://doi.org/bg73sd

Quartermain D, Li YS, Jonas S. The low molecular weight heparin enoxaparin reduces infarct size in a rat model of temporary focal ischemia. Cerebrovasc. Dis. [Internet]. 2003; 16(4):346–355. doi: https://doi.org/ftsbxg