Nöroinflamasyonun Epileptogenezdeki Rolü ve Antiepileptojenik Tedavide Nöroinflamasyona Yönelik Hedefler

Özet Deneysel epilepsi modellerinde ve epilepsi hastalarında yapılan klinik çalışmalar sonucunda, nöroinflamasyonun epilepsi patofizyolojisinde etkin bir rolü olduğuna dair önemli kanıtlar elde edilmiştir. Özellikle, nöroinflamasyonla ilişkili yolaklar ve mediyatörlerin epileptogenez sürecindeki etkisi yoğun araştırma konusu olmuş, antiepileptojenik tedavilerin ve epileptojenik biyobelirteçlerin geliştirilebilmesi için bu süreçlerin aydınlatılması önem kazanmıştır. Bu çalışmalar sonucunda birçok patofizyolojik süreç incelenmiş ve antiepileptojenik tedavi hedefleri tanımlanmıştır. Bu derlemede epileptogenez sürecinde nöroinflamasyon ile ilişkili başlıca mekanizmalar ele alınmış, antiepileptojenik tedavi geliştirilmesi odaklı olarak potansiyel hedefler gözden geçirilmiştir.Abstract Research in experimental epilepsy models and clinical investigations on epilepsy patients have provided important evidence that neuroinflammation has an effective role in epilepsy pathophysiology. Particularly, the effects of neuroinflammation-related pathways and mediators in the epileptogenesis process have been the subject of intensive research, and the elucidation of these processes has become important for the development of antiepileptogenic therapies and epileptogenic biomarkers. As a result of these studies, many pathophysiological processes have been determined and antiepileptogenic therapeutic targets have been defined. In this review, the main mechanisms involved in neuroinflammation in the epileptogenesis process are addressed and potential targets are reviewed focusing on developing antiepileptogenic therapy.

Anahtar Kelimeler:

Nöroinflamasyon, Epileptogenez, Epilepsi, Antiepileptojenik

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Dey A, Kang X, Qiu JG, Du YF, Jiang JX. Anti-Inflammatory small molecules to treat seizures and epilepsy: From bench to bedside. Trends Pharmacol Sci. 2016;37(6):463-84.
Vezzani A, Aronica E, Mazarati A, Pittman QJ. Epilepsy and brain inflammation. Exp Neurol. 2013;244:11-21.
Vezzani A. Epilepsy and inflammation in the brain: Overview and pathophysiology. Epilepsy Curr. 2014;14:3-7.
Vezzani A, Ruegg S. Introduction to the 2nd Meeting on Immunity and Inflammation in Epilepsy (IIE2016). Epilepsia. 2017;58:7-10.
Pitkanen A, Engel J. Past and present definitions of epileptogenesis and its biomarkers. Neurotherapeutics. 2014;11(2):231-41.
Terrone G, Pauletti A, Pascente R, Vezzani A. Preventing epileptogenesis: A realistic goal? Pharmacol Res. 2016;110:96-100.
Schmidt D, Sillanpaa M. Evidence-based review on the natural history of the epilepsies. Current Opinion in Neurology. 2012;25(2):159-63.
Pitkanen A, Lukasiuk K, Dudek FE, Staley KJ. Epileptogenesis. Csh Perspect Med. 2015;5(10):a022822-a022838.
Becker AJ. Review: Animal models of acquired epilepsy: insights into mechanisms of human epileptogenesis. Neuropathol Appl Neurobiol. 2018;44(1):112-29.
D'Ambrosio R, Eastman CL, Fattore C, Perucca E. Novel frontiers in epilepsy treatments: preventing epileptogenesis by targeting inflammation. Expert Rev Neurother. 2013;13(6):615-25.
Akin D, Ravizza T, Maroso M, Carcak N, Eryigit T, Vanzulli I, et al. IL-1 beta is induced in reactive astrocytes in the somatosensory cortex of rats with genetic absence epilepsy at the onset of spike-and-wave discharges, and contributes to their occurrence. Neurobiol Dis. 2011;44(3):259-69.
Ravizza T, Gagliardi B, Noe F, Boer K, Aronica E, Vezzani A. Innate and adaptive immunity during epileptogenesis and spontaneous seizures: Evidence from experimental models and human temporal lobe epilepsy. Neurobiol Dis. 2008;29(1):142-60.
Nomura DK, Lombardi DP, Chang JW, Niessen S, Ward AM, Long JZ, et al. Monoacylglycerol lipase exerts dual control over endocannabinoid and fatty acid pathways to support prostate cancer. Chem Biol. 2011;18(7):846-56.
Aronica E, Bauer S, Bozzi Y, Caleo M, Dingledine R, Gorter JA, et al. Neuroinflammatory targets and treatments for epilepsy validated in experimental models. Epilepsia. 2017;58:27-38.
von Ruden EL, Bogdanovic RM, Wotjak CT, Potschka H. Inhibition of monoacylglycerol lipase mediates a cannabinoid 1-receptor dependent delay of kindling progression in mice. Neurobiol Dis. 2015;77:238-45.
Patel M, Li QY, Chang LY, Crapo J, Liang LP. Activation of NADPH oxidase and extracellular superoxide production in seizure-induced hippocampal damage. J Neurochem. 2005;92(1):123-31.
Kim JH, Jang BG, Choi BY, Kim HS, Sohn M, Chung TN, et al. Post-treatment of an NADPH oxidase inhibitor prevents seizure-induced neuronal death. Brain Res. 2013;1499:163-72.
Vezzani A, French J, Bartfai T, Baram TZ. The role of inflammation in epilepsy. Nat Rev Neurol. 2011;7(1):31-40.
Vezzani A, Moneta D, Conti M, Richichi C, Ravizza T, De Luigi A, et al. Powerful anticonvulsant action of IL-1 receptor antagonist on intracerebral injection and astrocytic overexpression in mice. Proc Natl Acad Sci U S A. 2000;97(21):11534-9.
Marchi N, Fan Q, Ghosh C, Fazio V, Bertolini F, Betto G, et al. Antagonism of peripheral inflammation reduces the severity of status epilepticus. Neurobiol Dis. 2009;33(2):171-81.
Auvin S, Shin D, Mazarati A, Sankar R. Inflammation induced by LPS enhances epileptogenesis in immature rat and may be partially reversed by IL1RA. Epilepsia. 2010;51 (3):34-8.
Ravizza T, Noe F, Zardoni D, Vaghi V, Sifringer M, Vezzani A. Interleukin Converting Enzyme inhibition impairs kindling epileptogenesis in rats by blocking astrocytic IL-1beta production. Neurobiol Dis. 2008;31(3):327-33.
Maroso M, Balosso S, Ravizza T, Iori V, Wright CI, French J, et al. Interleukin-1 beta biosynthesis inhibition reduces acute seizures and drug resistant chronic epileptic activity in mice. Neurotherapeutics. 2011;8(2):304-15.
Fu L, Liu KY, Wake H, Teshigawara K, Yoshino T, Takahashi H, et al. Therapeutic effects of anti-HMGB1 monoclonal antibody on pilocarpine-induced status epilepticus in mice. Sci Rep. 2017;7(1):1179-1191.
Zhao JL, Wang Y, Xu CL, Liu KY, Wang Y, Chen LY, et al. Therapeutic potential of an anti-high mobility group box-1 monoclonal antibody in epilepsy. Brain Behavior and Immunity. 2017;64:308-19.
Balosso S, Ravizza T, Perego C, Peschon J, Campbell IL, De Simoni MG, et al. Tumor necrosis factor-alpha inhibits seizures in mice via p75 receptors. Ann Neurol. 2005;57(6):804-12.
Weinberg MS, Blake BL, McCown TJ. Opposing actions of hippocampus TNFalpha receptors on limbic seizure susceptibility. Exp Neurol. 2013;247:429-37.
Iori V, Frigerio F, Vezzani A. Modulation of neuronal excitability by immune mediators in epilepsy. Curr Opin Pharmacol. 2016;26:118-23.
Weissberg I, Wood L, Kamintsky L, Vazquez O, Milikovsky DZ, Alexander A, et al. Albumin induces excitatory synaptogenesis through astrocytic TGF-beta/ALK5 signaling in a model of acquired epilepsy following blood-brain barrier dysfunction. Neurobiol Dis. 2015;78:115-25.
Bar-Klein G, Cacheaux LP, Kamintsky L, Prager O, Weissberg I, Schoknecht K, et al. Losartan prevents acquired epilepsy via TGF-beta signaling suppression. Ann Neurol. 2014;75(6):864-75.
Inoki K, Corradetti MN, Guan KL. Dysregulation of the TSC-mTOR pathway in human disease. Nat Genet. 2005;37(1):19-24.
Crino PB. mTOR: A pathogenic signaling pathway in developmental brain malformations. Trends Mol Med. 2011;17(12):734-42.
Galanopoulou AS, Gorter JA, Cepeda C. Finding a better drug for epilepsy: The mTOR pathway as an antiepileptogenic target. Epilepsia. 2012;53(7):1119-30.
Mishto M, Ligorio C, Bellavista E, Martucci M, Santoro A, Giulioni M, et al. Immunoproteasome expression is induced in mesial temporal lobe epilepsy. Biochem Bioph Res Co. 2011;408(1):65-70.
Broekaart DWM, van Scheppingen J, Geijtenbeek KW, Zuidberg MRJ, Anink JJ, Baayen JC, et al. Increased expression of (immuno)proteasome subunits during epileptogenesis is attenuated by inhibition of the mammalian target of rapamycin pathway. Epilepsia. 2017;58(8):1462-72.
Gaudet AD, Fonken LK, Watkins LR, Nelson RJ, Popovich PG. MicroRNAs: Roles in Regulating Neuroinflammation. Neuroscientist. 2017:1073858417721150.
Iori V, Iyer AM, Ravizza T, Beltrame L, Paracchini L, Marchini S, et al. Blockade of the IL-1R1/TLR4 pathway mediates disease-modification therapeutic effects in a model of acquired epilepsy. Neurobiol Dis. 2017;99:12-23.
Tan CL, Plotkin JL, Veno MT, von Schimmelmann M, Feinberg P, Mann S, et al. MicroRNA-128 governs neuronal excitability and motor behavior in mice. Science. 2013;342(6163):1254-58.
Jimenez-Mateos EM, Engel T, Merino-Serrais P, McKiernan RC, Tanaka K, Mouri G, et al. Silencing microRNA-134 produces neuroprotective and prolonged seizure-suppressive effects. Nat Med. 2012;18(7):1087-94.
Patel DC, Wilcox KS, Metcalf CS. Novel targets for developing antiseizure and, potentially, antiepileptogenic drugs. Epilepsy Curr. 2017;17(5):293-8.