The role of inflammation in etiopathogenesis of pharmacoresistant epilepsy and refractory status epilepticus

Czech version

Authors: Š. Aulická ^1-3; K. Česká ¹; J. Šána ^2,4; T. Loja ²; P. Jabandžiev ^2,5; J. Papež ⁵; P. Danhofer ¹; H. Vinohradská ⁶; I. Doležalová ⁷; M. Brázdil ⁷; P. Štourač ⁸; H. Ošlejšková ¹; O. Slabý ²
Authors‘ workplace: Centrum pro epilepsie Brno, Klinika dětské neurologie LF MU a FN Brno ¹; Výzkumná skupina Ondřeje Slabého – Středoevropský technologický institut (CEITEC) ²; Klinika dětské onkologie LF MU a FN Brno ³; Klinika komplexní onkologické péče, Masarykův onkologický ústav, Brno ⁴; Pediatrická klinika LF MU a FN Brno ⁵; Oddělení klinické biochemie, FN Brno ⁶; Centrum pro epilepsie Brno, I. neurologická klinika LF MU a FN u sv. Anny v Brně ⁷; Klinika dětské anesteziologie a resuscitace LF MU a FN Brno ⁸
Published in: Cesk Slov Neurol N 2020; 83(1): 8-13
Category: Review Article
doi: https://doi.org/10.14735/amcsnn20208

Overview

Brain inflammation represents a common substrate of pharmacoresistant epilepsy of different etiologies and it can directly affect neuronal excitability. Neuromodulatory properties of some proinflammatory molecules (cytokines, chemokines) may be responsible for hyperexcitability in neuronal networks. The relation between inflammation and epilepsy is reciprocal. The inflammatory processes in the brain may participate in initiating seizure activity and simultaneously they may be a consequence of the recurrence of the seizures. Pharmacological studies on experimental models focused on IL-1β/ IL-1R1, HMGB1/ TLR4 and COX-2/ prostaglandin systems demostrate that these inflammatory pathways significantly in triggering and recurring seizure activity. Status epilepticus (SE) leads to development of inflammatory processes which can be detected in brain tissue, cerebrospinal fluid and blood serum. Prolonged seizures and SE lead to fast and prolonged activation of specific inflammatory pathways in brain areas accordant with the epileptogenic zone. Understanding the complex role of inflammation in the generation and exacerbation of epilepsy and development of pharmacoresistance in epilepsy is crucial for the identification of new molecular targets for therapeutic intervention in these patients.

The Editorial Board declares that the manuscript met the ICMJE “uniform requirements” for biomedical papers.

Keywords:

Cytokines – chemokines – pharmacoresistant epilepsy – refractory status epilepticus – polymorphisms

Sources

1. Vezzani A, Dingledine R, Rossetti A. Immunity and inflammation in status epilepticus and its sequelae: possibilities for therapeutic application. Expert Rev Neurother 2015; 15(9): 1081–1092. doi: 10.1586/ 14737175.2015.1079130.

2. Kubová H. Vývoj kvalitativně nových látek pro léčbu epilepsie – naděje pro 21. století? Neurol praxi 2006; 5: 284–286.

3. Vezzani A, Balosso S, Ravizza T. The role of cytokines in the pathophysiology of epilepsy. Brain Behav Immun 2008; 22(6): 797–803. doi: 10.1016/ j.bbi.2008.03.009.

4. Maroso M, Balosso S, Ravizza T. Toll-like receptor 4 and high-mobility group box-1 are involved in ictogenesis and be targeted to reduce seizures. Nat Med 2010; 16(4): 413–419. doi: 10.1038/ nm.2127.

5. Jiang J, Yang MS, Quan Y. Therapeutic window of cyclooxygenase-2 related anti-inflammatory therapy after status epilepticus. Neurobiol Dis 2015; 76: 126–136. doi: 10.1016/ j.nbd.2014.12.032.

6. Cerri CH, Caleo M, Bozzi Y. Chemokines as new inflammatory players in the pathogenesis of epilepsy. Epilepsy Res 2017; 136: 77–83. doi: 10.1016/ j.eplepsyres.2017.07.016.

7. Banisadr G, Rosténe W, Kitabgi P et al. Chemokines and brain functions. Curr Drug Targets Inflamm Allergy 2005; 4(3): 387–399. doi: 10.2174/ 1568010054022097.

8. Vezzani A, Friedman A. Brain inflammation as a biomarker in epilepsy. Biomark Med 2011; 5(5): 607–614. doi: 10.2217/ bmm.11.61.

9. Rojas A, Ganesh T, Lelutiu N et al. Inhibition of the prostaglandin EP2 receptor is neuroprotective and accelerates functional recovery in a rat model of organophosphorus induces status epilepticus. Neuropharmacology 2015; 93: 15–27. doi: 10.1016/ j.neuropharm.2015.01.017.

10. Forgeaud L, Boulanger LM. Role of immune molecules in the establishment and plasticity of glutamatergic synapses. Eur J Neurosci 2010; 32(2): 207–217. doi: 10.1111/ j.1460-9568.2010.07342.x.

11. Dubé CM, Ravizza T, Hamamura M. Epileptogenesis provoked by prolonged experimental febrile seizures: mechanisms and biomarkers. J Neurosci 2010; 30(22): 7484–7494. doi: 10.1523/ JNEUROSCI.0551-10.2010.

12. Patterson KP, Brennan GP, Curran M. Rapid coordinate inflammatory responses after experimetal status epilepticus: implications for epileptogenesis. eNeuro 2015; 2(5): pii: ENEURO.0034-15.2015. doi: 10.1523/ ENEURO.0034-15.2015.

13. Gallentine WB, Shinnar S, Hesdorffer DC et al. Plasma cytokines associated with febrile status epilepticus in children: a potential biomarker for acute hippocampal injury. Epilepsia 2017; 58(6): 1102–1111. doi: 10.1111/ epi.13750.

14. Choi J, Min HJ, Shin JS. Increase levels og HMGB1 and pro-inflammatory cytokines in children with febrile seizures. Neuroinflammation 2011; 8: 135. doi: 10.1186/ 1742-2094-8-135.

15. Sakuma H, Tanuma N, Kuki I et al. Intrathecal overproduction of proinflammatory cytokines and chemokines in febrile infection-related refraktory status epilepticus. J Neurol Neurosurg Psychiatry 2015; 86(7): 820–822. doi: 10.1136/ jnnp-2014-309388.

16. Galic MA, Riazi K, Henderson AK et al. Postnatal inflammation increases seizure susceptibility in adult rats. J Neurosci 2008; 28(27): 6904–6913. doi: 10.1523/ JNEUROSCI.1901-08.2008.

17. Zattoni M, Mura ML, Deprez F et al. Brain infiltration of leukocytes contributes to the pathophysiology of temporal lobe epilepsy. J Neurosci 2011; 31(11): 4037–4050. doi: 10.1523/ JNEUROSCI.6210-10.2011.

18. Vezzani A, Lang B, Aronica E. Immunity and inflammation in epilepsy. Cold Spring Harb Perspect Med 2015; 6(2): a022699. doi: 10.1101/ cshperspect.a022699.

19. Rana Amnam Musto EA. The role of proinflammation in the development of epilepsy. J Neuroinfamm 2018; 15: 144.

20. Aronica E, Bauer S, Bozzi Y et al. Neuroinflammatory targets and treatments for epilepsy validated in experimental models. Epilepsia 2017; 58 (Suppl 3): 27–38. doi: 10.1111/ epi.13783.

21. Koepp MJ, Arstad E, Bankstahl JP et al. Neuroinflammation imaging markers for epileptogenesis. Epilepsia 2017; 58 (Suppl 3): 11–19. doi: 10.1111/ epi.13778.

22. French JA, Koepp M, Naegelin Y et al. Clinical studies and anti-inflammatory mechanisms of treatments. Epilepsia 2017; 58 (Suppl 3): 69–82. doi: 10.1111/ epi.13779.

23. Horák O. Ketogenní dieta – účinná nefarmakologická léčba dětské a adolescentní epilepsie. Cesk Slov Neurol N 2019; 82/ 115(1): 8–14. doi: 10.14735/ amcsnn20198.

24. Vliet EA, Aronica E, Vezzani A et al. Review: neuroinflammatory pathways as treatment targets and biomarker candidates in epilepsy: emerging evidence from preclinical and clinical studies. Neuropathol Appl Neurobiol 2018; 44(1): 91–111. doi: 10.1111/ nan.12444.

25. Česká K, Horák O, Ošlejšková H et al. Nově vzniklý refrakterní status epilepticus a syndromy z blízkého spektra (NORSE/ FIRES). Cesk Slov Neurol N 2018; 81/ 114(6): 658–662. doi: 10.14735/ amcsnn2018658.

26. Henshall DC, Engel T. P2X purinoreceptor as a link between hyperexcitability and neuroinflammation in status epilepticus. Epilepsy Behav 2015; 49: 8–12. doi: 10.1016/ j.yebeh.2015.02.031.

27. Henshall DC, Diaz-Hernandez M, Miras-Portugal MT et al. P2X receptors as targets for the treatment of status epilepticus. Front Cell Neurscience 2013; 7: 237. doi: 10.3389/ fncel.2013.00237.

28. Rojas A, Jiang J, Ganesh T et al. Cyclooxygenase-2 in epilepsy. Epilepsia 2014; 55(1): 17–25. doi: 10.1111/ epi.12461.

29. Rojas A, Jiang J, Ganesh T et al. Role of cyclooxygenase-2 in epileptogenesis with a focus on its involvement in neurodegeneration. Epilepsia 2014; 55(1): 17–25. doi: 10.1111/ epi.12461.

30. Sierra-Marcos A, Alvarez V, Faouzi M. Statins are associated with decreased mortality risk after status epilepticus. Eur J Neurol 2015; 22(2): 402–405. doi: 10.1111/ ene.12428.

31. Pitsch J, Kuehn JC, Gnatkovsky V et al. Anti-epileptogenic and anti-convulsive effects of fingolimod in experimental temporal lobe epilepsy. Mol Neurobiol 2019; 56(3): 1825–1840. doi: 10.1007/ s12035-018-1181-y.

32. Carmona-Aparicio L, Pérez-Cruz C, Zavala-Tecuapetla C et al. Overview of Nrf2 as therapeutic target in epilepsy. Int J Mol Sci 2015; 16(8): 18348–18367. doi: 10.3390/ ijms160818348.