炎癥反應和氧化應激在癲癇中的作用研究進展_Journal of Epilepsy

Authors：

張冉冉 ,  劉學伍

山東大學齊魯醫院神經內科（濟南 250012）;

Corresponding?author：

劉學伍, Email: snlxw1966@163.com

Keywords：

癲癇; 神經炎癥; 氧化應激; 生物標志物

DOI：

10.7507/2096-0247.20210024

Video：

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急性腦損傷會在大腦中迅速誘發神經炎癥以及活性氧和活性氮的產生，增加癲癇發作的易感性。這些現象可相互促進，并在癲癇發生以及慢性自發性癲癇發作期間持續存在。一些具有抗炎和抗氧化作用的藥物已經在臨床上開始使用，且具有安全性，它們的治療作用通過靶向分子信號通路來介導，如 IL-1β-IL-1R1 軸和 TLR4、P2X7 受體，抗氧化應激轉錄因子 Nrf2 等，因此可為防治癲癇提供潛在的新療法。本文就可能參與癲癇發生發展的神經炎癥和氧化應激，以及相關的生物學指標作一綜述。

Citation： 張冉冉, 劉學伍. 炎癥反應和氧化應激在癲癇中的作用研究進展. Journal of Epilepsy, 2021, 7(2): 142-146. doi: 10.7507/2096-0247.20210024 Copy

1.	Devinsky O, Vezzani A, O'Brien, TJ, et al. Epilepsy. Nat Rev Dis Primer, 2018, 4: 18024.
2.	Dalic L, Cook MJ. Managing drug-resistant epilepsy: challenges and solutions. Neuropsychiatr Dis Treat, 2016, 12: 2605-2616.
3.	Pitkanen A, Ekolle Ndode-Ekane X, Lapinlampi N, et al. Epilepsy biomarkers toward etiology and pathology specificity. Neurobiol Dis, 2019, 123: 42-58.
4.	Pauletti A, Terrone G., Shekh-Ahmad T, et al Targeting oxidative stress improves disease outcomes in a rat model of acquired epilepsy. Brain, 2019, 142(7): e38.
5.	Vezzani A, Balosso S, Ravizza T. Neuroinflammatory pathways as treatment targets and biomarker candidates in epilepsy. Nat Rev Neurol, 2019, 15: 459-472.
6.	Vezzani A, Aronica E, Mazarati A, et al. Epilepsy and brain inflammation. Exp Neurol, 2013, 244(1): 11-21.
7.	van Vliet EA, Aronica E, Vezzani A, et al. 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.
8.	Klement W, Blaquiere M, Zub E, et al. A pericyte-glia scarring develops at the leaky capillaries in the hippocampus during seizure activity. Epilepsia, 2019, 60(7): 1399-1411.
9.	Bauer J, Becker AJ, Elyaman W, et al. Innate and adaptive immunity in human epilepsies. Epilepsia, 2017, 58(Suppl. 3): 57-68.
10.	Varvel NH, Neher JJ, Bosch A, et al. Infiltrating monocytes promote brain inflam-mation and exacerbate neuronal damage after status epilepticus. Proc. Natl. Acad. Sci. U. S. A, 2016, 113(38): E5665-E5674.
11.	Ravizza T, Vezzani A. Pharmacological targeting of brain inflammation in epilepsy: therapeutic perspectives from experimental and clinical studies. Epilepsia Open, 2018, 3(S2): 133-142.
12.	Iori V, Iyer AM, Ravizza T, 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.
13.	Zhao J, Wang Y, Xu C, et al. Therapeutic potential of an anti‐high mobility group box‐1 monoclonal antibody in epilepsy. Brain Behav Immun, 2017, 64: 308-319.
14.	Dhir A. An update of cyclooxygenase (COX)-inhibitors in epilepsy disorders. Expert Opin Investig Drugs, 2019, 28(2): 191-205.
15.	Rojas A, Jiang J, Ganesh T, et al. Cyclooxygenase-2 in epilepsy. Epilepsia, 2014, b, 55(1): 17-25.
16.	Rojas A, Ganesh T, Wang W, et al. A rat model of organophosphate-induced status epilepticus and the beneficial effects of EP2 receptor inhibition. Neurobiol Dis, 2020, 133: 104399.
17.	Balosso S, Maroso M, Sanchez-Alavez M, et al. A novel non-transcriptional pathway mediates the proconvulsive effects of interleukin-1beta. Brain, 2008, 131(12): 3256-3265.
18.	Balosso S, Liu J, Bianchi ME, et al. Disulfide-containing High Mobility Group Box-1 promotes N-methyl-d-aspartate receptor function and excitotoxicity by activating Toll-like receptor 4-dependent signaling in hippocampal neurons. Antioxid Redox Signal, 2014, 21(12): 1726-1740.
19.	Balosso S, Ravizza T, Pierucci M, et al. Molecular and functional interactions between TNFalpha receptors and the glutamatergic system in the mouse hippocampus: implications for seizure susceptibility. Neuroscience, 2009, 161(1): 293-300.
20.	Galic MA, Riazi K, Pittman QJ. Cytokines and brain excitability. Front Neuroendocrinol, 2012, 33(1): 116-125.
21.	Orioli E, De Marchi E, Giuliani AL, et al. P2X7receptor orchestrates multiple signalling pathways triggering inflammation, autophagy and metabolic/trophic responses. Curr Med Chem, 2017, 24(21): 2261-2275.
22.	Roseti C, van Vliet EA, Cifelli P, et al. GABA currents are decreased by IL-1beta in epileptogenic tissue of patients with temporal lobe epilepsy: implications for ictogenesis. Neurobiol Dis, 2015, 82: 311-320.
23.	Stellwagen D, Beattie EC, Seo JY, et al. Differential regulation ofAMPA receptor and GABA receptor trafficking by tumor necrosis factor-alpha. J Neurosci, 2005, 25(12): 3219-3228.
24.	Rojas A, Bueorguieva P, Lelutiu N, et al. The prostaglandin EP1 receptor potentiates kainate recptor activation via a protein kinase C pathway and exacerbates statusepilepticus. Neurobiol Dis, 2014a, 70: 74-89.
25.	Jiang J, Dingledine R. Prostaglandin receptor EP2 in the crosshairs of anti-inflammation, anti-cancer, and neuroprotection. Trends Pharmacol Sci, 2013, 34(7): 413-423.
26.	Bauer B, Hartz AM, Pekcec A, et al. Seizureinduced up-regulation of P- glycoprotein at the blood-brain barrier through glutamate and cyclooxygenase-2 signaling. Mol Pharmacol, 2008, 73(5): 1444-1453.
27.	Librizzi L, Noe F, Vezzani A, et al. Seizure-induced brainborne inflammation sustains seizure recurrence and blood-brain barrier damage. Ann. Neurol, 2012, 72,(1): 82-90.
28.	Weissberg I, Wood L, Kamintsky L, 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: 115-125.
29.	Ravizza T, Terrone G, Salamone A, et al. High Mobility Group Box 1 is a novel pathogenic factor and a mechanistic biomarker for epilepsy. Brain Behav Immun, 2018, 72: 14-21.
30.	Cardenas-Rodriguez N, Coballase-Urrutia E, Perez-Cruz C, et al. Relevance of the glutathione system in temporal lobe epilepsy: evidence in human and experimental models. Oxid Med Cell Longev, 2014: 759293.
31.	Pearson-Smith JN, Patel M. Metabolic dysfunction and oxidative stress in epilepsy. Int J Mol Sci, 2017, 18(11): 2365.
32.	Shekh-Ahmad T, Eckel R, Dayalan Naidu S, et al. KEAP1 inhibition is neuroprotective and suppresses the development of epilepsy. Brain, 2018, 141(5): 1390-1403.
33.	Diamond ML, Ritter AC, Failla MD, et al. IL-1beta associations with posttraumatic epilepsy development: a genetics and biomarker cohort study. Epilepsia, 2014, 55(7): 1109-1119.
34.	Wang KY, Yu GF, Zhang ZY, et al. Plasma high-mobility group box 1 levels and prediction of outcome in patients with traumatic brain injury. Clin Chim Acta Int J Clin Chem, 2012, 413(21-22): 1737-1741.
35.	Kalita J, Misra UK, Singh LS, et al. Oxidative stress in status epilepticus: a clinical-radiological correlation. Brain Res, 2019, 1704: 85-93.
36.	Lopez J, Gonzalez ME, Lorigados L, et al. Oxidative stress markers in surgically treated patients with refractory epilepsy. Clin Biochem, 2007, 40(5-6): 292-298.
37.	Koepp MJ, Arstad E, Bankstahl JP, et al. Neuroinflammation imaging markers for epileptogenesis. Epilepsia, 2017, 58(Suppl. 3): 11-19.
38.	Dilena R, Mauri E, Aronica E, et al. Therapeutic effect of Anakinra in the relapsing chronic phase of febrile infection–related epilepsy syndrome. Epilepsia Open, 2019, 4(2): 344-350.
39.	Ben-Menachem E, Kyllerman M, Marklund S. Superoxide dismutase and glutathione peroxidase function in progressive myoclonus epilepsies. Epilepsy Res, 2000, 40(1): 33-39.
40.	Wu Y, Dissing-Olesen L, MacVicar BA, et al. Microglia: Dynamic Mediators of Synapse Development and Plasticity. Trends Immunol, 2015, 36(10): 605-613.

1. Devinsky O, Vezzani A, O'Brien, TJ, et al. Epilepsy. Nat Rev Dis Primer, 2018, 4: 18024.
2. Dalic L, Cook MJ. Managing drug-resistant epilepsy: challenges and solutions. Neuropsychiatr Dis Treat, 2016, 12: 2605-2616.
3. Pitkanen A, Ekolle Ndode-Ekane X, Lapinlampi N, et al. Epilepsy biomarkers toward etiology and pathology specificity. Neurobiol Dis, 2019, 123: 42-58.
4. Pauletti A, Terrone G., Shekh-Ahmad T, et al Targeting oxidative stress improves disease outcomes in a rat model of acquired epilepsy. Brain, 2019, 142(7): e38.
5. Vezzani A, Balosso S, Ravizza T. Neuroinflammatory pathways as treatment targets and biomarker candidates in epilepsy. Nat Rev Neurol, 2019, 15: 459-472.
6. Vezzani A, Aronica E, Mazarati A, et al. Epilepsy and brain inflammation. Exp Neurol, 2013, 244(1): 11-21.
7. van Vliet EA, Aronica E, Vezzani A, et al. 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.
8. Klement W, Blaquiere M, Zub E, et al. A pericyte-glia scarring develops at the leaky capillaries in the hippocampus during seizure activity. Epilepsia, 2019, 60(7): 1399-1411.
9. Bauer J, Becker AJ, Elyaman W, et al. Innate and adaptive immunity in human epilepsies. Epilepsia, 2017, 58(Suppl. 3): 57-68.
10. Varvel NH, Neher JJ, Bosch A, et al. Infiltrating monocytes promote brain inflam-mation and exacerbate neuronal damage after status epilepticus. Proc. Natl. Acad. Sci. U. S. A, 2016, 113(38): E5665-E5674.
11. Ravizza T, Vezzani A. Pharmacological targeting of brain inflammation in epilepsy: therapeutic perspectives from experimental and clinical studies. Epilepsia Open, 2018, 3(S2): 133-142.
12. Iori V, Iyer AM, Ravizza T, 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.
13. Zhao J, Wang Y, Xu C, et al. Therapeutic potential of an anti‐high mobility group box‐1 monoclonal antibody in epilepsy. Brain Behav Immun, 2017, 64: 308-319.
14. Dhir A. An update of cyclooxygenase (COX)-inhibitors in epilepsy disorders. Expert Opin Investig Drugs, 2019, 28(2): 191-205.
15. Rojas A, Jiang J, Ganesh T, et al. Cyclooxygenase-2 in epilepsy. Epilepsia, 2014, b, 55(1): 17-25.
16. Rojas A, Ganesh T, Wang W, et al. A rat model of organophosphate-induced status epilepticus and the beneficial effects of EP2 receptor inhibition. Neurobiol Dis, 2020, 133: 104399.
17. Balosso S, Maroso M, Sanchez-Alavez M, et al. A novel non-transcriptional pathway mediates the proconvulsive effects of interleukin-1beta. Brain, 2008, 131(12): 3256-3265.
18. Balosso S, Liu J, Bianchi ME, et al. Disulfide-containing High Mobility Group Box-1 promotes N-methyl-d-aspartate receptor function and excitotoxicity by activating Toll-like receptor 4-dependent signaling in hippocampal neurons. Antioxid Redox Signal, 2014, 21(12): 1726-1740.
19. Balosso S, Ravizza T, Pierucci M, et al. Molecular and functional interactions between TNFalpha receptors and the glutamatergic system in the mouse hippocampus: implications for seizure susceptibility. Neuroscience, 2009, 161(1): 293-300.
20. Galic MA, Riazi K, Pittman QJ. Cytokines and brain excitability. Front Neuroendocrinol, 2012, 33(1): 116-125.
21. Orioli E, De Marchi E, Giuliani AL, et al. P2X7receptor orchestrates multiple signalling pathways triggering inflammation, autophagy and metabolic/trophic responses. Curr Med Chem, 2017, 24(21): 2261-2275.
22. Roseti C, van Vliet EA, Cifelli P, et al. GABA currents are decreased by IL-1beta in epileptogenic tissue of patients with temporal lobe epilepsy: implications for ictogenesis. Neurobiol Dis, 2015, 82: 311-320.
23. Stellwagen D, Beattie EC, Seo JY, et al. Differential regulation ofAMPA receptor and GABA receptor trafficking by tumor necrosis factor-alpha. J Neurosci, 2005, 25(12): 3219-3228.
24. Rojas A, Bueorguieva P, Lelutiu N, et al. The prostaglandin EP1 receptor potentiates kainate recptor activation via a protein kinase C pathway and exacerbates statusepilepticus. Neurobiol Dis, 2014a, 70: 74-89.
25. Jiang J, Dingledine R. Prostaglandin receptor EP2 in the crosshairs of anti-inflammation, anti-cancer, and neuroprotection. Trends Pharmacol Sci, 2013, 34(7): 413-423.
26. Bauer B, Hartz AM, Pekcec A, et al. Seizureinduced up-regulation of P- glycoprotein at the blood-brain barrier through glutamate and cyclooxygenase-2 signaling. Mol Pharmacol, 2008, 73(5): 1444-1453.
27. Librizzi L, Noe F, Vezzani A, et al. Seizure-induced brainborne inflammation sustains seizure recurrence and blood-brain barrier damage. Ann. Neurol, 2012, 72,(1): 82-90.
28. Weissberg I, Wood L, Kamintsky L, 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: 115-125.
29. Ravizza T, Terrone G, Salamone A, et al. High Mobility Group Box 1 is a novel pathogenic factor and a mechanistic biomarker for epilepsy. Brain Behav Immun, 2018, 72: 14-21.
30. Cardenas-Rodriguez N, Coballase-Urrutia E, Perez-Cruz C, et al. Relevance of the glutathione system in temporal lobe epilepsy: evidence in human and experimental models. Oxid Med Cell Longev, 2014: 759293.
31. Pearson-Smith JN, Patel M. Metabolic dysfunction and oxidative stress in epilepsy. Int J Mol Sci, 2017, 18(11): 2365.
32. Shekh-Ahmad T, Eckel R, Dayalan Naidu S, et al. KEAP1 inhibition is neuroprotective and suppresses the development of epilepsy. Brain, 2018, 141(5): 1390-1403.
33. Diamond ML, Ritter AC, Failla MD, et al. IL-1beta associations with posttraumatic epilepsy development: a genetics and biomarker cohort study. Epilepsia, 2014, 55(7): 1109-1119.
34. Wang KY, Yu GF, Zhang ZY, et al. Plasma high-mobility group box 1 levels and prediction of outcome in patients with traumatic brain injury. Clin Chim Acta Int J Clin Chem, 2012, 413(21-22): 1737-1741.
35. Kalita J, Misra UK, Singh LS, et al. Oxidative stress in status epilepticus: a clinical-radiological correlation. Brain Res, 2019, 1704: 85-93.
36. Lopez J, Gonzalez ME, Lorigados L, et al. Oxidative stress markers in surgically treated patients with refractory epilepsy. Clin Biochem, 2007, 40(5-6): 292-298.
37. Koepp MJ, Arstad E, Bankstahl JP, et al. Neuroinflammation imaging markers for epileptogenesis. Epilepsia, 2017, 58(Suppl. 3): 11-19.
38. Dilena R, Mauri E, Aronica E, et al. Therapeutic effect of Anakinra in the relapsing chronic phase of febrile infection–related epilepsy syndrome. Epilepsia Open, 2019, 4(2): 344-350.
39. Ben-Menachem E, Kyllerman M, Marklund S. Superoxide dismutase and glutathione peroxidase function in progressive myoclonus epilepsies. Epilepsy Res, 2000, 40(1): 33-39.
40. Wu Y, Dissing-Olesen L, MacVicar BA, et al. Microglia: Dynamic Mediators of Synapse Development and Plasticity. Trends Immunol, 2015, 36(10): 605-613.

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