Mechanism of blood brain barrier in the pathogenesis of epilepsy_West China Medical Journal

Authors：

WANG Baoxiang ¹ , ZHANG Xiutian ² ,  CHAI Changfeng ²

1. Department of Neurology, Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang 314000, P. R. China;
2. Department of Neurology, the First Affiliated Hospital of Naval Medical University, Shanghai 200433, P. R. China;

Corresponding author：

CHAI Changfeng, Email: chaicf0206@126.com

Keywords：

Blood brain barrier; epilepsy; pathogenesis; treatment

DOI：

10.7507/1002-0179.202408289

Video：

Export PDF Favorites Scan Get Citation

Abstract Full text Figures/Tables Video References Cited by

Epilepsy is one of the common chronic diseases in neurology, and antiepileptic medication is the main treatment method. Studies have shown that epileptic seizures may disrupt the permeability of the blood brain barrier (BBB), and BBB disruption may also lead to epilepsy. This article reviews the mechanism of BBB in the pathogenesis of epilepsy based on relevant research progress, elucidates the relationship between BBB and epilepsy, and proposes possible directions for future research and development of antiepileptic drugs.

1.	Löscher W, Friedman A. Structural, molecular, and functional alterations of the blood-brain barrier during epileptogenesis and epilepsy: a cause, consequence, or both?. Int J Mol Sci, 2020, 21(2): 591.
2.	van Vliet EA, da Costa Araújo S, Redeker S, et al. Blood-brain barrier leakage may lead to progression of temporal lobe epilepsy. Brain, 2007, 130(Pt 2): 521-534.
3.	Cudna A, Bronisz E, Jopowicz A, et al. Changes in serum blood-brain barrier markers after bilateral tonic-clonic seizures. Seizure, 2023, 106: 129-137.
4.	Bronisz E, Cudna A, Wierzbicka A, et al. Blood-brain barrier-associated proteins are elevated in serum of epilepsy patients. Cells, 2023, 12(3): 368.
5.	Rigau V, Morin M, Rousset MC, et al. Angiogenesis is associated with blood-brain barrier permeability in temporal lobe epilepsy. Brain, 2007, 130(Pt 7): 1942-1956.
6.	Marchi N, Lerner-Natoli M. Cerebrovascular remodeling and epilepsy. Neuroscientist, 2013, 19(3): 304-312.
7.	van Vliet EA, Aronica E, Gorter JA. Blood-brain barrier dysfunction, seizures and epilepsy. Semin Cell Dev Biol, 2015, 38: 26-34.
8.	Michalak Z, Lebrun A, Di Miceli M, et al. IgG leakage may contribute to neuronal dysfunction in drug-refractory epilepsies with blood-brain barrier disruption. J Neuropathol Exp Neurol, 2012, 71(9): 826-838.
9.	Ndode-Ekane XE, Hayward N, Gröhn O, et al. Vascular changes in epilepsy: functional consequences and association with network plasticity in pilocarpine-induced experimental epilepsy. Neuroscience, 2010, 166(1): 312-332.
10.	Cornford EM. Epilepsy and the blood brain barrier: endothelial cell responses to seizures. Adv Neurol, 1999, 79: 845-862.
11.	Cornford EM, Oldendorf WH. Epilepsy and the blood-brain barrier. Adv Neurol, 1986, 44: 787-812.
12.	Giannoni P, Badaut J, Dargazanli C, et al. The pericyte-glia interface at the blood-brain barrier. Clin Sci (Lond), 2018, 132(3): 361-374.
13.	Klement W, Garbelli R, Zub E, et al. Seizure progression and inflammatory mediators promote pericytosis and pericyte-microglia clustering at the cerebrovasculature. Neurobiol Dis, 2018, 113: 70-81.
14.	Jabs R, Seifert G, Steinhäuser C. Astrocytic function and its alteration in the epileptic brain. Epilepsia, 2008, 49(Suppl 2): 3-12.
15.	Coulter DA, Steinhäuser C. Role of astrocytes in epilepsy. Cold Spring Harb Perspect Med, 2015, 5(3): a022434.
16.	Xhima K, Weber-Adrian D, Silburt J. Glutamate induces blood-brain barrier permeability through activation of N-methyl-D-aspartate receptors. J Neurosci, 2016, 36(49): 12296-12298.
17.	Rempe RG, Hartz AMS, Soldner ELB, et al. Matrix metalloproteinase-mediated blood-brain barrier dysfunction in epilepsy. J Neurosci, 2018, 38(18): 4301-4315.
18.	Lischper M, Beuck S, Thanabalasundaram G, et al. Metalloproteinase mediated occludin cleavage in the cerebral microcapillary endothelium under pathological conditions. Brain Res, 2010, 1326: 114-127.
19.	Feng ZH, Hao J, Ye L, et al. Overexpression of μ-calpain in the anterior temporal neocortex of patients with intractable epilepsy correlates with clinicopathological characteristics. Seizure, 2011, 20(5): 395-401.
20.	Greene C, Hanley N, Reschke CR, et al. Microvascular stabilization via blood-brain barrier regulation prevents seizure activity. Nat Commun, 2022, 13(1): 2003.
21.	Woitzik J, Hohenstein A, Hecht N, et al. Short period of early reperfusion aggravates blood-brain barrier dysfunction during permanent focal ischemia in rats. Transl Stroke Res, 2011, 2(1): 67-71.
22.	David Y, Cacheaux LP, Ivens S, et al. Astrocytic dysfunction in epileptogenesis: consequence of altered potassium and glutamate homeostasis?. J Neurosci, 2009, 29(34): 10588-10599.
23.	Rohatgi T, Henrich-Noack P, Sedehizade F, et al. Transient focal ischemia in rat brain differentially regulates mRNA expression of protease-activated receptors 1 to 4. J Neurosci Res, 2004, 75(2): 273-279.
24.	Savotchenko A, Klymenko M, Shypshyna M, et al. The role of thrombin in early-onset seizures. Front Cell Neurosci, 2023, 17: 1101006.
25.	Heinemann U, Kaufer D, Friedman A. Blood-brain barrier dysfunction, TGFβ signaling, and astrocyte dysfunction in epilepsy. Glia, 2012, 60(8): 1251-1257.
26.	Friedman A, Bar-Klein G, Serlin Y, et al. Should losartan be administered following brain injury?. Expert Rev Neurother, 2014, 14(12): 1365-1375.
27.	Vezzani A, Friedman A, Dingledine RJ. The role of inflammation in epileptogenesis. Neuropharmacology, 2013, 69: 16-24.
28.	Ravizza T, Vezzani A. Pharmacological targeting of brain inflammation in epilepsy: therapeutic perspectives from experimental and clinical studies. Epilepsia Open, 2018, 3(Suppl 2): 133-142.
29.	Klein P, Dingledine R, Aronica E, et al. Commonalities in epileptogenic processes from different acute brain insults: do they translate?. Epilepsia, 2018, 59(1): 37-66.
30.	Löscher W, Potschka H. Drug resistance in brain diseases and the role of drug efflux transporters. Nat Rev Neurosci, 2005, 6(8): 591-602.
31.	Löscher W, Schmidt D. Modern antiepileptic drug development has failed to deliver: ways out of the current dilemma. Epilepsia, 2011, 52(4): 657-678.
32.	Tang F, Hartz AMS, Bauer B. Drug-resistant epilepsy: multiple hypotheses, few answers. Front Neurol, 2017, 8: 301.
33.	Bankstahl JP, Hoffmann K, Bethmann K, et al. Glutamate is critically involved in seizure-induced overexpression of P-glycoprotein in the brain. Neuropharmacology, 2008, 54(6): 1006-1016.
34.	Zibell G, Unkrüer B, Pekcec A, et al. Prevention of seizure-induced up-regulation of endothelial P-glycoprotein by COX-2 inhibition. Neuropharmacology, 2009, 56(5): 849-855.
35.	Pekcec A, Unkrüer B, Schlichtiger J, et al. Targeting prostaglandin E2 EP1 receptors prevents seizure-associated P-glycoprotein up-regulation. J Pharmacol Exp Ther, 2009, 330(3): 939-947.
36.	Römermann K, Helmer R, Löscher W. The antiepileptic drug lamotrigine is a substrate of mouse and human breast cancer resistance protein (ABCG2). Neuropharmacology, 2015, 93: 7-14.
37.	Uchida Y, Ohtsuki S, Katsukura Y, et al. Quantitative targeted absolute proteomics of human blood-brain barrier transporters and receptors. J Neurochem, 2011, 117(2): 333-345.
38.	Luna-Tortós C, Fedrowitz M, Löscher W. Evaluation of transport of common antiepileptic drugs by human multidrug resistance-associated proteins (MRP1, 2 and 5) that are overexpressed in pharmacoresistant epilepsy. Neuropharmacology, 2010, 58(7): 1019-1032.
39.	Ghosh C, Puvenna V, Gonzalez-Martinez J, et al. Blood-brain barrier P450 enzymes and multidrug transporters in drug resistance: a synergistic role in neurological diseases. Curr Drug Metab, 2011, 12(8): 742-749.
40.	中国抗癫痫协会. 临床诊疗指南癫痫病分册(2023 修订版). 人民卫生出版社, 2023.

1. Löscher W, Friedman A. Structural, molecular, and functional alterations of the blood-brain barrier during epileptogenesis and epilepsy: a cause, consequence, or both?. Int J Mol Sci, 2020, 21(2): 591.
2. van Vliet EA, da Costa Araújo S, Redeker S, et al. Blood-brain barrier leakage may lead to progression of temporal lobe epilepsy. Brain, 2007, 130(Pt 2): 521-534.
3. Cudna A, Bronisz E, Jopowicz A, et al. Changes in serum blood-brain barrier markers after bilateral tonic-clonic seizures. Seizure, 2023, 106: 129-137.
4. Bronisz E, Cudna A, Wierzbicka A, et al. Blood-brain barrier-associated proteins are elevated in serum of epilepsy patients. Cells, 2023, 12(3): 368.
5. Rigau V, Morin M, Rousset MC, et al. Angiogenesis is associated with blood-brain barrier permeability in temporal lobe epilepsy. Brain, 2007, 130(Pt 7): 1942-1956.
6. Marchi N, Lerner-Natoli M. Cerebrovascular remodeling and epilepsy. Neuroscientist, 2013, 19(3): 304-312.
7. van Vliet EA, Aronica E, Gorter JA. Blood-brain barrier dysfunction, seizures and epilepsy. Semin Cell Dev Biol, 2015, 38: 26-34.
8. Michalak Z, Lebrun A, Di Miceli M, et al. IgG leakage may contribute to neuronal dysfunction in drug-refractory epilepsies with blood-brain barrier disruption. J Neuropathol Exp Neurol, 2012, 71(9): 826-838.
9. Ndode-Ekane XE, Hayward N, Gröhn O, et al. Vascular changes in epilepsy: functional consequences and association with network plasticity in pilocarpine-induced experimental epilepsy. Neuroscience, 2010, 166(1): 312-332.
10. Cornford EM. Epilepsy and the blood brain barrier: endothelial cell responses to seizures. Adv Neurol, 1999, 79: 845-862.
11. Cornford EM, Oldendorf WH. Epilepsy and the blood-brain barrier. Adv Neurol, 1986, 44: 787-812.
12. Giannoni P, Badaut J, Dargazanli C, et al. The pericyte-glia interface at the blood-brain barrier. Clin Sci (Lond), 2018, 132(3): 361-374.
13. Klement W, Garbelli R, Zub E, et al. Seizure progression and inflammatory mediators promote pericytosis and pericyte-microglia clustering at the cerebrovasculature. Neurobiol Dis, 2018, 113: 70-81.
14. Jabs R, Seifert G, Steinhäuser C. Astrocytic function and its alteration in the epileptic brain. Epilepsia, 2008, 49(Suppl 2): 3-12.
15. Coulter DA, Steinhäuser C. Role of astrocytes in epilepsy. Cold Spring Harb Perspect Med, 2015, 5(3): a022434.
16. Xhima K, Weber-Adrian D, Silburt J. Glutamate induces blood-brain barrier permeability through activation of N-methyl-D-aspartate receptors. J Neurosci, 2016, 36(49): 12296-12298.
17. Rempe RG, Hartz AMS, Soldner ELB, et al. Matrix metalloproteinase-mediated blood-brain barrier dysfunction in epilepsy. J Neurosci, 2018, 38(18): 4301-4315.
18. Lischper M, Beuck S, Thanabalasundaram G, et al. Metalloproteinase mediated occludin cleavage in the cerebral microcapillary endothelium under pathological conditions. Brain Res, 2010, 1326: 114-127.
19. Feng ZH, Hao J, Ye L, et al. Overexpression of μ-calpain in the anterior temporal neocortex of patients with intractable epilepsy correlates with clinicopathological characteristics. Seizure, 2011, 20(5): 395-401.
20. Greene C, Hanley N, Reschke CR, et al. Microvascular stabilization via blood-brain barrier regulation prevents seizure activity. Nat Commun, 2022, 13(1): 2003.
21. Woitzik J, Hohenstein A, Hecht N, et al. Short period of early reperfusion aggravates blood-brain barrier dysfunction during permanent focal ischemia in rats. Transl Stroke Res, 2011, 2(1): 67-71.
22. David Y, Cacheaux LP, Ivens S, et al. Astrocytic dysfunction in epileptogenesis: consequence of altered potassium and glutamate homeostasis?. J Neurosci, 2009, 29(34): 10588-10599.
23. Rohatgi T, Henrich-Noack P, Sedehizade F, et al. Transient focal ischemia in rat brain differentially regulates mRNA expression of protease-activated receptors 1 to 4. J Neurosci Res, 2004, 75(2): 273-279.
24. Savotchenko A, Klymenko M, Shypshyna M, et al. The role of thrombin in early-onset seizures. Front Cell Neurosci, 2023, 17: 1101006.
25. Heinemann U, Kaufer D, Friedman A. Blood-brain barrier dysfunction, TGFβ signaling, and astrocyte dysfunction in epilepsy. Glia, 2012, 60(8): 1251-1257.
26. Friedman A, Bar-Klein G, Serlin Y, et al. Should losartan be administered following brain injury?. Expert Rev Neurother, 2014, 14(12): 1365-1375.
27. Vezzani A, Friedman A, Dingledine RJ. The role of inflammation in epileptogenesis. Neuropharmacology, 2013, 69: 16-24.
28. Ravizza T, Vezzani A. Pharmacological targeting of brain inflammation in epilepsy: therapeutic perspectives from experimental and clinical studies. Epilepsia Open, 2018, 3(Suppl 2): 133-142.
29. Klein P, Dingledine R, Aronica E, et al. Commonalities in epileptogenic processes from different acute brain insults: do they translate?. Epilepsia, 2018, 59(1): 37-66.
30. Löscher W, Potschka H. Drug resistance in brain diseases and the role of drug efflux transporters. Nat Rev Neurosci, 2005, 6(8): 591-602.
31. Löscher W, Schmidt D. Modern antiepileptic drug development has failed to deliver: ways out of the current dilemma. Epilepsia, 2011, 52(4): 657-678.
32. Tang F, Hartz AMS, Bauer B. Drug-resistant epilepsy: multiple hypotheses, few answers. Front Neurol, 2017, 8: 301.
33. Bankstahl JP, Hoffmann K, Bethmann K, et al. Glutamate is critically involved in seizure-induced overexpression of P-glycoprotein in the brain. Neuropharmacology, 2008, 54(6): 1006-1016.
34. Zibell G, Unkrüer B, Pekcec A, et al. Prevention of seizure-induced up-regulation of endothelial P-glycoprotein by COX-2 inhibition. Neuropharmacology, 2009, 56(5): 849-855.
35. Pekcec A, Unkrüer B, Schlichtiger J, et al. Targeting prostaglandin E2 EP1 receptors prevents seizure-associated P-glycoprotein up-regulation. J Pharmacol Exp Ther, 2009, 330(3): 939-947.
36. Römermann K, Helmer R, Löscher W. The antiepileptic drug lamotrigine is a substrate of mouse and human breast cancer resistance protein (ABCG2). Neuropharmacology, 2015, 93: 7-14.
37. Uchida Y, Ohtsuki S, Katsukura Y, et al. Quantitative targeted absolute proteomics of human blood-brain barrier transporters and receptors. J Neurochem, 2011, 117(2): 333-345.
38. Luna-Tortós C, Fedrowitz M, Löscher W. Evaluation of transport of common antiepileptic drugs by human multidrug resistance-associated proteins (MRP1, 2 and 5) that are overexpressed in pharmacoresistant epilepsy. Neuropharmacology, 2010, 58(7): 1019-1032.
39. Ghosh C, Puvenna V, Gonzalez-Martinez J, et al. Blood-brain barrier P450 enzymes and multidrug transporters in drug resistance: a synergistic role in neurological diseases. Curr Drug Metab, 2011, 12(8): 742-749.
40. 中国抗癫痫协会. 临床诊疗指南癫痫病分册(2023 修订版). 人民卫生出版社, 2023.

West China Medical Journal

Latest ArticlesMechanism of blood brain barrier in the pathogenesis of epilepsy

Abstract Full text Figures/Tables Video References Cited by

Format

Content