Emerging Role of Microglia-Mediated Neuroinflammation in Epilepsy after Subarachnoid Hemorrhage

Abstract

Epilepsy is a common and serious complication of subarachnoid hemorrhage (SAH), giving rise to increased morbidity and mortality. It’s difficult to identify patients at high risk of epilepsy and the application of anti-epileptic drugs (AEDs) following SAH is a controversial topic. Therefore, it’s pressingly needed to gain a better understanding of the risk factors, underlying mechanisms and the optimization of therapeutic strategies for epilepsy after SAH. Neuroinflammation, characterized by microglial activation and the release of inflammatory cytokines, has drawn growing attention due to its influence on patients with epilepsy after SAH. In this review, we discuss the risk factors for epilepsy after SAH and emphasize the critical role of microglia. Then we discuss how various molecules arising from pathophysiological changes after SAH activate specific receptors such as TLR4, NLRP3, RAGE, P2X7R and initiate the downstream inflammatory pathways. Additionally, we focus on the significant responses implicated in epilepsy including neuronal excitotoxicity, the disruption of blood-brain barrier (BBB) and the change of immune responses. As the application of AEDs for seizure prophylaxis after SAH remains controversial, the regulation of neuroinflammation targeting the key pathological molecules could be a promising therapeutic method. While neuroinflammation appears to contribute to epilepsy after SAH, more comprehensive experiments on their relationships are needed.

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Data Availability

All material and datasets are available as required.

Abbreviations

SAH:

subarachnoid hemorrhage

CNS:

central nervous system

AEDs:

anti-epileptic drugs

BBB:

blood-brain barrier

MCA:

middle cerebral artery

NCSz:

nonconvulsive seizures

VAM:

vessel-associated microglia

MMP-9:

Matrix metalloproteinase 9

HMGB1:

high mobility group box-1

VSMCs:

vascular smooth muscle cells

HO:

heme oxygenase

CO:

carbon monoxide

NMDA:

N-methyl-D-aspartate

TLR4:

Toll-like receptor 4

NLRP3:

NOD-like receptor 3

RAGE:

receptor for advanced glycation end products

P2X7R:

P2X7 receptor

NF-κB:

nuclear factor-κB

MAPKs:

mitogen-activated protein kinases

AP-1:

transcription factor activator protein-1

NEK7:

NIMA related kinase 7

TWIK2:

two-pore domain weak inwardly rectifying K + channel 2

Kir2:

the inward rectifier K+

CLICs:

Cl − intracellular channels

ELISA:

enzyme-linked immunosorbent assay

TGF-βR:

transforming growth factor-β receptor

MLV:

meningeal lymphatic vessels

GR:

glucocorticoid receptor

ANXA1:

annexin A1

(VPA):

valproic acid

References

  1. 1.

    Ramos MB, Teixeira MJ, Figueiredo EG (2018) Seizures and Epilepsy following Subarachnoid Hemorrhage: A Review on Incidence, Risk Factors, Outcome and Treatment. Braz Neurosurg (No.3):206–212

  2. 2.

    Ibrahim GM, Fallah A, Macdonald RL (2013) Clinical, laboratory, and radiographic predictors of the occurrence of seizures following aneurysmal subarachnoid hemorrhage. J Neurosurg 119(2):347–352. https://doi.org/10.3171/2013.3.Jns122097

    Article  PubMed  Google Scholar 

  3. 3.

    Baticulon C, Rivera, Legaspi, Lopez (2020) Predictive Factors for Seizures and Efficacy of Antiepileptic Drugs in Patients with Aneurysmal Subarachnoid Hemorrhage(Article). Acta Medica Philippina (No.2):101–108

  4. 4.

    Huttunen J, Kurki MI, von Und Zu Fraunberg M, Koivisto T, Ronkainen A, Rinne J, Jääskeläinen JE, Kälviäinen R et al (2015) Epilepsy after aneurysmal subarachnoid hemorrhage: A population-based, long-term follow-up study. Neurology 84(22):2229–2237. https://doi.org/10.1212/wnl.0000000000001643

    Article  PubMed  Google Scholar 

  5. 5.

    Nathan SK, Brahme IS, Kashkoush AI, Anetakis K, Jankowitz BT, Thirumala PD (2018) Risk factors for in-hospital seizures and new-onset epilepsy in coil embolization of aneurysmal subarachnoid hemorrhage. World Neurosurg 115:e523–e531. https://doi.org/10.1016/j.wneu.2018.04.086

    Article  PubMed  Google Scholar 

  6. 6.

    Hirano T, Enatsu R, Iihoshi S, Mikami T, Honma T, Ohnishi H, Mikuni N (2019) Effects of Hemosiderosis on epilepsy following subarachnoid hemorrhage. Neurol Med Chir (Tokyo) 59(1):27–32. https://doi.org/10.2176/nmc.oa.2018-0125

    Article  Google Scholar 

  7. 7.

    Raper DM, Starke RM, Komotar RJ, Allan R, Connolly ES Jr (2013) Seizures after aneurysmal subarachnoid hemorrhage: A systematic review of outcomes. World Neurosurg 79(5–6):682–690. https://doi.org/10.1016/j.wneu.2012.08.006

    Article  PubMed  Google Scholar 

  8. 8.

    Choi KS, Chun HJ, Yi HJ, Ko Y, Kim YS, Kim JM (2009) Seizures and epilepsy following aneurysmal subarachnoid hemorrhage : Incidence and risk factors. J Korean Neurosurg Soc 46(2):93–98. https://doi.org/10.3340/jkns.2009.46.2.93

    Article  PubMed  PubMed Central  Google Scholar 

  9. 9.

    Ohman J (1990) Hypertension as a risk factor for epilepsy after aneurysmal subarachnoid hemorrhage and surgery. Neurosurgery 27(4):578–581. https://doi.org/10.1097/00006123-199010000-00012

    CAS  Article  PubMed  Google Scholar 

  10. 10.

    Boling W, Kore L (2020) Subarachnoid hemorrhage-related epilepsy. Acta Neurochir Suppl 127:21–25. https://doi.org/10.1007/978-3-030-04615-6_4

    Article  PubMed  Google Scholar 

  11. 11.

    Baumann CR, Schuknecht B, Lo Russo G, Cossu M, Citterio A, Andermann F, Siegel AM (2006) Seizure outcome after resection of cavernous malformations is better when surrounding hemosiderin-stained brain also is removed. Epilepsia 47(3):563–566. https://doi.org/10.1111/j.1528-1167.2006.00468.x

    Article  PubMed  Google Scholar 

  12. 12.

    Claassen J, Albers D, Schmidt JM, De Marchis GM, Pugin D, Falo CM, Mayer SA, Cremers S et al (2014) Nonconvulsive seizures in subarachnoid hemorrhage link inflammation and outcome. Ann Neurol 75(5):771–781. https://doi.org/10.1002/ana.24166

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Chaudhry SR, Stoffel-Wagner B, Kinfe TM, Gresir E, Vatter H, Dietrich D, Lamprecht A, Muhammad S (2017) Elevated systemic IL-6 levels in patients with aneurysmal subarachnoid hemorrhage is an unspecific marker for post-SAH complications. Int J Mol Sci (No.12):2580

  14. 14.

    Zheng SF, Lin P, Lin ZY, Shang-Guan HC, Chen GR, Zhang YB, Lin YX, Kang DZ et al (2019) Lower serum Iron and hemoglobin levels are associated with acute seizures in patients with ruptured cerebral aneurysms. Neurocrit Care 31(3):501–506. https://doi.org/10.1007/s12028-019-00746-z

    CAS  Article  PubMed  Google Scholar 

  15. 15.

    Ludwiczek S, Aigner E, Theurl I, Weiss G (2003) Cytokine-mediated regulation of iron transport in human monocytic cells. Blood 101(10):4148–4154. https://doi.org/10.1182/blood-2002-08-2459

    CAS  Article  PubMed  Google Scholar 

  16. 16.

    Okada T, Suzuki H (2020) Mechanisms of neuroinflammation and inflammatory mediators involved in brain injury following subarachnoid hemorrhage. Histol Histopathol 35(7):623–636. https://doi.org/10.14670/hh-18-208

    CAS  Article  PubMed  Google Scholar 

  17. 17.

    Xu Z, Shi WH, Xu LB, Shao MF, Chen ZP, Zhu GC, Hou Q (2019) Resident microglia activate before peripheral monocyte infiltration and p75NTR blockade reduces microglial activation and early brain injury after subarachnoid hemorrhage. ACS Chem Neurosci 10(1):412–423. https://doi.org/10.1021/acschemneuro.8b00298

    CAS  Article  PubMed  Google Scholar 

  18. 18.

    Zheng ZV, Lyu H, Lam SYE, Lam PK, Poon WS, Wong GKC (2020) The dynamics of microglial polarization reveal the resident Neuroinflammatory responses after subarachnoid hemorrhage. Transl Stroke Res 11(3):433–449. https://doi.org/10.1007/s12975-019-00728-5

    CAS  Article  PubMed  Google Scholar 

  19. 19.

    Radon AM, Schneider UC, Turkowski K, Ghori A, Brandenburg S, Heppner F, Vajkoczy P (2010) Microglia activation after aneurysmal subarachnoid hemorrhage (aSAH) - characterization of the cytokine expression profile. Eur J Med Res 15:144–144

    Google Scholar 

  20. 20.

    Schneider UC, Davids AM, Brandenburg S, Müller A, Elke A, Magrini S, Atangana E, Turkowski K et al (2015) Microglia inflict delayed brain injury after subarachnoid hemorrhage. Acta Neuropathol 130(2):215–231. https://doi.org/10.1007/s00401-015-1440-1

    Article  PubMed  Google Scholar 

  21. 21.

    Akamatsu Y, Pagan VA, Hanafy KA (2020) The role of TLR4 and HO-1 in neuroinflammation after subarachnoid hemorrhage. J Neurosci Res 98(3):549–556. https://doi.org/10.1002/jnr.24515

    CAS  Article  PubMed  Google Scholar 

  22. 22.

    Coulibaly AP, Provencio JJ (2020) Aneurysmal subarachnoid hemorrhage: An overview of inflammation-induced cellular changes. Neurotherapeutics 17(2):436–445. https://doi.org/10.1007/s13311-019-00829-x

    CAS  Article  PubMed  Google Scholar 

  23. 23.

    Geraghty JR, Davis JL, Testai FD (2019) Neuroinflammation and microvascular dysfunction after experimental subarachnoid hemorrhage: Emerging components of early brain injury related to outcome. Neurocrit Care 31(2):373–389. https://doi.org/10.1007/s12028-019-00710-x

    Article  PubMed  PubMed Central  Google Scholar 

  24. 24.

    Morrison HW, Filosa JA (2019) Stroke and the neurovascular unit: Glial cells, sex differences, and hypertension. Am J Physiol Cell Physiol 316(3):C325–c339. https://doi.org/10.1152/ajpcell.00333.2018

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  25. 25.

    Koizumi T, Kerkhofs D, Mizuno T, Steinbusch HWM, Foulquier S (2019) Vessel-associated immune cells in cerebrovascular diseases: From perivascular macrophages to vessel-associated microglia. Front Neurosci 13:1291. https://doi.org/10.3389/fnins.2019.01291

    Article  PubMed  PubMed Central  Google Scholar 

  26. 26.

    Matsumoto J, Dohgu S, Takata F, Machida T, Bölükbaşi Hatip FF, Hatip-Al-Khatib I, Yamauchi A, Kataoka Y (2018) TNF-α-sensitive brain pericytes activate microglia by releasing IL-6 through cooperation between IκB-NFκB and JAK-STAT3 pathways. Brain Res 1692:34–44. https://doi.org/10.1016/j.brainres.2018.04.023

    CAS  Article  PubMed  Google Scholar 

  27. 27.

    Klement W, Garbelli R, Zub E, Rossini L, Tassi L, Girard B, Blaquiere M, Bertaso F et al (2018) Seizure progression and inflammatory mediators promote pericytosis and pericyte-microglia clustering at the cerebrovasculature. Neurobiol Dis 113:70–81. https://doi.org/10.1016/j.nbd.2018.02.002

    CAS  Article  PubMed  Google Scholar 

  28. 28.

    Pan P, Zhao H, Zhang X, Li Q, Qu J, Zuo S, Yang F, Liang G et al (2020) Cyclophilin a signaling induces pericyte-associated blood-brain barrier disruption after subarachnoid hemorrhage. J Neuroinflammation 17(1):16. https://doi.org/10.1186/s12974-020-1699-6

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  29. 29.

    Sakuma R, Kawahara M, Nakano-Doi A, Takahashi A, Tanaka Y, Narita A, Kuwahara-Otani S, Hayakawa T et al (2016) Brain pericytes serve as microglia-generating multipotent vascular stem cells following ischemic stroke. J Neuroinflammation 13(1):57. https://doi.org/10.1186/s12974-016-0523-9

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  30. 30.

    Dang B, Shen H, Li H, Zhu M, Guo C, He W (2016) Matrix metalloproteinase 9 may be involved in contraction of vascular smooth muscle cells in an in vitro rat model of subarachnoid hemorrhage. Mol Med Rep 14(5):4279–4284. https://doi.org/10.3892/mmr.2016.5736

    CAS  Article  PubMed  Google Scholar 

  31. 31.

    Wang L, Zhang Z, Liang L, Wu Y, Zhong J, Sun X (2019) Anti-high mobility group box-1 antibody attenuated vascular smooth muscle cell phenotypic switching and vascular remodelling after subarachnoid haemorrhage in rats. Neurosci Lett 708:134338. https://doi.org/10.1016/j.neulet.2019.134338

    CAS  Article  PubMed  Google Scholar 

  32. 32.

    Wan W, Ding Y, Xie Z, Li Q, Yan F, Budbazar E, Pearce WJ, Hartman R et al (2019) PDGFR-β modulates vascular smooth muscle cell phenotype via IRF-9/SIRT-1/NF-κB pathway in subarachnoid hemorrhage rats. J Cereb Blood Flow Metab 39(7):1369–1380. https://doi.org/10.1177/0271678x18760954

    CAS  Article  PubMed  Google Scholar 

  33. 33.

    Rymo SF, Gerhardt H, Wolfhagen Sand F, Lang R, Uv A, Betsholtz C (2011) A two-way communication between microglial cells and angiogenic sprouts regulates angiogenesis in aortic ring cultures. PLoS One 6(1):e15846. https://doi.org/10.1371/journal.pone.0015846

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Kacimi R, Giffard RG, Yenari MA (2011) Endotoxin-activated microglia injure brain derived endothelial cells via NF-κB, JAK-STAT and JNK stress kinase pathways. J Inflamm 8:7. https://doi.org/10.1186/1476-9255-8-7

    CAS  Article  Google Scholar 

  35. 35.

    Eyo UB, Murugan M, Wu LJ (2017) Microglia-neuron communication in epilepsy. Glia 65(1):5–18. https://doi.org/10.1002/glia.23006

    Article  PubMed  Google Scholar 

  36. 36.

    Chugh D, Ali I, Bakochi A, Bahonjic E, Etholm L, Ekdahl CT (2015) Alterations in brain inflammation, synaptic proteins, and adult hippocampal neurogenesis during Epileptogenesis in mice lacking Synapsin2. PLoS One 10(7):e0132366. https://doi.org/10.1371/journal.pone.0132366

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  37. 37.

    Zhao X, Liao Y, Morgan S, Mathur R, Feustel P, Mazurkiewicz J, Qian J, Chang J et al (2018) Noninflammatory changes of microglia are sufficient to cause epilepsy. Cell Rep 22(8):2080–2093. https://doi.org/10.1016/j.celrep.2018.02.004

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  38. 38.

    Cai W, Liu S, Hu M, Sun X, Qiu W, Zheng S, Hu X, Lu Z (2018) Post-stroke DHA treatment protects against acute ischemic brain injury by skewing macrophage polarity toward the M2 phenotype. Transl Stroke Res 9(6):669–680. https://doi.org/10.1007/s12975-018-0662-7

    CAS  Article  PubMed  Google Scholar 

  39. 39.

    Schallner N, Pandit R, LeBlanc R 3rd, Thomas AJ, Ogilvy CS, Zuckerbraun BS, Gallo D, Otterbein LE et al (2015) Microglia regulate blood clearance in subarachnoid hemorrhage by heme oxygenase-1. J Clin Invest 125(7):2609–2625. https://doi.org/10.1172/jci78443

    Article  PubMed  PubMed Central  Google Scholar 

  40. 40.

    Suzuki H (2019) Inflammation: A good research target to improve outcomes of poor-grade subarachnoid hemorrhage. Transl Stroke Res 10(6):597–600. https://doi.org/10.1007/s12975-019-00713-y

    CAS  Article  PubMed  Google Scholar 

  41. 41.

    Maciel CB, Gilmore EJ (2016) Seizures and Epileptiform patterns in SAH and their relation to outcomes. J Clin Neurophysiol 33(3):183–195. https://doi.org/10.1097/wnp.0000000000000268

    Article  PubMed  Google Scholar 

  42. 42.

    Kwon MS, Woo SK, Kurland DB, Yoon SH, Palmer AF, Banerjee U, Iqbal S, Ivanova S et al (2015) Methemoglobin is an endogenous toll-like receptor 4 ligand-relevance to subarachnoid hemorrhage. Int J Mol Sci 16(3):5028–5046. https://doi.org/10.3390/ijms16035028

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  43. 43.

    Ryazanov AG, Ovchinnikov LP, Spirin AS (1987) Development of structural organization of protein-synthesizing machinery from prokaryotes to eukaryotes. Biosystems 20(3):275–288. https://doi.org/10.1016/0303-2647(87)90035-9

    CAS  Article  PubMed  Google Scholar 

  44. 44.

    Fang H, Wang PF, Zhou Y, Wang YC, Yang QW (2013) Toll-like receptor 4 signaling in intracerebral hemorrhage-induced inflammation and injury. J Neuroinflammation 10:27. https://doi.org/10.1186/1742-2094-10-27

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  45. 45.

    Kamaşak T, Dilber B, Yaman S, Durgut BD, Kurt T, Çoban E, Arslan EA, Şahin S et al (2020) HMGB-1, TLR4, IL-1R1, TNF-α, and IL-1β: Novel epilepsy markers? Epileptic Disord 22(2):183–193. https://doi.org/10.1684/epd.2020.1155

    Article  PubMed  Google Scholar 

  46. 46.

    Iori V, Iyer AM, Ravizza T, Beltrame L, Paracchini L, Marchini S, Cerovic M, Hill C et al (2017) Blockade of the IL-1R1/TLR4 pathway mediates disease-modification therapeutic effects in a model of acquired epilepsy. Neurobiol Dis 99:12–23. https://doi.org/10.1016/j.nbd.2016.12.007

    CAS  Article  PubMed  Google Scholar 

  47. 47.

    Vezzani A, Friedman A, Dingledine RJ (2013) The role of inflammation in epileptogenesis. Neuropharmacology 69:16–24. https://doi.org/10.1016/j.neuropharm.2012.04.004

    CAS  Article  PubMed  Google Scholar 

  48. 48.

    Giansante G, Marte A, Romei A, Prestigio C, Onofri F, Benfenati F, Baldelli P, Valente P (2020) Presynaptic L-type Ca(2+) channels increase glutamate release probability and excitatory strength in the Hippocampus during chronic Neuroinflammation. J Neurosci 40(36):6825–6841. https://doi.org/10.1523/jneurosci.2981-19.2020

    CAS  Article  PubMed  Google Scholar 

  49. 49.

    Wu CT, Wen LL, Wong CS, Tsai SY, Chan SM, Yeh CC, Borel CO, Cherng CH (2011) Temporal changes in glutamate, glutamate transporters, basilar arteries wall thickness, and neuronal variability in an experimental rat model of subarachnoid hemorrhage. Anesth Analg 112(3):666–673. https://doi.org/10.1213/ANE.0b013e318207c51f

    CAS  Article  PubMed  Google Scholar 

  50. 50.

    Nicolo JP, O'Brien TJ, Kwan P (2019) Role of cerebral glutamate in post-stroke epileptogenesis. NeuroImage Clin 24:102069. https://doi.org/10.1016/j.nicl.2019.102069

    Article  PubMed  PubMed Central  Google Scholar 

  51. 51.

    Zhang Z, Liu J, Fan C, Mao L, Xie R, Wang S, Yang M, Yuan H et al (2018) The GluN1/GluN2B NMDA receptor and metabotropic glutamate receptor 1 negative allosteric modulator has enhanced neuroprotection in a rat subarachnoid hemorrhage model. Exp Neurol 301(Pt A):13–25. https://doi.org/10.1016/j.expneurol.2017.12.005

    CAS  Article  PubMed  Google Scholar 

  52. 52.

    Beamer E, Fischer W, Engel T (2017) The ATP-gated P2X7 receptor as a target for the treatment of drug-resistant epilepsy. Front Neurosci 11:21. https://doi.org/10.3389/fnins.2017.00021

    Article  PubMed  PubMed Central  Google Scholar 

  53. 53.

    Song P, Hu J, Liu X, Deng X (2019) Increased expression of the P2X7 receptor in temporal lobe epilepsy: Animal models and clinical evidence. Mol Med Rep 19(6):5433–5439. https://doi.org/10.3892/mmr.2019.10202

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  54. 54.

    Jamali-Raeufy N, Barati H, Baluchnejadmojarad T, Roghani M, Goudarzi M (2020) Combination therapy with dipeptidyl peptidase-4 and P2X7 purinoceptor inhibitors gives rise to antiepileptic effects in rats. J Chem Neuroanat 110:101855. https://doi.org/10.1016/j.jchemneu.2020.101855

    CAS  Article  PubMed  Google Scholar 

  55. 55.

    Zhu C, Yang F, Jiang R (2017) The effect of wulongdan on neuroinflammation factors and the expression of P2X7 receptor in the SAH rats. Biomed Res-India 28(12):5388–5392

    CAS  Google Scholar 

  56. 56.

    Wheeler D, Knapp E, Bandaru VV, Wang Y, Knorr D, Poirier C, Mattson MP, Geiger JD et al (2009) Tumor necrosis factor-alpha-induced neutral sphingomyelinase-2 modulates synaptic plasticity by controlling the membrane insertion of NMDA receptors. J Neurochem 109(5):1237–1249. https://doi.org/10.1111/j.1471-4159.2009.06038.x

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  57. 57.

    Stellwagen D, Beattie EC, Seo JY, Malenka RC (2005) Differential regulation of AMPA receptor and GABA receptor trafficking by tumor necrosis factor-alpha. J Neurosci 25(12):3219–3228. https://doi.org/10.1523/jneurosci.4486-04.2005

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  58. 58.

    Wang S, Cheng Q, Malik S, Yang J (2000) Interleukin-1b inhibits g-aminobutyric acid type a (GABAA) receptor current in cultured hippocampal neurons. J Pharmacol Exp Ther

  59. 59.

    Viviani B, Bartesaghi S, Gardoni F, Vezzani A, Behrens MM, Bartfai T, Binaglia M, Corsini E et al (2003) Interleukin-1beta enhances NMDA receptor-mediated intracellular calcium increase through activation of the Src family of kinases. J Neurosci 23(25):8692–8700. https://doi.org/10.1523/jneurosci.23-25-08692.2003

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  60. 60.

    Balosso S, Maroso M, Sanchez-Alavez M, Ravizza T, Frasca A, Bartfai T, Vezzani A (2008) A novel non-transcriptional pathway mediates the proconvulsive effects of interleukin-1beta. Brain J Neurol 131(Pt 12):3256–3265. https://doi.org/10.1093/brain/awn271

    Article  Google Scholar 

  61. 61.

    Kanellopoulos JM, Delarasse C (2019) Pleiotropic roles of P2X7 in the central nervous system. Front Cell Neurosci 13:401. https://doi.org/10.3389/fncel.2019.00401

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  62. 62.

    Wang D, Wang H, Gao H, Zhang H, Zhang H, Wang Q, Sun Z (2020) P2X7 receptor mediates NLRP3 inflammasome activation in depression and diabetes. Cell Biosci 10:28. https://doi.org/10.1186/s13578-020-00388-1

    Article  PubMed  PubMed Central  Google Scholar 

  63. 63.

    Duan Y, Kelley N, He Y (2020) Role of the NLRP3 inflammasome in neurodegenerative diseases and therapeutic implications. Neural Regen Res 15(7):1249–1250. https://doi.org/10.4103/1673-5374.272576

    Article  PubMed  PubMed Central  Google Scholar 

  64. 64.

    Tang XD, Xu R, Reynolds MF, Garcia ML, Heinemann SH, Hoshi T (2003) Haem can bind to and inhibit mammalian calcium-dependent Slo1 BK channels. Nature 425(6957):531–535. https://doi.org/10.1038/nature02003

    CAS  Article  PubMed  Google Scholar 

  65. 65.

    Pétrilli V, Papin S, Dostert C, Mayor A, Martinon F, Tschopp J (2007) Activation of the NALP3 inflammasome is triggered by low intracellular potassium concentration. Cell Death Differ 14(9):1583–1589. https://doi.org/10.1038/sj.cdd.4402195

    CAS  Article  PubMed  Google Scholar 

  66. 66.

    Yue J, Wei YJ, Yang XL, Liu SY, Yang H, Zhang CQ (2020) NLRP3 inflammasome and endoplasmic reticulum stress in the epileptogenic zone in temporal lobe epilepsy: Molecular insights into their interdependence. Neuropathol Appl Neurobiol 46(7):770–785. https://doi.org/10.1111/nan.12621

    CAS  Article  PubMed  Google Scholar 

  67. 67.

    Wu C, Zhang G, Chen L, Kim S, Yu J, Hu G, Chen J, Huang Y et al (2019) The role of NLRP3 and IL-1β in refractory epilepsy brain injury. Front Neurol 10:1418. https://doi.org/10.3389/fneur.2019.01418

    Article  PubMed  Google Scholar 

  68. 68.

    Zhang H, Chu X, Fu T, Lv H, Kong Q, Hao Y (2017) Inhibitory effect of interleukin-1 beta antibody for NLRP3 inflammasome on epilepsy rat model. Int J Clin Exp Pathol 10(2):1847–1853

    CAS  Google Scholar 

  69. 69.

    Barros-Barbosa AR, Oliveira Â, Lobo MG, Cordeiro JM, Correia-de-Sá P (2018) Under stressful conditions activation of the ionotropic P2X7 receptor differentially regulates GABA and glutamate release from nerve terminals of the rat cerebral cortex. Neurochem Int 112:81–95. https://doi.org/10.1016/j.neuint.2017.11.005

    CAS  Article  PubMed  Google Scholar 

  70. 70.

    He Y, Zeng MY, Yang D, Motro B, Núñez G (2016) NEK7 is an essential mediator of NLRP3 activation downstream of potassium efflux. Nature 530(7590):354–357. https://doi.org/10.1038/nature16959

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  71. 71.

    Schmid-Burgk JL, Chauhan D, Schmidt T, Ebert TS, Reinhardt J, Endl E, Hornung V (2016) A genome-wide CRISPR (clustered regularly interspaced short palindromic repeats) screen identifies NEK7 as an essential component of NLRP3 Inflammasome activation. J Biol Chem 291(1):103–109. https://doi.org/10.1074/jbc.C115.700492

    CAS  Article  PubMed  Google Scholar 

  72. 72.

    Di A, Xiong S, Ye Z, Malireddi RKS, Kometani S, Zhong M, Mittal M, Hong Z et al (2018) The TWIK2 potassium Efflux Channel in macrophages mediates NLRP3 Inflammasome-induced inflammation. Immunity 49(1):56–65.e54. https://doi.org/10.1016/j.immuni.2018.04.032

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  73. 73.

    Young CC, Stegen M, Bernard R, Müller M, Bischofberger J, Veh RW, Haas CA, Wolfart J (2009) Upregulation of inward rectifier K+ (Kir2) channels in dentate gyrus granule cells in temporal lobe epilepsy. J Physiol 587(Pt 17):4213–4233. https://doi.org/10.1113/jphysiol.2009.170746

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  74. 74.

    Li H, Wu W, Sun Q, Liu M, Li W, Zhang XS, Zhou ML, Hang CH (2014) Expression and cell distribution of receptor for advanced glycation end-products in the rat cortex following experimental subarachnoid hemorrhage. Brain Res 1543:315–323. https://doi.org/10.1016/j.brainres.2013.11.023

    CAS  Article  PubMed  Google Scholar 

  75. 75.

    Chaudhry SR, Güresir A, Stoffel-Wagner B, Fimmers R, Kinfe TM, Dietrich D, Lamprecht A, Vatter H et al (2018) Systemic high-mobility group Box-1: A novel predictive biomarker for cerebral vasospasm in aneurysmal subarachnoid hemorrhage. Crit Care Med 46(11):e1023–e1028. https://doi.org/10.1097/ccm.0000000000003319

    CAS  Article  PubMed  Google Scholar 

  76. 76.

    Kaneko Y, Pappas C, Malapira T, Vale F, Tajiri N, Borlongan CV (2017) Extracellular HMGB1 modulates glutamate metabolism associated with Kainic acid-induced epilepsy-like hyperactivity in primary rat neural cells. Cell Physiol Biochem 41(3):947–959. https://doi.org/10.1159/000460513

    CAS  Article  PubMed  Google Scholar 

  77. 77.

    Zhong H, Li X, Zhou S, Jiang P, Liu X, Ouyang M, Nie Y, Chen X et al (2020) Interplay between RAGE and TLR4 regulates HMGB1-induced inflammation by promoting cell surface expression of RAGE and TLR4. J Immunol 205(3):767–775. https://doi.org/10.4049/jimmunol.1900860

    CAS  Article  PubMed  Google Scholar 

  78. 78.

    Mazarati A, Maroso M, Iori V, Vezzani A, Carli M (2011) High-mobility group box-1 impairs memory in mice through both toll-like receptor 4 and receptor for advanced Glycation end products. Exp Neurol 232(2):143–148. https://doi.org/10.1016/j.expneurol.2011.08.012

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  79. 79.

    Yang W, Li J, Shang Y, Zhao L, Wang M, Shi J, Li S (2017) HMGB1-TLR4 Axis plays a regulatory role in the pathogenesis of mesial temporal lobe epilepsy in immature rat model and children via the p38MAPK signaling pathway. Neurochem Res 42(4):1179–1190. https://doi.org/10.1007/s11064-016-2153-0

    CAS  Article  PubMed  Google Scholar 

  80. 80.

    Lawton MT, Vates GE (2017) Subarachnoid hemorrhage. N Engl J Med 377(3):257–266. https://doi.org/10.1056/NEJMcp1605827

    Article  PubMed  Google Scholar 

  81. 81.

    Balosso S, Liu J, Bianchi ME, Vezzani A (2014) 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 21(12):1726–1740. https://doi.org/10.1089/ars.2013.5349

    CAS  Article  PubMed  Google Scholar 

  82. 82.

    Pauletti A, Terrone G, Shekh-Ahmad T, Salamone A, Ravizza T, Rizzi M, Pastore A, Pascente R et al (2019) Targeting oxidative stress improves disease outcomes in a rat model of acquired epilepsy. Brain J Neurol 142(7):e39. https://doi.org/10.1093/brain/awz130

    Article  Google Scholar 

  83. 83.

    Germanò A, d'Avella D, Imperatore C, Caruso G, Tomasello F (2000) Time-course of blood-brain barrier permeability changes after experimental subarachnoid haemorrhage. Acta Neurochir 142(5):575–580; discussion 580-571. https://doi.org/10.1007/s007010050472

    Article  PubMed  Google Scholar 

  84. 84.

    Oby ECCF, Department of Neurological Surgery, Cerebrovascular Research, Cleveland, OH, US, Janigro D, ORCID ---. Cleveland Clinic Foundation, Department of Neurological Surgery, Cerebrovascular Research, Cleveland, OH, US, janigrd@ccf.org (2006) The Blood-Brain Barrier and Epilepsy. Epilepsia (No.11):1761–1774

  85. 85.

    Zhu Q, Enkhjargal B, Huang L, Zhang T, Sun C, Xie Z, Wu P, Mo J et al (2018) Aggf1 attenuates neuroinflammation and BBB disruption via PI3K/Akt/NF-κB pathway after subarachnoid hemorrhage in rats. J Neuroinflammation 15(1):178. https://doi.org/10.1186/s12974-018-1211-8

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  86. 86.

    Kanamaru H, Suzuki H (2019) Potential therapeutic molecular targets for blood-brain barrier disruption after subarachnoid hemorrhage. Neural Regen Res 14(7):1138–1143. https://doi.org/10.4103/1673-5374.251190

    Article  PubMed  PubMed Central  Google Scholar 

  87. 87.

    Okada T, Kawakita F, Nishikawa H, Nakano F, Liu L, Suzuki H (2019) Selective toll-like receptor 4 antagonists prevent acute blood-brain barrier disruption after subarachnoid hemorrhage in mice. Mol Neurobiol 56(2):976–985. https://doi.org/10.1007/s12035-018-1145-2

    CAS  Article  PubMed  Google Scholar 

  88. 88.

    Sarrafzadeh A, Copin JC, Bengualid DJ, Turck N, Vajkoczy P, Bijlenga P, Schaller K, Gasche Y (2012) Matrix metalloproteinase-9 concentration in the cerebral extracellular fluid of patients during the acute phase of aneurysmal subarachnoid hemorrhage. Neurol Res 34(5):455–461. https://doi.org/10.1179/1743132812y.0000000018

    CAS  Article  PubMed  Google Scholar 

  89. 89.

    Li G, Dong Y, Liu D, Zou Z, Hao G, Gao X, Pan P, Liang G (2020) NEK7 coordinates rapid Neuroinflammation after subarachnoid hemorrhage in mice. Front Neurol 11:551. https://doi.org/10.3389/fneur.2020.00551

    Article  PubMed  PubMed Central  Google Scholar 

  90. 90.

    Ivens S, Kaufer D, Flores LP, Bechmann I, Zumsteg D, Tomkins O, Seiffert E, Heinemann U et al (2007) TGF-beta receptor-mediated albumin uptake into astrocytes is involved in neocortical epileptogenesis. Brain J Neurol 130(Pt 2):535–547. https://doi.org/10.1093/brain/awl317

    Article  Google Scholar 

  91. 91.

    David Y, Cacheaux LP, Ivens S, Lapilover E, Heinemann U, Kaufer D, Friedman A (2009) Astrocytic dysfunction in epileptogenesis: Consequence of altered potassium and glutamate homeostasis? J Neurosci 29(34):10588–10599. https://doi.org/10.1523/jneurosci.2323-09.2009

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  92. 92.

    Florence G, Pereira T, Kurths J (2012) Extracellular potassium dynamics in the hyperexcitable state of the neuronal ictal activity. J Commun Nonlinear Sci Numer Simulat (No.12):4700–4706

  93. 93.

    Herrera-Peco I, Sola RG, Osejo V, Wix-Ramos R, Pastor J (2008) Role of astrocytes activated by albumin in epileptogenesis. Rev Neurol 47(11):582–587

    CAS  PubMed  Google Scholar 

  94. 94.

    Braganza O, Bedner P, Hüttmann K, Von Staden E, Friedman A, Seifert G, Steinhäuser C (2012) Albumin is taken up by hippocampal NG2 cells and astrocytes and decreases gap junction coupling(Article). J Epilepsia (No.11):1898–1906

  95. 95.

    Weissberg I, Wood L, Kamintsky L, Vazquez O, Milikovsky DZ, Alexander A, Oppenheim H, Ardizzone C et al (2015) Albumin induces excitatory synaptogenesis through astrocytic TGF-β/ALK5 signaling in a model of acquired epilepsy following blood-brain barrier dysfunction. Neurobiol Dis 78:115–125. https://doi.org/10.1016/j.nbd.2015.02.029

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  96. 96.

    Isaeva E, Hernan A, Isaev D, Holmes GL (2012) Thrombin facilitates seizures through activation of persistent sodium current. Ann Neurol 72(2):192–198. https://doi.org/10.1002/ana.23587

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  97. 97.

    Ben Shimon M, Shavit-Stein E, Altman K, Pick CG, Maggio N (2019) Thrombin as key mediator of seizure development following traumatic brain injury. Front Pharmacol 10:1532. https://doi.org/10.3389/fphar.2019.01532

    CAS  Article  PubMed  Google Scholar 

  98. 98.

    Noé FM, Marchi N (2019) Central nervous system lymphatic unit, immunity, and epilepsy: Is there a link? Epilepsia Open 4(1):30–39. https://doi.org/10.1002/epi4.12302

    Article  PubMed  PubMed Central  Google Scholar 

  99. 99.

    Frigerio F, Pasqualini G, Craparotta I, Marchini S, van Vliet EA, Foerch P, Vandenplas C, Leclercq K et al (2018) N-3 Docosapentaenoic acid-derived protectin D1 promotes resolution of neuroinflammation and arrests epileptogenesis. Brain J Neurol 141(11):3130–3143. https://doi.org/10.1093/brain/awy247

    Article  Google Scholar 

  100. 100.

    Zub E, Canet G, Garbelli R, Blaquiere M, Rossini L, Pastori C, Sheikh M, Reutelingsperger C et al (2019) The GR-ANXA1 pathway is a pathological player and a candidate target in epilepsy. FASEB J 33(12):13998–14009. https://doi.org/10.1096/fj.201901596R

    CAS  Article  PubMed  Google Scholar 

  101. 101.

    Panczykowski D, Pease M, Zhao Y, Weiner G, Ares W, Crago E, Jankowitz B, Ducruet AF (2016) Prophylactic Antiepileptics and seizure incidence following subarachnoid hemorrhage: A propensity score-matched analysis. Stroke 47(7):1754–1760. https://doi.org/10.1161/strokeaha.116.013766

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  102. 102.

    Yoon SJ, Joo JY, Kim YB, Hong CK, Chung J (2015) Effects of prophylactic antiepileptic drugs on clinical outcomes in patients with a good clinical grade suffering from aneurysmal subarachnoid hemorrhage. J Cerebrovasc Endovasc Neurosurg 17(3):166–172. https://doi.org/10.7461/jcen.2015.17.3.166

    Article  PubMed  PubMed Central  Google Scholar 

  103. 103.

    Mahmoud SH, Buxton J (2017) Seizures and choice of antiepileptic drugs following subarachnoid hemorrhage: A review. Can J Neurol Sci 44(6):643–653. https://doi.org/10.1017/cjn.2017.206

    Article  PubMed  Google Scholar 

  104. 104.

    Low* WH, Goh QY, Teo MM (2019) Extended Antiepileptic Drug Prophylaxis and Late Onset Seizures in Aneurysmal Subarachnoid Hemorrhage. Open J Mod Neurosurg (No.4):401–409

  105. 105.

    Ying GY, Jing CH, Li JR, Wu C, Yan F, Chen JY, Wang L, Dixon BJ et al (2016) Neuroprotective effects of Valproic acid on blood-brain barrier disruption and apoptosis-related early brain injury in rats subjected to subarachnoid hemorrhage are modulated by heat shock protein 70/matrix Metalloproteinases and heat shock protein 70/AKT pathways. Neurosurgery 79(2):286–295. https://doi.org/10.1227/neu.0000000000001264

    Article  PubMed  Google Scholar 

  106. 106.

    Chang CZ, Wu SC, Lin CL, Kwan AL (2015) Valproic acid attenuates intercellular adhesion molecule-1 and E-selectin through a chemokine ligand 5 dependent mechanism and subarachnoid hemorrhage induced vasospasm in a rat model. J Inflamm 12:27. https://doi.org/10.1186/s12950-015-0074-3

    CAS  Article  Google Scholar 

  107. 107.

    Tso MK, Lass E, Ai J, Loch Macdonald R (2015) Valproic acid treatment after experimental subarachnoid hemorrhage. Acta Neurochir Suppl 120:81–85. https://doi.org/10.1007/978-3-319-04981-6_14

    Article  PubMed  Google Scholar 

  108. 108.

    Wang H, Gao J, Lassiter TF, McDonagh DL, Sheng H, Warner DS, Lynch JR, Laskowitz DT (2006) Levetiracetam is neuroprotective in murine models of closed head injury and subarachnoid hemorrhage. Neurocrit Care 5(1):71–78. https://doi.org/10.1385/ncc:5:1:71

    CAS  Article  PubMed  Google Scholar 

  109. 109.

    Maroso M, Balosso S, Ravizza T, Liu J, Aronica E, Iyer AM, Rossetti C, Molteni M et al (2010) Toll-like receptor 4 and high-mobility group box-1 are involved in ictogenesis and can be targeted to reduce seizures. Nat Med 16(4):413–419. https://doi.org/10.1038/nm.2127

    CAS  Article  PubMed  Google Scholar 

  110. 110.

    Yew WP, Djukic ND, Jayaseelan JSP, Walker FR, Roos KAA, Chataway TK, Muyderman H, Sims NR (2019) Early treatment with minocycline following stroke in rats improves functional recovery and differentially modifies responses of peri-infarct microglia and astrocytes. J Neuroinflammation 16(1):6. https://doi.org/10.1186/s12974-018-1379-y

    Article  PubMed  PubMed Central  Google Scholar 

  111. 111.

    Li J, Chen S, Fan J, Zhang G, Ren R (2019) Minocycline attenuates experimental subarachnoid hemorrhage in rats. Open Life Sci 14(1):595–602. https://doi.org/10.1515/biol-2019-0067

    CAS  Article  Google Scholar 

  112. 112.

    Guo Z-d, Wu H-t, X-c S, X-d Z, Zhang JH (2011) Protection of minocycline on early brain injury after subarachnoid hemorrhage in rats. Acta Neurochir Suppl 110(Pt 1):71–74. https://doi.org/10.1007/978-3-7091-0353-1_13

    Article  PubMed  Google Scholar 

  113. 113.

    Wang N, Mi X, Gao B, Gu J, Wang W, Zhang Y, Wang X (2015) Minocycline inhibits brain inflammation and attenuates spontaneous recurrent seizures following pilocarpine-induced status epilepticus. Neuroscience 287:144–156. https://doi.org/10.1016/j.neuroscience.2014.12.021

    CAS  Article  PubMed  Google Scholar 

  114. 114.

    Nowak M, Strzelczyk A, Reif PS, Schorlemmer K, Bauer S, Norwood BA, Oertel WH, Rosenow F et al (2012) Minocycline as potent anticonvulsant in a patient with astrocytoma and drug resistant epilepsy. Seizure 21(3):227–228. https://doi.org/10.1016/j.seizure.2011.12.009

    CAS  Article  PubMed  Google Scholar 

  115. 115.

    Ieong C, Sun H, Wang Q, Ma J (2018) Glycyrrhizin suppresses the expressions of HMGB1 and ameliorates inflammative effect after acute subarachnoid hemorrhage in rat model. J Clin Neurosci 47:278–284. https://doi.org/10.1016/j.jocn.2017.10.034

    CAS  Article  PubMed  Google Scholar 

  116. 116.

    Zhao J, Wang Y, Xu C, Liu K, Wang Y, Chen L, Wu X, Gao F et al (2017) Therapeutic potential of an anti-high mobility group box-1 monoclonal antibody in epilepsy. Brain Behav Immun 64:308–319. https://doi.org/10.1016/j.bbi.2017.02.002

    CAS  Article  PubMed  Google Scholar 

  117. 117.

    Chen S, Ma Q, Krafft PR, Chen Y, Tang J, Zhang J, Zhang JH (2013) P2X7 receptor antagonism inhibits p38 mitogen-activated protein kinase activation and ameliorates neuronal apoptosis after subarachnoid hemorrhage in rats. Crit Care Med 41(12):e466–e474. https://doi.org/10.1097/CCM.0b013e31829a8246

    CAS  Article  PubMed  Google Scholar 

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Acknowledgments

This work was supported by grants from the Natural Science Fund of Guangdong Province (No. 2017A030313597), “Climbing Program” Special Fund of Guangdong Province (No. pdjh2019b0100, No. pdjh2020b0112) and Southern Medical University (No. LX2016N006, No. KJ20161102, No.201912121004S, No.201912121013, No. S202012121088, No. X202012121354, No. 19NJ-YB03).

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Jun Wang initiated this project. Jingxue Liang and Jiahong Deng performed the literature research and contributed to the original draft. Other authors participated in the revision of the manuscript.

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Correspondence to Jun Wang.

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Highlights

1. There is a close relationship between epilepsy and inflammatory state after SAH.

2. Microglia and specific receptors are involved in neuroinflammation after SAH.

3. Several anti-inflammatory therapies have been reported to exert neuroprotective effects on epilepsy.

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Wang, J., Liang, J., Deng, J. et al. Emerging Role of Microglia-Mediated Neuroinflammation in Epilepsy after Subarachnoid Hemorrhage. Mol Neurobiol (2021). https://doi.org/10.1007/s12035-021-02288-y

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Keywords

  • Microglia
  • Epilepsy
  • Subarachnoid hemorrhage
  • Neuroinflammation