Increased blood-brain barrier permeability correlate with microglial activation at hippocampal CA1 region in acute and chronic bilateral common carotid artery ligation in rats

https://doi.org/10.19106/JMedSci005402202201

Dian Prasetyo Wibisono(1*), Nur Arfian(2), Handoyo Pramusinto(3), Fauziyatul Munawaroh(4), Yeshua Putra Krisnugraha(5), Daniel Agriva Tamba(6), Dwi Cahyani Ratna Sari(7)

(1) Division of Neurosurgery, Department of Surgery, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada/Dr. Sardjito General Hospital, Yogyakarta
(2) Department of Anatomy, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Yogyakarta
(3) Division of Neurosurgery, Department of Surgery, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada/Dr. Sardjito General Hospital, Yogyakarta
(4) Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Yogyakarta, Indonesia
(5) Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Yogyakarta, Indonesia
(6) Division of Neurosurgery, Department of Surgery, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada/Dr. Sardjito General Hospital, Yogyakarta,
(7) Department of Anatomy, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Yogyakarta,
(*) Corresponding Author

Abstract


Inflammatory processes might play a key role in the pathogenesis of post-stroke epilepsy. The activation of microglia and release of vascular cell adhesion molecule-1 (VCAM1) might induce blood-brain barrier (BBB) disintegration. However, the influence of such pathomechanisms in the generation of post-stroke epilepsy is still not clear. We investigated whether cerebral ischemia exerts effects on inflammation in the hippocampus by measuring the hippocampal injury score, expression of a microglial marker, and expression of VCAM1 in rats. A total of 24 Sprague Dawley rats were randomized into four groups with 6 rats in eachgroup i.e. sham operation (SO) as control, carotid ligation 1 (GCL1) as an acute model, carotid ligation 3 (GCL3) as a subacute model, and carotid ligation 7 (GCL7) as a chronic model. Immunostaining for microglia marker (CD68) was measured in rat brain tissue sections. The VCAM1 expression was evaluated by reverse transcription-polymerase chain reaction (RT-PCR). Cerebral ischemia increased the amount of microglial immunostaining and expression of VCAM1. The hippocampal injury score and microglial immunopositivity were significantly correlated with the duration of brain ischemia. We conclude that cerebral ischemia is correlated with neuroinflammatory reaction and disturbance of BBB permeability, and the correlation of those molecular impairments with the generation of post-stroke epilepsy remains to be elucidated.


Keywords


blood-brain barrier; hippocampus; microglia; post-stroke epilepsy; VCAM1

Full Text:

PDF


References


1.Fiest KM, Sauro KM, Wiebe S, Patten SB, Kwon CS, Dykeman J, et al. Prevalence and incidence of epilepsy: a systematic review and meta-analysis of international studies. Neurology 2017; 88(3):296-303.
https://doi.org/10.1212/WNL.0000000000003509
2.Pack AM. Epilepsy overview and revised classification of seizures and epilepsies. Continuum 2019; 25(2):306-21.
https://doi.org/10.1212/CON.0000000000000707
3.Hernández-Ronquillo L, Adams S, Ballendine S, Téllez-Zenteno JF. Epilepsy in an elderly population: Classification, etiology and drug resistance. Epilepsy Res 2018; 140:90-4.
https://doi.org/10.1016/j.eplepsyres.2017.12.016
4.Myint PK. Post-stroke seizure and post-stroke epilepsy. Postgrad Med J 2006; 82(971):568-72.
https://doi.org/10.1136/pgmj.2005.041426
5.Yang H, Rajah G, Guo A, Wang Y, Wang Q. Pathogenesis of epileptic seizures and epilepsy after stroke. Neurol Res 2018; 40(6):426-32.
https://doi.org/10.1080/01616412.2018.1455014
6.El Khoury J, Hickman SE, Thomas CA, Loike JD, Silverstein SC. Microglia, scavenger receptors, and the pathogenesis of alzheimer’s disease. Neurobiol Aging 1998; 19(1 Suppl):S81-4.
https://doi.org/10.1016/s0197-4580(98)00036-0.
7.van Vliet EA, da Costa Araujo S, Redeker S, van Schaik R, Aronica E, Gorter JA. Blood-brain barrier leakage may lead to progression of temporal lobe epilepsy. Brain 2007; 130(Pt2):521-34.
https://doi.org/10.1093/brain/awl318
8.Sosunov AA, Wu X, McGovern RA, Couglin DG, Mikell CB, Goodman RR, et al. The mTOR pathway is activated in glial cells in mesial temporal sclerosis. Epilepsia 2012; 53(Suppl 1):78-86.
https://doi.org/10.1111/j.1528-1167.2012.03478.x
9.Liu M, Chen Z, Beaulieu C, Gross DW. Disrupted anatomic white matter network in left mesial temporal lobe epilepsy. Epilepsia 2014; 55(5):674-82.
https://doi.org/10.1111/epi.12581
10.Oby E, Janigro D. The blood-brain barrier and epilepsy. Epilepsia 2006; 47(11):1761-74.
https://doi.org/10.1111/j.1528-1167.2006.00817.x
11.van Vliet EA, Forte G, Ho;man L, den Burger JCG, Sinjewel A, de Vries HE, et al. Inhibition of mammalian target of rapamycin reduces epileptogenesis and blood-brain barrier leakage but not microglia activation. Epilepsia 2012; 53(7):1254-63.
https://doi.org/10.1111/j.1528-1167.2012.03513.x
12.Marchi N, Angelov L, Masaryk T, Fazio V, Granata T, Hernandez N, et al. Seizure-promoting effect of blood-brain barrier disruption. Epilepsia 2007; 48(4):732-42.
https://doi.org/10.1111/j.1528-1167.2007.00988.x
13.Tomkins O, Shelef I, Kaizerman I, Eliushin A, Afawi Z, Misk A, et al. Blood-brain barrier disruption in post-traumatic epilepsy. J Neurol Neurosurg Psychiatry 2009; 79(7):774-7.
https://doi.org/10.1136/jnnp.2007.126425
14.Yousef H, Czupalla CJ, Lee D, Chen MB, Burke AN, Zera KA, et al. Aged blood impairs hippocampal neural precursor activity and activates microglia via brain endothelial cell VCAM1. Nat Med 2019; 25(6):988-1000.
https://doi.org/10.1038/s41591-019-0440-4
15.Haarmann A, Nowak E, Deiß A, van der Pol S, Monoranu CM, Kooij G, et al. Soluble VCAM-1 impairs human brain endothelial barrier integrity via integrin α-4-transduced outside-in signalling. Acta Neuropathol 2015; 129(5):639-52.
https://doi.org/10.1007/s00401-015-1417-0
16.Yamashima T. Implication of cysteine proteases calpain, cathepsin and caspase in ischemic neuronal death of primates. Prog Neurobiol 2000; 62(3):273-95.
https://doi.org/10.1016/s0301-0082(00)00006-x
17.Nikonenko AG, Radenovic L, Andjus PR, Skibo GG. Structural features of ischemic damage in the hippocampus. Anat Rec (Hobogken) 2009; 292(12):1914-21.
https://doi.org/10.1002/ar.20969
18.Møller A. Results with calcium antagonists. In: New Strategies to Prevent Neuronal Damage from Ischemic Stroke. CHI Press 1994; 125-33.
19.Gulyás B, Toth M, Schain M, Airaksinen A, Vas A, Kostulas K, et al. Evolution of microglial activation in ischaemic core and peri-infarct regions after stroke: a PET study with the TSPO molecular imaging biomarker [((11))C]vinpocetine. J Neurol Sci 2012; 320(1-2):110-7.
https://doi.org/10.1016/j.jns.2012.06.026
20.Li T, Pang S, Yu Y, Wu X, Guo J, Zhang S. Proliferation of parenchymal microglia is the main source of microgliosis after ischaemic stroke. Brain 2013; 136(Pt 12):3578-88.
https://doi.org/10.1093/brain/awt287
21.Schilling M, Besselmann M, Leonhard C, Mueller M, Ringelstein EB, Kiefer R. Microglial activation precedes and predominates over macrophage infiltration in transient focal cerebral ischemia: a study in green fluorescent protein transgenic bone marrow chimeric mice. Exp Neurol 2003; 183(1):25-33.
https://doi.org/10.1016/s0014-4886(03)00082-7
22.Frijns CJM, Kappelle LJ. Inflammatory cell adhesion molecules in ischemic cerebrovascular disease. Stroke 2002; 33(8):2115-22.
https://doi.org/10.1161/01.str.0000021902.33129.69
23.Cook-Mills JM, Marchese ME, Abdala-Valencia H. Vascular cell adhesion molecule-1 expression and signaling during disease: regulation by reactive oxygen species and antioxidants. Antioxid Redox Signal 2011; 15(6):1607-38.
https://doi.org/10.1089/ars.2010.3522
24.Taylor RA, Sansing LH. Microglial responses after Ischemic Stroke and intracerebral hemorrhage. Clin Dev Immunol 2013; 20113:746068.
https://doi.org/10.1155/2013/746068
25.Liu R, Pian MX, Tang JC, Zhang Y, Liao HB, Zhuang Y, et al. Role of neuroinflammation in ischemic stroke. Neuroimmunol Neuroinflammation 2017; 4:158-66.
https://doi.org/10.20517/2347-8659.2017.09
26.Xiong XY, Liu L, Yang QW. Functions and mechanisms of microglia/macrophages in neuroinflammation and neurogenesis after stroke. Prog Neurobiol 2016; 142:23-44.
https://doi.org/ 0.1016/j.pneurobio.2016.05.001
27.Liu X, Wen S, Yan F, Liu K, Liu L, Wang L, et al. Salidroside provides neuroprotection by modulating microglial polarization after cerebral ischemia. J Neuroinflammation 2018; 15(1):39.
https://doi.org/10.1186/s12974-018-1081-0
28.Boddaert J, Bielen K, Jongers B, Manocha E, Yperzeele L, Cras P, et al. CD8 signaling in microglia/macrophage M1 polarization in a rat model of cerebral ischemia. PLoS One 2018; 13(1):e0186937.
https://doi.org/10.1371/journal.pone.0186937
29.Wang Q, Tang XN, Yenari MA. The inflammatory response in stroke. J Neuroimmunol 2007; 184(1-2):53-68.
https://doi.org/10.1016/j.jneuroim.2006.11.014
30.Cherry JD, Olschowka JA, O’Banion MK. Neuroinflammation and M2 microglia: the good, the bad, and the inflamed. J Neuroinflammation 2014; 11:98.
https://doi.org/10.1186/1742-2094-11-98
31.Fabene PF, Mora GN, Martinello M, Rossi B, Merigo F, Ottoboni L, et al. A role for leukocyte-endothelial adhesion mechanisms in epilepsy. Nat Med 2008; 14(12):1377-83.
https://doi.org/10.1038/nm.1878
32.Ivens S, Gabriel S, Greenberg G, Friedman A, Shelef I. Blood–brain barrier breakdown as a novel mechanism underlying cerebral hyperperfusion syndrome. J Neurol 2010; 257(4):615-20.
https://doi.org/10.1007/s00415-009-5384-z
33.Vezzani A, French J, Bartfai T, Baram TZ. The role of inflammation in epilepsy. Nat Rev Neurol 2011; 7(1):31-40.
https://doi.org/10.1038/nrneurol.2010.178
34.Kim SY, Buckwalter M, Soreq H, Vezzani A, Kaufer D. Blood-brain barrier dysfunction-induced inflammatory signaling in brain pathology and epileptogenesis. Epilepsia 2012; 53(Suppl 6):37-44.
https://doi.org/10.1111/j.1528-1167.2012.03701.x
35.Sumi N, Nishioku T, Takata F, Matsumoto J, Watanabe T, Shuto H, et al. Lipopolysaccharide-activated microglia induce dysfunction of the blood–brain barrier in rat microvascular endothelial cells co-cultured with microglia. Cell Mol Neurobiol 2010; 30(2):247-53.
https://doi.org/10.1007/s10571-009-9446-7
36.da Fonseca ACC, Matias D, Garcia C, Amarel L, Geraldo LH, Freitas C, et al. The impact of microglial activation on blood-brain barrier in brain diseases. Front Cell Neurosci 2014; 8:368.
https://doi.org/10.3389/fncel.2014.00362



DOI: https://doi.org/10.19106/JMedSci005402202201

Article Metrics

Abstract views : 1890 | views : 1488


Bookmark and Share


Copyright (c) 2022 Dian Prasetyo Wibisono

Creative Commons License
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.