Inflammation and endothelium response in epileptic patients: A case-control study
Amir Farhang1, Saghayegh Haghjooy Javanmard2, Jafar Mehvari3, Mohammad Zare3, Mohammad Saadatnia3
1 Department of Physiology, Applied Physiology Research Center; Medical Student Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
2 Department of Physiology, Applied Physiology Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
3 Isfahan Neurosciences Research Center, Isfahan Medical Education Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
|Date of Submission||20-Mar-2015|
|Date of Acceptance||18-Nov-2015|
|Date of Web Publication||30-Aug-2016|
Isfahan Neurosciences Research Center, Isfahan Medical Education Research Center, Isfahan University of Medical Sciences, Isfahan
Source of Support: None, Conflict of Interest: None
Background: Blood brain barrier (BBB) permeability plays an important role in the brain impairments. The barrier is composed of endothelium cells, due to the presence of tight junctions that connect endothelium cells. The failure of BBB function has triggering chronic or acute seizures through brain inflammation and BBB permeability. Seizure induces vasodilation, BBB leakage and up-regulation of vascular cell adhesion molecules which able to bind integrins blood leukocytes.
Materials and Methods: In this case-control study we included 40 epileptic patients who were sampled during a seizure as a case group and 20 healthy subjects as a healthy control group. Plasma levels of the inflammation and endothelium markers including intercellular adhesion molecule (ICAM), vascular adhesion molecule (VCAM), interleukin 1 beta (IL-1β) and C-reactive protein (CRP) were measured by enzyme-linked immunosorbent assays (ELISAs).
Results: The ICAM and VCAM concentration in the epileptic patients (135.8 ± 5.35) (52.04 ± 4.24) were significantly higher than healthy control group (110.32 ± 5.04) (23.38 ± 3.01) (P < 0.005). IL-1 beta concentration was not significantly different between groups (P = 0.594). However, CRP level was significantly up-regulated in epileptic patients (P < 0.005).
Conclusion: Epileptic patients have BBB leakage and dysfunction as the up-regulation of the endothelium cytokines showed. The BBB leakage may be the result of the inflammatory impairment.
Keywords: Endothelium, epileptic, Inflammation
|How to cite this article:|
Farhang A, Javanmard SH, Mehvari J, Zare M, Saadatnia M. Inflammation and endothelium response in epileptic patients: A case-control study. Adv Biomed Res 2016;5:131
|How to cite this URL:|
Farhang A, Javanmard SH, Mehvari J, Zare M, Saadatnia M. Inflammation and endothelium response in epileptic patients: A case-control study. Adv Biomed Res [serial online] 2016 [cited 2020 Feb 20];5:131. Available from: http://www.advbiores.net/text.asp?2016/5/1/131/187370
| Introduction|| |
Due to its unique structure, the blood-brain barrier (BBB) permeability plays an important role in the brain impairments. The barrier is composed of endothelium cells, due to the presence of tight junctions that connect endothelium cells. The failure of BBB function has triggering chronic or acute seizures through brain inflammation and BBB permeability. Blood vessels in the brain can respond to the electrical activity due to seizure, causing either transient hyperperfusion in healthy tissue or severe hypoperfusion in tissue at risk of progressive damage., Epilepsy could be resulted of the inflammatory response and the endothelium impairments. The inflammatory response includes the secretion of several inflammatory factors from neurons, astrocytes and microglia such as interleukins (ILs) (e.g. IL-1β) and C-reactive protein.,, Infiltration of leukocytes through the BBB through the adhesion molecules (e.g., Intercellular Adhesion Molecule 1 [ICAM-1] and Vascular Adhesion Molecule 1 [VCAM-1] might be the reason of endothelium dysfunction and BBB leakage in epileptic patients.
Brain inflammation and increased level of IL-1β was found after the seizure has been detected in the post-epileptic animal model.,, The level of IL-1β increased during and after induced seizure in rats. Several human studies has been reported a post-ictal increase in IL-1β in blood. However, IL-1β plasma level after seizures has not yet proved. In animal induced seizure model an increased level of CRP in blood considered to be brain ischemia, stroke, and vascular events.
Seizure induces vasodilation, BBB leakage and up-regulation of vascular cell adhesion molecules which able to bind integrins blood leukocytes. An acute induced seizure associated with vascular leakage which was prevented by inhibiting leukocyte-vascular adhesion, which could linked to vascular damage. Chronic expression of VCAM after seizure suggests that leukocyte-vascular interactions may continue, contributing to BBB permeability and brain damage. To the best of our knowledge, there are rare study showed BBB dysfunction including endothelium factors and inflammation response together in epileptic patients versus none epileptic patients. Therefore we aimed to evaluate the serum concentration of endothelium and inflammatory cytokines in epileptic patients versus none epileptic patients.
| Materials and Methods|| |
This case-control study has been performed in January to March 2012 to evaluate the hypothesis that epileptic patients have BBB dysfunction and leakage. The study was conducted in Ayatollah Kashani and Alzahra hospital, Isfahan, Iran over the 40 epileptic patients as the case group and 20 healthy control people as a control group. All the patients were checked for other diseased, which can effect on the serum level of inflammation cytokines such as a rheumatologic disease, diabetes mellitus (DM) and history of allergy. Epileptic patents were defined as age more than 16 years, idiopathic epilepsy, starting epilepsy at least in the last 6 months. Patients with a disease which can effect on the serum level of inflammation cytokines symptomatic epilepsy, history of trauma, stroke, metabolic disorder, metabolic syndrome, smoking and drug abuser were excluded from the study.
This study was approved in local ethic committee of Isfahan University of Medical Sciences and all patients and control signed a consent form.
Blood was sampled at the seizure-free period of epileptic patients. Five milliliters of venous blood was drawn from each participant and immediately centrifuged. Serum samples were then frozen and kept at -70°C.
Plasma samples were thawed and further processed according to manufacturer's instructions. ICAM, VCAM, IL-1β and CRP concentrations in plasma were quantified by enzyme-linked immunosorbent assay.
Data have been analyzed by using SPSS 18 and are presented as mean values ± standard deviation. Plasma concentrations (ICAM, VCAM, IL-1β and CRP) between groups were statistically assessed Kruskal-Wallis one-way analysis of variance on ranks followed by Dunn's post hoc test for variable group sizes. The Pearson Chi-square test or Fisher's exact test was used for comparing the individual variables between groups. P < 0.05 was taken as statistically significant.
| Results|| |
Forty epileptic patients had been included as the case group and 20 non-epileptic people as the control group. About 30 patients were excluded because of the reason of their seizures (e.g., Head trauma, drug using, pseudo-epilepsy). Baseline characteristic (sex and age) as [Table 1] shows were not significantly different between groups.
The groups contain 20 (50%) and 12 (60%) male subjects respectively. The means (±standard error) of age in each group were 30.48 ± 2.03 and 27.35 ± 3.42 respectively [Table 1].
[Table 2] shows mean levels of serum concentration of ICAM, VCAM, IL-1β and CRP in each group; ICAM and VCAM serum concentration, as endothelium cytokines, were investigated in epileptic patients and non-epileptic control group. There were significant differences between groups in serum concentration of ICAM (P = 0.004) and VCAM (P = 0.003). As inflammatory cytokines, IL-1β and CRP were measured. Serum concentration of CRP were significantly different between groups (P = 0.04). However, serum concentration of IL-1β was not significantly different (P = 0.594). Although serum concentration of CRP were significantly different between the two groups (P = 0.04), the serum concentration of IL-1β was not significantly different (P = 0.594).
|Table 2: The relation between endothelium and inflammatory cytokines in epileptic patients and nonepileptic people|
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| Discussion|| |
The results revealed significant higher serum concentrations of ICAM and VCAM in epileptic patients versus non-epileptic people. Furthermore, two inflammatory cytokines were measured, and there were no significant difference in the level of IL-1β serum concentration between the epileptics and non-epileptics; however, the level of CRP serum concentration was significantly higher in epileptic patients.
BBB disruption can be triggered by a direct insult to the endothelium or by systemic factors, including activation of circulating leukocytes and release of molecular mediators (ICAM and VCAM) that increases vascular permeability and inflammation (CRP and IL1beta).,, To the best of our knowledge, there are rare study showed BBB dysfunction including endothelium factors and inflammation response together in epileptic patients versus none epileptic patients.
Our results demonstrated that there are higher levels of ICAM and VCAM concentration in epileptic patients which represented the higher permeability of BBB; the up-regulation might show BBB dysfunction in epileptic patients versus non-epileptic people. BBB permeability plays an important role in the pathogenesis of epilepsy; on the other hand, microvascular permeability has a close relation to endothelium and inflammatory cytokines. Previous studies showed up-regulation of ICAM and VCAM as pro-convulsant agents in the in-vivo and in-vitro models of provoke seizures in animals and increased infiltration of leukocytes. ICAM and VCAM had a major role in controlling leukocyte traffic into the CNS., Therefore, the infiltration induces BBB leakage and widening the BBB junctions which aggravate the epileptic condition.
The results showed significant higher serum concentration of CRP in epileptic patients in contrast with non-epileptic people but serum concentration of IL-1β was not significantly different between these groups. Other study showed IL-1β had a direct effect on BBB permeability and lowers the seizure threshold and promotes epileptogenesis on-the-spot. However, IL-1β up-regulates in the acute phase of the seizure. The current study evaluated the patients in inter-ictal phase; therefore IL-1β did not significantly different between groups. In contrast the CRP that up-regulated in inter-ictal phase were significantly higher in epileptic patients. CRP participates in brain ischemia, stroke, vascular events and act as a chronic inflammatory cytokine. Previous studies investigated CRP baseline concentration in epileptic patients. They showed that CRP baseline concentration was higher in epileptic patients versus non-epileptic people., Higher baseline CRP levels were also detected in those with older age at diagnosis. In addition, CRP level was higher in elder participants than in youngers in control group.
Small sample size should have been considered as a limitation of this study.
| Conclusion|| |
The endothelium mediators (ICAM and VCAM) were higher in epileptic patients may show BBB dysfunction in epileptic patients. From the inflammatory cytokines; CRP was higher in epileptic patients in inter-ictal phase and IL-1b had no significant level in epileptic patients in inter-ictal phase.
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Conflicts of interest
There are no conflicts of interest.
| References|| |
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;257:615-20.
Oby E, Janigro D. The blood-brain barrier and epilepsy. Epilepsia 2006;47:1761-74.
Dreier JP. The role of spreading depression, spreading depolarization and spreading ischemia in neurological disease. Nat Med 2011;17:439-47.
Winkler MK, Chassidim Y, Lublinsky S, Revankar GS, Major S, Kang EJ, et al.
Impaired neurovascular coupling to ictal epileptic activity and spreading depolarization in a patient with subarachnoid hemorrhage: Possible link to blood-brain barrier dysfunction. Epilepsia 2012;53 Suppl 6:22-30.
Vezzani A, French J, Bartfai T, Baram TZ. The role of inflammation in epilepsy. Nat Rev Neurol 2011;7:31-40.
Vezzani A, Aronica E, Mazarati A, Pittman QJ. Epilepsy and brain inflammation. Exp Neurol 2011;232:143-8.
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.
Fabene PF, Navarro Mora G, Martinello M, Rossi B, Merigo F, Ottoboni L, et al.
A role for leukocyte-endothelial adhesion mechanisms in epilepsy. Nat Med 2008;14:1377-83.
Zattoni M, Mura ML, Deprez F, Schwendener RA, Engelhardt B, Frei K, et al.
Brain infiltration of leukocytes contributes to the pathophysiology of temporal lobe epilepsy. J Neurosci 2011;31:4037-50.
Marchi N, Oby E, Batra A, Uva L, De Curtis M, Hernandez N, et al
. In vivo
and in vitro
effects of pilocarpine: Relevance to ictogenesis. Epilepsia 2007;48:1934-46.
Marchi N, Johnson AJ, Puvenna V, Johnson HL, Tierney W, Ghosh C, et al.
Modulation of peripheral cytotoxic cells and ictogenesis in a model of seizures. Epilepsia 2011;52:1627-34.
Holtman L, van Vliet EA, Aronica E, Wouters D, Wadman WJ, Gorter JA. Blood plasma inflammation markers during epileptogenesis in post-status epilepticus rat model for temporal lobe epilepsy. Epilepsia 2013;54:589-95.
Lehtimäki KA, Keränen T, Palmio J, Mäkinen R, Hurme M, Honkaniemi J, et al.
Increased plasma levels of cytokines after seizures in localization-related epilepsy. Acta Neurol Scand 2007;116:226-30.
Alapirtti T, Rinta S, Hulkkonen J, Mäkinen R, Keränen T, Peltola J. Interleukin-6, interleukin-1 receptor antagonist and interleukin-1beta production in patients with focal epilepsy: A video-EEG study. J Neurol Sci 2009;280:94-7.
Tuttolomondo A, Di Sciacca R, Di Raimondo D, Renda C, Pinto A, Licata G. Inflammation as a therapeutic target in acute ischemic stroke treatment. Curr Top Med Chem 2009;9:1240-60.
Librizzi L, Regondi MC, Pastori C, Frigerio S, Frassoni C, de Curtis M. Expression of adhesion factors induced by epileptiform activity in the endothelium of the isolated guinea pig brain in vitro
. Epilepsia 2007;48:743-51.
Eid T, Brines ML, Cerami A, Spencer DD, Kim JH, Schweitzer JS, et al.
Increased expression of erythropoietin receptor on blood vessels in the human epileptogenic hippocampus with sclerosis. J Neuropathol Exp Neurol 2004;63:73-83.
Seiffert E, Dreier JP, Ivens S, Bechmann I, Tomkins O, Heinemann U, et al.
Lasting blood-brain barrier disruption induces epileptic focus in the rat somatosensory cortex. J Neurosci 2004;24:7829-36.
Uva L, Librizzi L, Marchi N, Noe F, Bongiovanni R, Vezzani A, et al.
Acute induction of epileptiform discharges by pilocarpine in the in vitro
isolated Guinea-pig brain requires enhancement of blood-brain barrier permeability. Neuroscience 2008;151:303-12.
van Vliet EA, Aronica E, Gorter JA. Blood-brain barrier dysfunction, seizures and epilepsy. Semin Cell Dev Biol 2015;38:26-34.
Tomkins O, Feintuch A, Benifla M, Cohen A, Friedman A, Shelef I. Blood-brain barrier breakdown following traumatic brain injury: A possible role in posttraumatic epilepsy. Cardiovasc Psychiatry Neurol 2011;2011:765923.
Mantovani A, Garlanda C, Doni A, Bottazzi B. Pentraxins in innate immunity: From C-reactive protein to the long pentraxin PTX3. J Clin Immunol 2008;28:1-13.
Alapirtti T, Waris M, Fallah M, Soilu-Hänninen M, Mäkinen R, Kharazmi E, et al.
C-reactive protein and seizures in focal epilepsy: A video-electroencephalographic study. Epilepsia 2012;53:790-6.
Tan TY, Lu CH, Chuang HY, Lin TK, Liou CW, Chang WN, et al.
Long-term antiepileptic drug therapy contributes to the acceleration of atherosclerosis. Epilepsia 2009;50:1579-86.
[Table 1], [Table 2]
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