Inflammatory mediators in human epilepsy: A systematic review and meta-analysis

Vries, Evelien E. de; Munckhof, Bart van den; Braun, Kees P.J.; Royen‐Kerkhof, Annet van; Jager, Wilco de; Jansen, Floor E.

doi:10.1016/j.neubiorev.2016.02.007

Cited by 240 publications

(205 citation statements)

References 109 publications

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“…Therefore, the use of different stimulants could result in different immunomodulatory effects of lamotrigine. Regarding epilepsy, inhibition of IL-2 and TNF-α production might be beneficial in the management of epilepsy as these cytokines were found to be involved in the pathogenesis of epilepsy (6,7).…”

Section: Effects Of Lamotrigine On Immune System Parameters In Vivomentioning

confidence: 99%

“…It has recently been shown that modulation of the immune system and inflammation are implicated in the pathogenesis of epilepsy (5). This partially involves alteration in cytokine secretion, in particular, increased pro-inflammatory cytokines such as IL-1β, IL-6 and TNF-a production (6)(7)(8). IL-2, in addition, was found to promote seizure generation in various murine models of epilepsy (9).…”

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confidence: 99%

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Evaluation of immunomodulatory effects of lamotrigine in BALB/c mice

et al. 2017

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Modulation of the immune system has recently been shown to be involved in the pharmacological effects of old antiepileptic drugs and in the pathogenesis of epilepsy. Therefore, the most recent guidelines for immunotoxicological evaluation of drugs were consulted to investigate the immunomodulatory effects of lamotrigine, a newer antiepileptic drug, in BALB/c mice. These included the in vivo effects of lamotrigine on delayed-type hypersensitivity (DTH) response to sheep red blood cell (SRBC) antigens, hemagglutination titer assays and hematological changes. In vitro effects of lamotrigine on ConA-induced splenocyte proliferation and cytokine secretion were assessed. The results showed that lamotrigine treatment significantly increased the DTH response to SRBC in the mouse model of this study. This was accompanied by a significant increase in relative monocyte and neutrophil counts and in spleen cellularity. Lamotrigine significantly inhibited ConA-induced splenocyte proliferation in vitro and it significantly inhibited IL-2 and TNF-α secretion in ConA-stimulated splenocytes. In conclusion, the results demonstrated significant immunomodulatory effects of lamotrigine in BALB/c mice. These data could expand the understanding of lamotrigine-induced adverse reactions and its role in modulating the immune system in epilepsy.

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Section: Effects Of Lamotrigine On Immune System Parameters In Vivomentioning

confidence: 99%

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confidence: 99%

Evaluation of immunomodulatory effects of lamotrigine in BALB/c mice

et al. 2017

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“…Furthermore, an absence of neural autoantibodies does not rule out the success of immunotherapies, or exclude a diagnosis of limbic encephalitis [13,15]. This lack of consensus and growing evidence of an immune/inflammatory component in epilepsy development makes it necessary to enlarge diagnostic and prognostic assessment to include other immunological biomarkers [16]. In response to this need, the involvement of different immune pathways in epilepsy pathogenesis is increasingly investigated in animal models and in humans [17][18][19].…”

Section: Introductionmentioning

confidence: 99%

Complement system biomarkers in epilepsy

Kopczynska

Zelek

Vespa

et al. 2018

Seizure

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Purpose: To explore whether complement dysregulation occurs in a routinely recruited clinical cohort of epilepsy patients, and whether complement biomarkers have potential to be used as markers of disease severity and seizure control. analysis were used to test whether combinations of complement analytes were predictive of epilepsy diagnoses and seizure occurrence. Correlation between number and type of antiepileptic drugs (AED) and complement analytes was also performed. Methods Results:We found: 1) significant differences between all epilepsy patients and controls for TCC (p˂ 0.01) and FH (p˂ 0.01) after performing univariate analysis.2) multivariate analysis combining six analytes (C3, C4, Properdin, FH, C1Inh, Clu) to give a predictive value (area under the curve) of 0.80 for differentiating epilepsy from controls.3) significant differences in complement levels between patients with controlled seizures (n=65) in comparison with uncontrolled seizures (n=87). Levels of iC3b, Properdin and Clu were decreased and levels of C4 were increased in patients with uncontrolled seizures. 4) no correlation was found between the level of complement biomarkers and the number of AEDs taken, but an association between some analyte levels and drug therapy was seen in patients taking sodium valproate, clobazam, and perampanel. Complement biomarkers in EpilepsyPage 3 Conclusion: This study adds to evidence implicating complement in pathogenesis of epilepsy and may allow the development of better therapeutics and prognostic markers in the future.Replication in a larger sample set is needed to validate the findings of the study. Highlights:• Plasma complement biomarkers distinguish epilepsy patients from controls (area under the curve: 0.8).• Plasma complement biomarkers differ between controlled and uncontrolled epilepsy patients.• The data implicate complement dysregulation and inflammation in the pathogenesis of epilepsy.

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“…Accordingly, based on this background, it is not possible to exclude that fingolimod can exert antiepileptogenic effects in this strain through some kind of antiinflammatory mechanisms, which could also be linked to a modulation of neuronal S1P receptors [13]. It is known that glial activation and the related overexpression of proinflammatory cytokines seem to play a crucial role in epileptogenesis both in humans and in several animal models of epilepsy [58][59][60][61]; however, to date, such a relationship between neuroinflammation and absence seizure development in WAG/Rij rats remains unclear [27,28]. Indeed, neuroinflammation and related mediators worsen absence seizures in this strain [28-30, 62, 63], while cyclooxygenase inhibitors have some partial antiabsence properties [11,63,64] and etoricoxib, a selective COX-2 inhibitor, also possesses antiepileptogenic effects in this strain, which appear to be more effective than fingolimod with a reduction in the development of absence seizures of about 45% vs 30% obtained with fingolimod [11].…”

Section: Discussionmentioning

confidence: 99%

Fingolimod Exerts only Temporary Antiepileptogenic Effects but Longer-Lasting Positive Effects on Behavior in the WAG/Rij Rat Absence Epilepsy Model

et al. 2017

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One of the major challenges in the epilepsy field is identifying disease-modifying drugs in order to prevent or delay spontaneous recurrent seizure onset or to cure already established epilepsy. It has been recently reported that fingolimod, currently approved for the treatment of relapsing-remitting multiple sclerosis, has demonstrated antiepileptogenic effects in two different preclinical models of acquired epilepsy. However, to date, no data exist regarding the role of fingolimod against genetic epilepsy. Therefore, we have addressed this issue by studying the effects of fingolimod in WAG/Rij rats, a well-established genetic model of absence epilepsy, epileptogenesis, and neuropsychiatric comorbidity. Our results have demonstrated that an early-long term treatment with fingolimod (1 mg/Kg/day), started before absence seizure onset, has both antiepileptogenic and antidepressant-like effects in the WAG/Rij rats. However, these effects were transitory, since 5 months after treatment discontinuation, both absence seizure and depressive like-behavior returned to control level.Furthermore, a temporary reduction of mTOR signaling pathway activity, indicated by reduced p-mTOR and p-p70S6k levels and by an increased p-AKT in WAG/Rij rats of 6 months of age accompanied the transitory antiepileptogenic fingolimod effects. Surprisingly, fingolimod has demonstrated longer-lasting positive effects on cognitive decline in this strain. This effect was accompanied by an increased acetylation of Lysine 8 of histone H4 (both 6 and 10 months of age). In conclusion, our results support the antiepileptogenic effects fingolimod. However, these antiepileptogenic effects were transitory. Moreover, fingolimod might also have a positive impact on animal behavior and particularly in protecting the development of memory decline.

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Inflammatory mediators in human epilepsy: A systematic review and meta-analysis

Cited by 240 publications

References 109 publications

Evaluation of immunomodulatory effects of lamotrigine in BALB/c mice

Evaluation of immunomodulatory effects of lamotrigine in BALB/c mice

Complement system biomarkers in epilepsy

Fingolimod Exerts only Temporary Antiepileptogenic Effects but Longer-Lasting Positive Effects on Behavior in the WAG/Rij Rat Absence Epilepsy Model

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