Serum Proteins Associated with Blood–Brain Barrier as Potential Biomarkers for Seizure Prediction

Abstract

As 30% of epileptic patients remain drug-resistant, seizure prediction is vital. Induction of epileptic seizure is a complex process that can depend on factors such as intrinsic neuronal excitability, changes in extracellular ion concentration, glial cell activity, presence of inflammation and activation of the blood–brain barrier (BBB). In this study, we aimed to assess if levels of serum proteins associated with BBB can predict seizures. Serum levels of MMP-9, MMP-2, TIMP-1, TIMP-2, S100B, CCL-2, ICAM-1, P-selectin, and TSP-2 were examined in a group of 49 patients with epilepsy who were seizure-free for a minimum of seven days and measured by ELISA. The examination was repeated after 12 months. An extensive medical history was taken, and patients were subjected to a follow-up, including a detailed history of seizures. Serum levels of MMP-2, MMP-9, TIMP-1, CCL-2, and P-selectin differed between the two time points (p < 0.0001, p < 0.0001, p < 0.0001, p < 0.0001, p = 0.0035, respectively). General linear model analyses determined the predictors of seizures. Levels of MMP-2, MMP-9, and CCL-2 were found to influence seizure count in 1, 3, 6, and 12 months of observation. Serum levels of MMP-2, MMP-9, and CCL-2 may be considered potential biomarkers for seizure prediction and may indicate BBB activation.

Meta-analysis of MMP-9 levels in the serum of patients with epilepsy

“…These included studies were published and peer reviewed. All 13 studies were case–control ( Zhang and Hao, 2009 ; Zhang et al, 2013 ; Cudna et al, 2017 ; Bronisz et al, 2018 ; Meguid et al, 2018 ; El Moneam Abdallah et al, 2019 ; Wang, 2019 ; Zhang, 2019 ; Huang et al, 2020 ; Li et al, 2020 ; Tao et al, 2020 ; Bronisz et al, 2023 ; Cudna et al, 2023 ) studies. Enzyme-linked immunoassay is a unified method for MMP-9 detection.…”

“…Since only 8 out of the 13 papers had complete total MMP-9 data, we conducted a random-effects meta-analysis of the 8 studies that were included and performed to generate forest plots ( Bronisz et al, 2018 ; Meguid et al, 2018 ; El Moneam Abdallah et al, 2019 ; Wang, 2019 ; Huang et al, 2020 ; Li et al, 2020 ; Tao et al, 2020 ; Bronisz et al, 2023 ). The remaining 5 papers were used for subgroup analysis.…”

“…A sensitivity analysis was conducted to evaluate the stability of the results. The studies by Bronisz et al (2018) , Meguid et al (2018) , Tao et al (2020) had a substantial influence on the results. Such studies significantly extended the effect size, which may have a detrimental effect on the robustness of the meta-analysis results ( Figure 2 B ).…”

“…(B) Sensitivity analysis of this meta-analysis. (C) Association between MMP-9 level and epilepsy, following exclusion of the study by Tao et al (2020) , Meguid et al (2018) , and Bronisz et al (2018) . (D) A funnel plot to assess publication bias.…”

“…Consequently, upregulated MMP-9 degrades many extracellular matrix molecules to disrupt the BBB. The increased MMP-9 can also rearrange the molecular structure of peripheral cells and cellular matrix, resulting in synaptic remodeling, which can lead to epilepsy ( Bronisz et al, 2022 ).…”