Disruption of the blood–brain barrier after generalized tonic-clonic seizures correlates with cerebrospinal fluid MMP-9 levels
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Increasing evidence suggests seizures cause blood–brain barrier (BBB) dysfunction including decreased seizure threshold and higher onset potential of future seizures.
However, the mechanisms underlying BBB damage in seizures remains poorly understood.
Evidence in human and animal models shows BBB disruption is associated with activation of matrix metalloproteinase-9 (MMP-9) after cerebral ischemia and inflammation. The objective of this study was to determine whether MMP-9 concentrations in cerebral spinal fluid (CSF) are associated with BBB disruption in patients after epileptic seizures.
Thirty-one patients with generalized tonic-clonic (GTC) seizures were included in the study: 20 had recurrent GTC seizures (RS), and 11 had a single GTC seizure (SS) episode. Twenty-five adult non-seizure patients were used as controls. CSF samples were collected by lumbar puncture within 24 h after seizure cessation (range: 3–15 h, mean 6.2 h). CSF MMP-9 levels were determined by an enzyme-linked immunosorbent assay (ELISA). MMP enzyme activity was measured by gelatin zymography. The CSF/serum albumin ratio (albumin quotient, QAlb) was used as a measure of blood–brain barrier permeability.
We found significantly higher CSF MMP-9 concentrations in seizure patients compared with controls (P < 0.001). CSF MMP-9 levels and QAlb values were higher in RS patients compared with SS and controls.
Moreover, CSF MMP-9 concentration showed strong correlation between QAlb values (r = 0.76, P < 0.0001) and between CSF leukocyte counts (r = 0.77, P < 0.0001) in patients after seizures.
Gelatin zymography showed MMP-9 proteolytic activity only in GTC seizure patients.
Our results suggest MMP-9 plays a role in BBB dysfunction, characterized by invasion of leukocytes into the CSF during seizures.
Further Readings of Interest
Amniotic fluid MMP-9 and neurotrophins in autism spectrum disorders: an exploratory study.
Evidence suggests that some developmental disorders, such as autism spectrum disorders (ASDs), are caused by errors in brain plasticity.
Given the important role of matrix metalloproteinases (MMPs) and neurotrophins (NTs) in neuroplasticity, amniotic fluid samples for 331 ASD cases and 698 frequency-matched controls were analyzed for levels of MMP-9, brain-derived neurotrophic factor, NT-4 and transforming growth factor-β utilizing a Danish historic birth cohort and Danish nationwide health registers.
Laboratory measurements were performed using an in-house multiplex sandwich immunoassay Luminex xMAP method, and measurements were analyzed using tobit and logistic regression.
Results showed elevated levels of MMP-9 in ASD cases compared with controls (crude and adjusted tobit regression P-values: 0.01 and 0.06).
Our results highlight the importance of exploring the biologic impact of MMP-9 and potential therapeutic roles of its inhibitors in ASD and may indicate that neuroplastic impairments in ASD may present during pregnancy.