Seizure-induced brain-borne inflammation sustains seizure recurrence and blood-brain barrier damage
Abstract
OBJECTIVE: Epilepsy is a common neurological disorder characterized by recurrent seizures often unresponsive to pharmacological treatment. Brain inflammation is considered a crucial etiopathogenetic mechanism of epilepsy that could be targeted to control seizures. Specific inflammatory mediators overexpressed in human epileptogenic foci are known to promote seizures in animal models. We investigated whether seizures induce brain inflammation independently on extracerebral factors. We also investigated whether brain-borne inflammation is required and sufficient to maintain seizure activity and whether it causes blood-brain barrier (BBB) impairment. We addressed these questions by studying the relation between seizures, inflammation, and BBB permeability in a brain preparation isolated from extracerebral compartments. METHODS: Epileptiform activity was induced by arterial perfusion of bicuculline in the in vitro isolated guinea pig brain. Seizure-induced brain inflammation was evaluated by quantitative immunohistochemical analysis of interleukin (IL)-1β in parenchymal cells. BBB damage was assessed by extravasation of intravascular fluorescein isothiocyanate-albumin. The effects of arterially perfused anakinra, a human recombinant IL-1β receptor antagonist, were investigated on epileptiform discharges, brain inflammation, and BBB damage. RESULTS: Seizure induction in the absence of extracerebral factors promoted the release of IL-1β from brain resident cells and enhanced its biosynthesis in astrocytes. Anakinra rapidly terminated seizures, prevented their recurrence, and resolved seizure-associated BBB breakdown. INTERPRETATION: Seizures initiate brain inflammation in glia and promote BBB damage that is independent of either leukocytes or blood-borne inflammatory molecules. Brain inflammation contributes to the duration and recurrence of seizures. This study supports the use of specific anti-inflammatory drugs in clinical conditions that present with intractable recurrent seizures.
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IL-1R1 activation on ECs increases BBB permeability through downregulation of tight junction proteins, mainly ZO-1, and upregulation of NO and MMPs.
“IL-1R1 activation on ECs increases BBB permeability through downregulation of tight junction proteins, mainly ZO-1, and upregulation of NO and MMPs (Ravizza et al., 2008a,b; Morin-Brureau et al., 2011; Librizzi et al., 2012).”
From The impact of microglial activation on blood-brain barrier in brain diseases (2014) · cites this paper as Librizzi et al., 2012
Microglial and astrocytic IL-1β act directly on the endothelium, altering BBB permeability and contributing to epileptogenesis.
“Microglial and astrocytic IL-1β act directly on the endothelium, altering BBB permeability and contributing to epileptogenesis.”
From The impact of microglial activation on blood-brain barrier in brain diseases (2014) · cites this paper as Librizzi et al., 2012
The interaction between microglia and ECs is important in epilepsy.
“These studies further suggest the importance of the interaction between microglia and ECs in epilepsy.”
From The impact of microglial activation on blood-brain barrier in brain diseases (2014) · cites this paper as Librizzi et al., 2012
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- Authors
- Librizzi, L., Noè, F., Vezzani, A., de Curtis, M., & Ravizza, T.
- Affiliations
- Fondazione IRCCS Istituto Neurologico Carlo Besta (IT)
- Mario Negri Institute for Pharmacological Research (IT)
- Corresponding author
- Ravizza, Teresa
- Venue
- Annals of Neurology
- Publisher
- Wiley
- Published
- 2012-07
- Volume
- 72
- Issue
- 1
- Pages
- 82-90
- ISSN
- 0364-5134 (ISSN-L)
- 1531-8249
- OpenAlex
- W2104387508
- Cited by
- 253
- References
- 50
- Citations by year
- 2026: 6 · 2025: 13 · 2024: 11 · 2023: 16 · 2022: 13 · 2021: 22 · 2020: 13 · 2019: 26 · 2018: 21 · 2017: 13 · 2016: 24 · 2015: 23 · 2014: 27 · 2013: 20 · 2012: 5
- FWCI
- 17.10
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Annals of Neurology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Epilepsy research and treatment
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Neurology › Traumatic Brain Injury and Neurovascular Disturbances
- Keywords
- seizure recurrence, blood-brain barrier disruption, IL-1β, anakinra, interleukin-1 receptor antagonist, astrocytes, epileptiform activity, bicuculline, anti-inflammatory therapy, drug-resistant epilepsy
- MeSH terms
- Animals, Astrocytes, Bicuculline, Blood-Brain Barrier, Brain, Encephalitis, Epilepsy, Guinea Pigs, Recurrence, Seizures, Interleukin-1beta, Interleukin 1 Receptor Antagonist Protein, GABA-A Receptor Antagonists
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