Epilepsy is a chronic neurological disease characterized by an enduring propensity for generation of seizures. The pathogenic processes of seizure generation and recurrence are the subject of intensive preclinical and clinical investigations as their identification would enable development of novel treatments that prevent epileptic seizures and reduce seizure burden. Such treatments are particularly needed for pharmacoresistant epilepsies, which affect ~30% of patients. Neuroinflammation is commonly activated in epileptogenic brain regions in humans and is clearly involved in animal models of epilepsy. An increased understanding of neuroinflammatory mechanisms in epilepsy has identified cellular and molecular targets for new mechanistic therapies or existing anti-inflammatory drugs that could overcome the limitations of current medications, which provide only symptomatic control of seizures. Moreover, inflammatory mediators in the blood and molecular imaging of neuroinflammation could provide diagnostic, prognostic and predictive biomarkers for epilepsy, which will be instrumental for patient stratification in future clinical studies. In this Review, we focus on our understanding of the IL-1 receptor–Toll-like receptor 4 axis, the arachidonic acid–prostaglandin cascade, oxidative stress and transforming growth factor-β signalling associated with blood–brain barrier dysfunction, all of which are pathways that are activated in pharmacoresistant epilepsy in humans and that can be modulated in animal models to produce therapeutic effects on seizures, neuronal cell loss and neurological comorbidities.
Activation of neuroinflammatory pathways in epileptogenic brain areas is common in structural (acquired or genetic) epilepsies.
Neuroinflammation is an intrinsic brain response that involves activation of innate immunity mechanisms in glia, neurons and the microvasculature.
Inflammatory mediators, such as IL-1β, tumour necrosis factor, high mobility group box 1, transforming growth factor-β and prostaglandins, can alter neuronal, glial and blood–brain barrier functions by activating transcriptional and post-translational mechanisms in brain cells.
If not adequately controlled, neuroinflammation contributes to seizures, neuronal cell loss, maladaptive synaptic plasticity and comorbidities.
Target-specific anti-inflammatory interventions in animal models of epilepsy have anti-ictogenic, anti-epileptogenic and disease-modifying therapeutic effects.
Initial clinical studies have shown that some anti-inflammatory drugs have therapeutic effects on drug-resistant seizures and that neuroinflammatory factors could act as disease biomarkers.
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The authors gratefully acknowledge their sources of support: the European Union Seventh Framework Programme (FP7/2007-2013) under grant agreement n°602102 (EPITARGET), the Associazione Italiana Contro l’Epilessia (AICE-FIRE) and Citizen United for Research in Epilepsy (CURE).
The authors declare no competing interests.
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A cytosolic, multiprotein, intracellular complex that assembles upon detection of pathogen-associated molecular patterns and damage-associated molecular patterns, resulting in activation of caspase 1, a protease that is responsible for the maturation and release of IL-1β and IL-18.
- Ketogenic diet
A dietary treatment with a high fat content, moderate protein content and low carbohydrate content, mimicking the biochemical changes of starvation. This diet and its variants represent alternative treatments for patients with pharmacoresistant seizures.
- Unverricht–Lundborg disease
An autosomal recessive neurodegenerative disease, also called progressive myoclonic epilepsy type 1, caused by mutation of the gene that encodes cystatin B (CSTB) on chromosome 21q22.3. Typical clinical features are myoclonic and tonic–clonic seizures and ataxia.
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Vezzani, A., Balosso, S. & Ravizza, T. Neuroinflammatory pathways as treatment targets and biomarkers in epilepsy. Nat Rev Neurol 15, 459–472 (2019). https://doi.org/10.1038/s41582-019-0217-x
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