Inflammation Mediated Mechanisms in Epilepsy Disorders

Epilepsy is increasingly recognised as not only a disorder of neuronal hyperexcitability but also one driven by a cascade of inflammatory events. Activation of innate immune receptors such as Toll-like receptor 4 (TLR4) and interleukin-1 receptor 1 (IL-1R1) on glial cells and neurons leads to release of pro-inflammatory cytokines (for example IL-1β, TNF-α and HMGB1), disruption of the blood–brain barrier and recruitment of peripheral immune cells. Reactive microglia and astrocytes amplify these signals, promoting epileptogenesis, seizure recurrence and, in some cases, drug resistance. Peripheral lymphoid organs, including the spleen, can further modulate central neuroinflammation via lymphocyte trafficking. Together, these pathways underpin the bidirectional communication between the central nervous system and the systemic immune system, offering novel biomarker candidates and therapeutic targets to mitigate seizure initiation, propagation and long-term neuronal damage.

Research from Nature Portfolio

Recent experimental work has demonstrated that antibody-mediated neutralisation of HMGB1 markedly attenuates status epilepticus in rodent models. Treatment with an anti-HMGB1 monoclonal antibody preserved blood–brain barrier integrity, reduced translocation of HMGB1 from nuclei to extracellular space and down-regulated expression of MCP-1, CXCL-1, TLR4 and IL-6 in hippocampus and cortex. Concomitantly, glial activation and neuronal apoptosis were diminished, and the onset and severity of convulsive seizures were delayed. These findings support targeting HMGB1-driven signalling as a disease-modifying strategy in epilepsy.

Inflammation Mediated Mechanisms in Epilepsy Disorders publication trend

The graph below shows the total number of articles in inflammation mediated mechanisms in epilepsy disorders across all publications each year (not limited to Nature Index journals).

Technical terms

HMGB1: A nuclear protein released by stressed cells acting as a damage-associated molecular pattern that activates innate immune receptors.

Toll-like receptor 4 (TLR4): A pattern-recognition receptor on microglia and endothelial cells that senses DAMPs and initiates inflammatory signalling.

Interleukin-1β (IL-1β): A pro-inflammatory cytokine released by activated glia that enhances neuronal excitability and blood–brain barrier permeability.

Blood–brain barrier (BBB): A selective vascular interface whose integrity is critical to prevent infiltration of circulating immune cells and inflammatory mediators.

Microglia: The resident immune cells of the central nervous system that orchestrate inflammatory responses and phagocytic clearance.

Astrogliosis: The reactive change in astrocytes characterised by hypertrophy, proliferation and release of cytokines contributing to neuronal dysfunction.

References

1. Therapeutic effects of anti-HMGB1 monoclonal antibody on pilocarpine-induced status epilepticus in mice. Scientific Reports (2017).
2. Participation of the spleen in the neuroinflammation after pilocarpine-induced status epilepticus: implications for epileptogenesis and epilepsy. Clinical Science (2024).
3. A Systematic Review of the Predictive and Diagnostic Uses of Neuroinflammation Biomarkers for Epileptogenesis. International Journal of Molecular Sciences (2024).
4. Role of HMGB1/TLR4 and IL-1β/IL-1R1 Signaling Pathways in Epilepsy. Frontiers in Neurology (2022).