Neuroinflammation in epilepsy:opportunities for novel therapeutic targets: Dr Annamaria Vezzani

Epilepsy is a chronic neurological disease characterized by an enduring propensity to generate epileptic seizures. The pathogenic processes leading to the generation and recurrence of seizures are the subject of intensive investigations in both human epilepsy and animal models of the disease. Their identification would allow to design novel treatments apt to prevent the generation of epileptic seizures or for reducing seizure burden. These new treatments are urgently needed to fill the gaps in the development of preventative or disease-modifying interventions, and for controlling pharmaco-resistant seizures which affect about 30% of patients.

Neuroinflammation is a maladaptive response commonly ignited in human epileptogenic brain regions from structural epilepsies, as well as in animal models of the disease. Most recently, neuroinflammation has been described also in genetic epilepsy models. This brain response includes the biosynthesis and release of inflammatory mediators from brain parenchymal cells, chiefly by reactive glial cells and neurons. Inflammatory molecules are endowed of neuromodulatory properties by affecting neuronal ion channels activity and by promoting glial dysfunctions (Vezzani and Viviani, 2005; Vezzani et al, 2022). Neuroinflammation has been the focus of much attention for its involvement in the pathogenesis of seizures, neuronal cell loss and neurological comorbidities in animal models of epileptogenesis.

The elucidation of the complexity and dynamics of neuroinflammation in epilepsy has generated potential cellular and molecular targets for developing new drugs, or for repurposing available anti-inflammatory drugs, acting on key pathogenic mechanisms. This mechanistic approach to therapy should overcome the mere symptomatic control of seizures which is attained with the current medications.

Proof-of-concept clinical studies have shown that specific anti-inflammatory interventions reduce seizures in epilepsy patients who are resistant to current antiseizure medications (Vezzani et al, 2019; Lai et al, 2020).

Neuroinflammation also offers the possibility of discovering and validating potential biomarkers of epileptogenesis, as recently described in animal models and in proof-of-concept clinical studies (Vezzani et al, 2019; Vezzani et al, 2022).

• Lai, Y.-C., et al. (2020). Anakinra usage in febrile infection related epilepsy syndrome: an international cohort. Ann. Clin. Transl. Neurol. 7(12), 2467-2474. doi:10.1002/acn3.51229
• Vezzani, A. & Viviani, B. (2015). Neuromodulatory properties of inflammatory cytokines and their impact on neuronal excitability. Neuropharmacol. 70-82. doi:10.1016/j.neuropharm.2014.10.027
• Vezzani, A., Balosso, S. & Ravizza, T. (2019). Neuroinflammatory pathways as treatment targets and biomarkers in epilepsy. Nat. Rev. Neurol. 15(8), 459-472. doi:10.1038/s41582-019-0217-x
• Vezzani, A., Ravizza, T., Bedner, P., Aronica, E., Steinhäuser, C. & Boison, D. (2022). Astrocytes in the initiation and progression of epilepsy. Nat. Rev. Neurol. 18(12), 707-722. doi:10.1038/s41582-022-00727-5