Title:Inflammation and Epilepsy: Preclinical Findings and Potential Clinical Translation
Volume: 23
Issue: 37
Author(s): Gaetano Terrone, Alessia Salamone and Annamaria Vezzani*
Affiliation:
- Department of Neurosciene, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", via G. La Masa 19, 20123 Milano,Italy
Keywords:
Anti-epileptogenesis, animal models of epilepsy, disease-modification, glia, immunity, neuroinflammation, pharmaco-resistant
epilepsy.
Abstract: Background: The lack of treatments which can prevent epilepsy development or improve disease
prognosis represents an unmet and urgent clinical need. The development of such drugs requires a deep understanding
of the mechanisms underlying disease pathogenesis. In the last decade, preclinical studies in models of
acute seizures and of chronic epilepsy highlighted that neuroinflammation arising in brain areas of seizure onset
and generalization is a key contributor to neuronal hyper-excitability underlying seizure generation. Microglia
and astrocytes are pivotal cells involved in both the induction and perpetuation of the inflammatory response to
epileptogenic injuries or seizures; other cell contributors are neurons, cell components of the blood brain barrier
and leukocytes.
Methods: From the clinical standpoint, neuroinflammation is now considered an hallmark of epileptogenic foci in
various forms of focal onset pharmacoresistant epilepsies. Moreover, pharmacological studies in animal model
with drugs targeting specific inflammatory molecules, and changes in intrinsic seizure susceptibility of transgenic
mice with perturbed neuroinflammatory mechanisms, have demonstrated that neuroinflammation is not a bystander
phenomenon but has a pathogenic role in seizures, cell loss and neurological co-morbidities.
Understanding the role of neuroinflammation in seizure pathogenesis is instrumental for a mechanism-based
discovery of selective therapies targeting the epilepsy causes rather than its symptoms, thereby allowing the development
of novel disease-modifying treatments. Notably, clinical translation of laboratory findings may take
advantage of anti-inflammatory drugs already in medical use for peripheral autoinflammatory or autoimmune
disorders.
Conclusion: This review reports key preclinical and clinical findings supporting a role for brain inflammation in
the pathogenesis of seizures. It also highlights the emerging proof-of-concept studies showing signs of clinical
efficacy of target-specific anti-inflammatory interventions in epilepsies of differing etiologies. We will discuss
the need for biomarkers and novel clinical trial designs for anti-inflammatory therapies that have a mechanism of
action very different than standard antiepileptic drugs.
