Neuroinflammatory targets and treatments for epilepsy validated in experimental models

Abstract

A large body of evidence that has accumulated over the past decade strongly supports the role of inflammation in the pathophysiology of human epilepsy. Specific inflammatory molecules and pathways have been identified that influence various pathologic outcomes in different experimental models of epilepsy. Most importantly, the same inflammatory pathways have also been found in surgically resected brain tissue from patients with treatment-resistant epilepsy. New anti-seizure therapies may be derived from these novel potential targets. An essential and crucial question is whether targeting these molecules and pathways may result in anti-ictogenesis, anti-epileptogenesis and/or disease-modification effects. Therefore, preclinical testing in models mimicking relevant aspects of epileptogenesis is needed to guide integrated experimental and clinical trial designs. We discuss the most recent preclinical proof-of-concept studies validating a number of therapeutic approaches against inflammatory mechanisms in animal models that could represent novel avenues for drug development in epilepsy. Finally, we suggest future directions to accelerate preclinical to clinical translation of these recent discoveries.

Therapeutic effect of Anakinra in the relapsing chronic phase of febrile infection–related epilepsy syndrome

“…FIRES is a condition that may be sustained by brain inflammation, possibly as mirror focus of a systemic inflammatory response to a common infection in predisposed patients. In support, neuroinflammation in animal models is associated with long‐term reduction in seizure threshold together with lasting alterations of brain physiology and gene expression . Moreover, specific antiinflammatory drugs reduce ongoing seizures and inhibit epileptogenesis .…”

“…In support, neuroinflammation in animal models is associated with long-term reduction in seizure threshold together with lasting alterations of brain physiology and gene expression. 12,13 Moreover, specific antiinflammatory drugs reduce ongoing seizures and inhibit epileptogenesis. 13 Early brain biopsy is performed rarely, but it could help to clarify FIRES pathogenesis: as in our case, brain biopsy indicated a sustained activation of the innate immune response.…”

“…12,13 Moreover, specific antiinflammatory drugs reduce ongoing seizures and inhibit epileptogenesis. 13 Early brain biopsy is performed rarely, but it could help to clarify FIRES pathogenesis: as in our case, brain biopsy indicated a sustained activation of the innate immune response. Overproduction of proinflammatory cytokines and chemokines by microglia in FIRES could contribute to epileptogenesis.…”

Indoleamine 2,3‐dioxygenase 1 deletion promotes Theiler's virus–induced seizures in C57BL/6J mice

“…Subsequent up‐regulation of chemokines attract inflammatory monocytes to the CNS that contribute to neuronal death and seizure onset . Alternatively, cytokines and chemokines may interact with neurons and/or astrocytes to directly modulate synaptic activity . It is likely that there is no single molecular event that entirely accounts for the effects of neuroinflammation on seizure risk.…”

Glial source of nitric oxide in epileptogenesis: A target for disease modification in epilepsy

“…Several studies have shown that epileptogenesis could start as soon as the SE begins (Bumanglag and Sloviter, 2008; Sloviter, 2008; Loscher and Brandt, 2010). The hyperexcitability of neurons, manifested by epileptiform spiking, occurring during SE triggers series of overlapping molecular and cellular changes in the brain (Aronica et al, 2017; Barker-Haliski et al, 2017; Klee et al, 2017). In the rat and mouse kainate models, though the behavioral seizures stopped after the diazepam treatment, the electrographic seizures persisted for several hours (Fig.…”