Immunity Activation in Brain Cells in Epilepsy: Mechanistic Insights and Pathological Consequences

Abstract

The search of targets for developing novel drugs that can control seizures resistant to available treatments in children and adults represents a great challenge for basic science. In the past decade, emerging evidence pointed out to the crucial role played by glia, the innate immunity brain-resident cells, in the generation of hyperexcitable neuronal networks underlying seizures. Molecular and pharmacological studies targeting glia, and the inflammatory mediators released by these cells in experimental models of epilepsy, highlighted novel targets for drug intervention aimed at interfering with the disease mechanisms, therefore providing putative disease-modifying treatments. This article will focus on the role of immunity activation in the brain and the concomitant release by glia of inflammatory molecules with neuromodulatory properties, in the pathogenesis of epileptic seizures, cell loss, and comorbidities.

Inflammation in Epileptic Encephalopathies

“…Recent studies have introduced the neurological sequelae, in which pro-inflammatory cytokines with proictogenic properties (such as IL-1β, high-mobility group box 1 [HMGB1], cyclooxygenase-2 [COX-2], prostaglandin E2 [PGE2], IL-6, TNF-α and nicotinamide adenine dinucleotide phosphate-oxidase [NOX2]) play an important role in seizure generation and exacerbation (Vezzani, Auvin, Ravizza & Aronica 2012, Wu & Huang 2015, Dey, Kang, Qiu, Du & Jiang 2016). IL-1β and HMGB1 induce the proinflammatory innate immunity IL-1 receptor type 1 (IL-1R1)/toll-like receptor 4 (TLR4) signaling (Ravizza, Kostoula & Vezzani 2013, Vezzani, Lang & Aronica 2016) leading to neuroinflammation, its perpetuation and thus modulating seizure susceptibility, lowering seizure threshold and epileptogenesis (Maroso, Balosso, Ravizza, Liu, Aronica, Iyer et al 2010, Riazi, Galic & Pittman 2010, Vitaliti, Pavone, Mahmood, Nunnari & Falsaperla 2014, Vezzani, Lang & Aronica 2016). …”

“…Each TLR family member, with the exception of TLR3, signals through the MyD88-dependent pathway, initiated by the MyD88 adaptor protein, resulting in the activation of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) (a mediator of acute inflammation (Lawrence 2009)), mammalian target of rapamycin (mTOR) (central pathway, involved in regulation of multiple processes including inflammation (Galanopoulou 2013)) and generation of the pro-inflammatory cytokines, such as IL-6 and tumor necrosis factor alpha (TNF-α) (Takeda & Akira 2004, Wang, Lin & Yang 2011, Ravizza, Kostoula & Vezzani 2013). This evidence arose from surgically resected epileptic tissues of adult and pediatric patients with epilepsy showing the presence of inflammatory molecules in activated glial cells, neurons and endothelial cells of the blood-brain barrier (BBB) and indicating the strong link between inflammation and seizures (Crespel, Coubes, Rousset, Brana, Rougier, Rondouin et al 2002, Ravizza, Boer, Redeker, Spliet, van Rijen, Troost et al 2006, Aronica, Boer, van Vliet, Redeker, Baayen, Spliet et al 2007, Ravizza, Gagliardi, Noe, Boer, Aronica & Vezzani 2008, Maroso, Balosso, Ravizza, Liu, Aronica, Iyer et al 2010, Vezzani, French, Bartfai & Baram 2011, Zurolo, Iyer, Maroso, Carbonell, Anink, Ravizza et al 2011, Balosso, Ravizza, Aronica & Vezzani 2013, Iori, Maroso, Rizzi, Iyer, Vertemara, Carli et al 2013, Pernhorst, Herms, Hoffmann, Cichon, Schulz, Sander et al 2013).…”

Mechanisms of Epileptogenesis in Pediatric Epileptic Syndromes: Rasmussen Encephalitis, Infantile Spasms, and Febrile Infection-related Epilepsy Syndrome (FIRES)

“…A major challenge for the future is to discover specific biomarkers of disease and pathogenesis detectable in CSF and/or serum. This might highlight novel targets for drug intervention aimed at interfering with the disease mechanisms, therefore providing putative diseasemodifying treatments [156].…”

A Hypothesis Regarding the Molecular Mechanism Underlying Dietary Soy-Induced Effects on Seizure Propensity

“…Finally, substantial evidence suggests that activation of the immune system is associated with epilepsy (115, 116), and consumption of soy and soy phytoestrogens is associated with activation of the immune system. Specifically, soy-based diets alter cytokine production through an ERα-dependent pathway (117).…”