Anti-Inflammatory Small Molecules To Treat Seizures and Epilepsy: From Bench to Bedside

Abstract

As a crucial component of brain innate immunity, neuroinflammation initially contributes to neuronal tissue repair and maintenance. However, chronic inflammatory processes within the brain and associated blood-brain barrier impairment often cause neurotoxicity and hyperexcitability. Mounting evidence points to a mutual facilitation between inflammation and epilepsy, suggesting that blocking the undesired inflammatory signaling within the brain might provide novel strategies to treat seizures and epilepsy. Neuroinflammation is primarily characterized by the upregulation of proinflammatory mediators in epileptogenic foci, among which, cyclooxygenase-2/prostaglandin E2, interleukin-1β, transforming growth factor-β, toll-like receptor 4, high-mobility group box 1, and tumor necrosis factor-α have been extensively studied. Small molecules that specifically target these key proinflammatory perpetrators have been evaluated for antiepileptic and antiepileptogenic effects in animal models. These important preclinical studies provide new insights into the regulation of inflammation in epileptic brains and guide drug discovery efforts aimed at developing novel anti-inflammatory therapies for seizures and epilepsy.

Inflammation in Epileptic Encephalopathies

“…Today, brain inflammation or neuroinflammation have been associated with many central nervous system (CNS) pathologies (Dey, Kang, Qiu, Du & Jiang 2016). Such processes may have beneficial effects, protecting against exogenous insults or promoting healing, but under certain situations they can be pathogenic.…”

“…Prior studies associated elevated levels of pro-inflammatory cytokines with seizures, the pathogenesis of epilepsy, and pathologies manifesting epilepsy (Table 1) (Vitaliti, Pavone, Mahmood, Nunnari & Falsaperla 2014). 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).…”

Novel Targets for Developing Antiseizure and, Potentially, Antiepileptogenic Drugs

“…Development of seizures and epilepsy in animal models and in humans following a variety of brain insults is correlated with neuroinflammation and increased expression of cytokines in brain (18). Cytokines can modulate neurotransmission by affecting the levels of excitatory and inhibitory neurotransmitters and their receptors, enzymes involved in the metabolism of neurotransmitters, and cellular signaling proteins (19).…”

Endothelial prostaglandin E2 regulates neuronal injury after seizure via activation of astrocytes

“…These findings indicate that astrocytic EP3 receptors may be upregulated under pathological conditions, and endothelial PGE 2 may directly activate EP3 receptors on astrocytic end-feet in neurotoxic brain diseases, such as epileptic seizures. PGE 2 also acts on other three receptors, namely EP1, EP2 and EP4, and activation of their receptors has been found to contribute to PGE 2 -mediated neurotoxicity 26 . Block of EP1 receptor reduces proinflammatory responses and neuronal damage in the hippocampus after KA injection in mice 27 .…”