Modulation of neuronal excitability by immune mediators in epilepsy

Abstract

A complex set of inflammatory molecules and their receptors has been described in epileptogenic foci in different forms of pharmacoresistant epilepsies. By activating receptor-mediated pathways in neurons, these molecules have profound neuromodulatory effects that are distinct from their canonical activation of immune functions. Importantly, the neuromodulatory actions of some inflammatory molecules contribute to hyperexcitability in neural networks that underlie seizures. This review summarizes recent findings related to the role of cytokines (IL-1beta and TNF-alpha) and danger signals (HMGB1) in decreasing seizure threshold, thereby contributing to seizure generation and the associated neuropathology. We will discuss preclinical studies suggesting that pharmacological inhibition of specific inflammatory signals may be useful to treat drug-resistant seizures in human epilepsy, and possibly arrest epileptogenesis in individuals at risk of developing the disease.

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

“…Furthermore, systemic administration of VX-765 shows powerful anticonvulsant activity on acute seizures and in chronic epileptic mice that are refractory to conventional AEDs in a dose-dependent manner [90]. These results taken together strongly support that pharmacological inhibition of caspase-1 by selective small molecules represents a possible therapeutic strategy to suppress acute seizures and the development of epilepsy [13]. …”

“…In contrast to our historical understanding that the central nervous system (CNS) is immune-privileged due to tight constriction of the blood-brain barrier (BBB), inflammation within the brain – or neuroinflammation – has emerged as a salient feature in virtually all neurological conditions (Box 1), and been proposed to facilitate disease progression in the CNS (Box 2). Over the past decade, an increasing body of clinical and preclinical evidence points to the involvement of inflammation in the pathophysiology of acute brain insults and subsequent epileptogenesis, a process that a normal brain becomes epileptic (Box 2) [3–6], and anti-inflammatory therapeutics targeting crucial inflammatory components have been proposed to treat seizures and epilepsy [7–13]. In this review, we highlight our current understanding of neuroinflammation in epilepsy by focusing on recent preclinical efforts to develop anti-inflammatory therapies that block acute seizures and/or the development of epilepsy via selective small molecules.…”

“…These clinical observations clearly suggest that the immune and inflammatory processes are involved in some forms of epilepsy. It now becomes clear that proinflammatory mediators such as COX-2, PGE 2 , IL-1β, IL-6, HMGB1, TLR4, TNF-α, TGF-β and NOX2 play important roles in seizure generation and exacerbation [3, 13, 74, 132]. For instance, systemic inflammatory processes induced by fever in children can cause seizures and the proinflammatory cytokines such as IL-1β are believed to play crucial roles [170].…”

Inflammation, Glutamate, and Glia: A Trio of Trouble in Mood Disorders

“…Immune mediators such as TNF modulate functioning and vitality of gap junctions (Santello and Volterra, 2012;Takeuchi and Suzumura, 2014). The role of the immune-related gap junction pathology in propagating neural activity through rapid transfer of glutamate has been blamed for the rapid dissemination of seizure discharges and the resulting kindling effects seen seizure disorder (Iori et al, 2016;Vezzani and Viviani, 2015;Viviani and Boraso, 2011). Mood disorders are known to be associated with Cx pathology and this remains an ongoing area of investigation (Miguel-Hidalgo et al, 2014).…”

Persistent Protection against Pathology and Paroxysms by P2X7R Antagonism

“…Regrettably, TLE is also the most common form of refractory epilepsy; approximately 30 to 40 percent of patients do not respond to current drug options (2). Recently, greater attention has been placed on the potential role of inflammation in the pathogenesis of TLE and in promoting pharmacoresistance (3,4). A major player in inflammation is ATP, which can be released upon seizure activity in epileptogenic brain areas (5).…”