The NLRP3 Inflammasome in Neurodegenerative Disorders: Insights from Epileptic Models

Abstract

Neuroinflammation represents a dynamic process of defense and protection against the harmful action of infectious agents or other detrimental stimuli in the central nervous system (CNS). However, the uncontrolled regulation of this physiological process is strongly associated with serious dysfunctional neuronal issues linked to the progression of CNS disorders. Moreover, it has been widely demonstrated that neuroinflammation is linked to epilepsy, one of the most prevalent and serious brain disorders worldwide. Indeed, NLRP3, one of the most well-studied inflammasomes, is involved in the generation of epileptic seizures, events that characterize this pathological condition. In this context, several pieces of evidence have shown that the NLRP3 inflammasome plays a central role in the pathophysiology of mesial temporal lobe epilepsy (mTLE). Based on an extensive review of the literature on the role of NLRP3-dependent inflammation in epilepsy, in this review we discuss our current understanding of the connection between NLRP3 inflammasome activation and progressive neurodegeneration in epilepsy. The goal of the review is to cover as many of the various known epilepsy models as possible, providing a broad overview of the current literature. Lastly, we also propose some of the present therapeutic strategies targeting NLRP3, aiming to provide potential insights for future studies.

Metabolomic Profiling and In Vivo Antiepileptic Effect of Zygophyllum album Aerial Parts and Roots Crude Extracts against Pentylenetetrazole-Induced Kindling in Mice

“…NLRP3, the most classic inflammasome, is implicated in a wide range of pathologies including epilepsy with NLRP3 being the sensor protein, ASC being the adaptor protein and caspase-1 being the effector protein. It is activated by binding of TNF or IL-1β to different types of pattern recognition receptors (PRRs) including toll-like receptors (TLRs) and nucleotide-binding oligomerization domain (NOD), leucine-rich repeat (LRR)-containing protein receptors (NLRs) and cytokine receptors [ 69 ]. Such activation leads to enhanced transcription of NLRP3 and pro-IL-1β, oligomerization and auto-proteolytic maturation of pro-caspase-1 which cleaves pro-IL-1β and pro-IL-18 into their active forms [ 69 ].…”

“…It is activated by binding of TNF or IL-1β to different types of pattern recognition receptors (PRRs) including toll-like receptors (TLRs) and nucleotide-binding oligomerization domain (NOD), leucine-rich repeat (LRR)-containing protein receptors (NLRs) and cytokine receptors [ 69 ]. Such activation leads to enhanced transcription of NLRP3 and pro-IL-1β, oligomerization and auto-proteolytic maturation of pro-caspase-1 which cleaves pro-IL-1β and pro-IL-18 into their active forms [ 69 ]. In the same context, TXNIP links redox signaling with inflammasome activation as it dissociates from Trx in a reactive oxygen species (ROS)-sensitive manner and is allowed it to bind NLRP3 with subsequent inflammasome activation [ 11 , 70 ].…”

Neuroimmune response and oxidative stress in the prefrontal cortex mediate seizure susceptibility in experimental colitis in male mice

“…[ 4 ] Previous studies have determined that inflammasome NOD‐like receptor protein 3 (NLRP3) activated throughout seizures, producing IL‐1β. [ 5 ] In addition to neuroinflammation, oxidative stress in different areas of the brain, like prefrontal cortex (PFC), also has a role in the pathophysiology of seizures. [ 6 ]…”