The Significance of NLRP Inflammasome in Neuropsychiatric Disorders

Abstract

The NLRP inflammasome is a multi-protein complex which mainly consists of the nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain. Its activation is linked to microglial-mediated neuroinflammation and partial neuronal degeneration. Many neuropsychiatric illnesses have increased inflammatory responses as both a primary cause and a defining feature. The NLRP inflammasome inhibition delays the progression and alleviates the deteriorating effects of neuroinflammation on several neuropsychiatric disorders. Evidence on the central effects of the NLRP inflammasome potentially provides the scientific base of a promising drug target for the treatment of neuropsychiatric disorders. This review elucidates the classification, composition, and functions of the NLRP inflammasomes. It also explores the underlying mechanisms of NLRP inflammasome activation and its divergent role in neuropsychiatric disorders, including Alzheimer’s disease, Huntington’s disease, Parkinson’s disease, depression, drug use disorders, and anxiety. Furthermore, we explore the treatment potential of the NLRP inflammasome inhibitors against these disorders.

Alpha-Synuclein at the Interface between Depression, Parkinson’s Disease and Dementia: Evidence from Epidemiology, Population Genetics and Gene-Environment Interactions

“…The current study found evidence of significant associations between the prevalence of depressive disorders -major depressive disorder (MDD) and dysthymia -and the prevalence of both Alzheimer's disease and Parkinson's disease at a cross-national level. These results are consistent with existing research on the shared pathogenic mechanisms for these disorders [55][56][57][58], as well as with the results of longitudinal research in individual countries demonstrating a prospective link between depressive disorders and neuro-degenerative disorders [59][60][61][62]. Prior evidence suggests that the links between depression, Parkinson's disease and Alzheimer's disease are mediated by both genetic vulnerability [63][64][65] and exposure to environmental risk factors, such as stress and environmental toxins [66][67][68].…”

Inflammation, Autoinflammation and Autoimmunity in Inflammatory Bowel Diseases

“…In autoinflammatory diseases, the deregulated innate immune response to exogenous or endogenous danger signals triggers activation of the inflammasome, which typically determines the overactivation and release of IL-1 and IL-18 [105]. Autoinflammatory triggers include signals from damaged cells (danger associated molecular patterns-DAMPs), pathogen derived molecules, such as PAMPs, LPS and unmethylated CpG DNA, but also metabolites, such as glucose, free fatty acids, oxidized low-density lipoprotein (oxLDL), cholesterol crystals, uric acid crystals, ceramide, amyloid-β, α-synuclein and prion protein or superoxide dismutase [105,106]. PAMPs are recognized by the transmembrane and intracellular Pattern Recognition Receptors (PRRs), prototypes of the former and of the latter being the TLRs and the NOD-like receptor (NLR) family respectively [107].…”

The central role of the gut in intensive care

“…Indeed, the inflammasome binds pathogenassociated and/or danger-associated molecular patterns, specific molecular motifs carried by gut microorganisms. Thus, a perturbation of the GM composition could overstimulate the inflammasome and compromise the GBA homeostasis, promoting neuroinflammation as seen in multiple sclerosis [36], Alzheimer's disease [37], Parkinson's disease [38], neuropsychiatric disorders [39], and sepsis [25,26]. While no human studies are available, a recent preclinical study has shown how the GM plays a part in sepsis-associated encephalopathy by improving neurological outcomes when indole-3-propionic acid, a microbial neuroprotective metabolite, is produced, leading to the inhibition of NLRP3 inflammasome activation and IL-1β secretion in the microglia [26].…”