Natural Immunosuppressants as a Treatment for Chronic Insomnia Targeting the Inflammatory Response Induced by NLRP3/caspase-1/IL-1ß Axis Activation: A Scooping Review.

Chronic insomnia is an inflammatory-related disease with an important pathological basis for various diseases which is a serious threat to a person's physical and mental health. So far, many hypotheses have been proposed to explain the pathogenesis of insomnia, among which inflammatory mechanisms have become the focus of scientific attention. In this regard, the aim of the present scooping review is to evaluate the potential benefits of natural compounds in treatment of chronic insomnia targeting nucleotide-binding oligomerization domain (NOD)-like receptor-pyrin-containing protein 3 (NLRP3)/caspase-1/IL-1ß axis as one of the most important activators of inflammatory cascades. The data show that compounds that have the potential to cause inflammation induce sleep disorders, and that inflammatory mediators are key molecules in regulating the sleep-related activity of neurons. In the inflammatory process of insomnia, the role of NLRP3 in the pathogenesis of insomnia has been gradually considered by researchers. NLRP3 is an intracellular sensor that recognizes the widest range of pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs). After identification and binding to damage factors, NLRP3 inflammasome is assembled to activate the caspase-1 and IL-1ß. Increased production and secretion of IL-1ß may be involved in central nervous system dysregulation of physiological sleep. The current scooping review reports the potential benefits of natural compounds that target NLRP3 inflammasome pathway activity and highlights the hypothesis which NLRP3 /caspase-1/IL-1ß may serve as a potential therapeutic target for managing inflammation and improving symptoms in chronic insomnia.

Interleukin-1α and tumor necrosis factor α as an inducer for reactive-oxygen-species-mediated NOD-like receptor protein 1/NOD-like receptor protein 3 inflammasome activation in mononuclear blood cells from individuals with chronic insomnia disorder.

BACKGROUND AND PURPOSE: There is some evidence that cytokines may play an important role in sleep deprivation; however, the underlying mechanisms are still unknown. So, the present study aimed to evaluate the relationship between NOD-like receptor protein 1 (NLRP1) and NOD-like receptor protein 3 (NLRP3) inflammasome activation of blood cells and serum levels of cytokines in individuals with chronic insomnia disorder (CID). METHODS: Blood samples were collected from 24 individuals with CID and 24 healthy volunteers. The inflammasome activation was evaluated using real-time polymerase chain reaction of NLRP1, NLRP3, apoptosis-associated speck-like protein containing a caspase-recruitment domain (ASC) and caspase-1; western blot of NLRP1 and NLRP3; caspase-1 activity assay; and serum levels of interleukin-1ß (IL-1ß), IL-18 and other cytokines using enzyme-linked immunosorbent assay. Reactive oxygen species generation in blood cells were detected by flow cytometry assay. Also, magnetic resonance imaging scans were obtained on a Siemens Magnetom Avanto 1.5 T MRI whole-body scanner using an eight-channel head coil. RESULTS: Increased activity of NLRP1 and NLRP3 inflammasomes in blood cells, increased serum levels of pro-inflammatory cytokines and decreased serum levels of IL-10 and transforming growth factor ß in individuals with CID were found. Significant correlation was observed between increased serum concentration of IL-1ß and the severity of insomnia in individuals with CID. The levels of reactive oxygen species in blood cells were found to be correlated with IL-1α and tumor necrosis factor α concentrations in sera from individuals with CID. Moreover, the individuals with CID demonstrated increased right cerebellum cortex and lateral ventricle mean diffusivity bilaterally compared to controls. CONCLUSIONS: This study provided new insights on the pathogenesis of CID and the effects of cytokines on inflammasome activation.

IgLON5 autoimmunity tested positive in patients with isolated chronic insomnia disease.

In the patients with neurological autoimmune diseases such as anti-IgLON5 disease, insomnia symptoms are very common. Clinical diagnosis of the anti-IgLON5 disease is usually made when neurodegenerative processes have occurred. To find the early signs of anti-IgLON5 disease, we evaluate the presence of IgLON5 autoantibodies in the serum of patients with chronic insomnia disease. Based on video-polysomnography, 22 individuals with isolated chronic insomnia disease were found. A control group of 22 healthy people was chosen using the Pittsburgh Sleep Quality Index (PSQI). An indirect immunofluorescence cell-based test of serum anti-IgLON5 antibodies was used to investigate IgLON5 autoimmunity. Anti-IgLON5 antibodies were detected in the serum of four of these patients with the titer of 1/10. The presence of IgLON5 autoantibodies in some patients with chronic insomnia disease can be considered a causing factor of insomnia which can be effective in more specific treatments of these patients. Moreover, the recognition of anti-IgLON5 disease in the early stages and before the progression of tauopathies can be useful in effective and timely treatment.