Paediatric acute-onset neuropsychiatric syndrome (PANS) is a wide spectrum of disorders characterised by sudden onset of obsessive-compulsive disorder (OCD).
A particular subtype of PANS is considered the paediatric autoimmune neuropsychiatic disorders associated with streptococcal infections syndrome (PANDAS) that identifies patients with acute onset of OCD and/or tic disorders related to Group-A streptococcus infection.
This disease is characterized by a neuroinflammatory process that could be generated by increased oxidative stress. Animal studies in PANS/PANDAS models have hypothesized a damage to the vascular system underlying the neuroinflammation.
NADPH oxidase is one of the most important source of O2- in human. Oxidative stress generated by NADPH oxidase modulates endothelial function. Considering that
previous studies have shown gut dysbiosis in PANS/PANDAS subjects, the LPS generated by the gut microbiota could translocate into the circulation activating NADPH oxidase-2 and TLR-4 and generating endothelial dysfunction and vascular damage to the brain barrier.
No studies have been explored this issue. Thus, the objective of this study is to evaluate NADPH oxidase-2 (NOX2) activation by serum sNOX2-dp levels, as well as 8-iso-prostaglandin F2-alpha (8-iso-PGF2-alpha) and lipopolysaccharide (LPS) of PANS and PANDAS patients. Serum zonulin will be used as intestinal permeability assay. Furthermore, artery endotheliial dysfunction will be evaluated with flow-mediated dilation technique.
Ninety consecutive subjects, including 30 children affected by PANDAS and 30 with PANS and 30 controls matched for age and gender will be recruited.
The results of this research could increase the knowledge in this field evaluating the role of dysbiosis, NOX2 generated oxidative stress and endothelial dysfunction in patients with PANS and PANDAS that could be useful to plann future studies with probiotics or antioxidants to reduce the neurologic crisis of these patients.
NOX2 activation seems to be involved in the pathogenesis of psychotic disorders, as schizophrenia, leading to an imbalance of excitation and inhibition in cortical neural circuits. To the best of our knowledge, NOX2 activation and oxidative stress has never been studied in patients with PANS. This research project could be a continuation of an our previous report where we demonstrated that PANDAS subjects have high levels of sNOX2-dp and high levels of isoprostanes, suggesting an increased systemic oxidative stress derived from NOX2 activation in this neuropsychiatric disorder. Analyzing NOX2 activation in PANS could contribute to increase the knowledge in this field.
Previous studies identified dysbiosis in patients suffering from neurologic diseases and proposed the concept of "gut-brain-axis" as source of neuroinflammation. Recently, Quagliarello et al. showed that children affected by PANDAS also have gut dysbiosis. Furthermore, the same authors hypothesized that streptococcal infections alter gut microbiota and consequently lead to a proinflammatory state in the gut by selection of specific bacterial strains. Gram negative bacteria of gastro-intestinal tract secrete LPS that exerts pro-inflammatory actions on neurons. Animal studies showed that LPS increases neuroinflammation by NOX2 activation; however, the mechanism through which LPS damages the nervous system is unclear.
LPS has been hypothesized to have a pathogenetic role in PANS, although no study evaluated LPS serum levels in this neuropsychiatric disorder. Thus, to address this issue we studied LPS levels in PANS/PANDAS. Previously, we found that subjects affected by PANDAS disease have higher LPS levels that are linearly associated with sNOX2-dp levels and with isoprostanes. This association suggests a link between LPS and oxidative stress in PANDAS. However, no study in PANS has been performed.
To evaluate whether gut permeability can explain the LPS increase in PANS/PANDAS, we want to assess the circulating levels of zonulin, which modulate gut permeability by disassembling the intercellular tight junctions. Previous studies showed that zonulin up-regulation increases gut permeability.
Our study want assess serum levels of zonulin in PANS/PANDAS patients and its correlation with serum LPS that could provide the evidence that gut permeability is enhanced in this neuropsychiatric disorder and may be responsible for the increased circulating levels of LPS.
Finally, this research for the first time will analyze endothelial function in PANS/PANDAS. This will allow to understand if there is a link between intestinal dysbiosis, increase in circulating LPS, activation of NADPH oxidase and TLR-4 with consequent increase in oxidative stress and vascular damage; this latter influences neuroinflammation and the progression of this neuropsychiatric disease. If these expected results will be confirmed, future studies with probiotics or antioxidants could be planned to reduce LPS, NOX2 and improve endothelial dysfunction in subjects with PANS / PANDAS.
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