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IntroductionIt is known that symptoms of major depressive disorder (MDD) are associated with neurodegeneration, that lipopolysaccharide (LPS) can induce symptoms of MDD, and that blood LPS levels are elevated in neurodegeneration. However, it is not known whether blood LPS and cytokine levels correlate with MDD, cognition and brain structure, and this is tested in this study.Methods and analysisThis cross-sectional study includes individuals with MDD (n = 100) and a control group of individuals with no one-year history of a mental disorder (n = 50). A comprehensive evaluation is performed, including the collection of basic sociodemographic information, data on smoking status, body mass index, course of MDD, past treatment, comorbid diseases, and current use of medications. Diagnosis of MDD is performed according to the WHO's [2019] International Classification of Diseases and related health problems by psychiatrist and severity of MDD is evaluated using the Montgomery-Åsberg Depression Scale. The Cambridge Neuropsychological Test Automated Battery is used to evaluate cognitive functioning. Venous blood samples are taken to measure genetic and inflammatory markers, and multiparametric brain magnetic resonance imaging is performed to evaluate for blood-brain barrier permeability, structural and neurometabolic brain changes. Descriptive and inferential statistics, including linear and logistic regression, will be used to analyse relationships between blood plasma LPS and inflammatory cytokine concentrations in MDD patients and controls. The proposed sample sizes are suitable for identifying significant differences between the groups, according to a power analysis.Administrative informationTrial registration: Clinicaltrials.gov NCT06203015.

Abstract  The four gases, nitric oxide (NO), carbon monoxide (CO), hydrogen sulfide (H2S) and hydrogen cyanide (HCN) all readily inhibit oxygen consumption by mitochondrial cytochrome oxidase. This inhibition is responsible for much of their toxicity when they are applied externally to the body. However, recently these gases have all been implicated, to greater or lesser extents, in normal cellular signalling events. In this review we analyse the chemistry of this inhibition, comparing and contrasting mechanism and discussing physiological consequences. The inhibition by NO and CO is dependent on oxygen concentration, but that of HCN and H2S is not. NO and H2S are readily metabolised by oxidative processes within cytochrome oxidase. In these cases the enzyme may act as a physiological detoxifier of these gases. CO oxidation is much slower and unlikely to be as physiologically important. The evidence for normal physiological levels of these gases interacting with cytochrome oxidase is equivocal, in part because there is little robust data about their steady state concentrations. A reasonable case can be made for NO, and perhaps CO and H2S, inhibiting cytochrome oxidase in vivo, but endogenous levels of HCN seem unlikely to be high enough. [ABSTRACT FROM AUTHOR]