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Dyspnea is the symptom that conveys the upsetting or distressing awareness of respiratory sensations. It is part of an ensemble of respiratory, neurovegetative, and behavioral manifestations resulting from the brain's reaction to abnormal respiratory-related afferents. This attests to a systemic phenomenon and suggests the existence of measurable biological changes. Different types of experimental respiratory challenges evoke different perceptual, physiological and psychological responses, suggesting distinct mechanisms and the possibility of varied systemic biological responses. We investigated this hypothesis in 34 healthy volunteers (17 women) exposed to inspiratory threshold loading (ITL) and carbon dioxide stimulation with restricted ventilation (CO2-rv), in a randomized cross-over design. Blood and saliva samples were collected at baseline (T0), at the end of a 5-minute dyspnea challenge (T1), and at 30 and 60 minutes post-challenge (T2 and T3). They were analyzed for neuromodulators and inflammatory biomarkers. Substance P levels rose at all time points during both challenges, but were significantly higher after CO2-rv than after ITL. β-endorphin levels rose similarly after both challenges, with a correlation to affective dyspnea ratings during ITL only (R=0.527, p=0.0023). Brain-derived neurotrophic factor (BDNF) decreased after both stimuli, with lower values following ITL. There were no significant changes in salivary alpha-amylase, FGF-2, TNF-α, IL-1β, IL-8, or IDO/TDO activity, and salivary cortisol decreased. These results provide a biological substrate for the differences between responses to respiratory challenges. They open new avenues toward biology-guided research into respiratory-related brain suffering. Show less

Extended periods of microgravity during orbital flights can impair astronauts' cognitive abilities, including learning and memory, posing a persistent health concern in the field of aerospace medicine. The study examined the pharmacological effects of agmatine and its influence on simulated neurobehavioral changes in rats under microgravity conditions. Rats were exposed to simulated microgravity (SMG) conditions using the hindlimb unloading (HU) model for 28 days and evaluated for behavioural alterations using the open field test, elevated plus maze, and forced swim test, and cognitive deficits using the novel object recognition test and Morris water maze. Further, brain agmatine levels, neurochemical and structural alterations in the hippocampus, and prefrontal cortex were examined. Chronic agmatine treatment dose-dependently (40 and 80mg/kg) and its endogenous modulation by l-arginine, and aminoguanidine prevented behavioral and cognitive deficits by improving exploratory behaviour, reducing anxiety-depressive-like symptoms, and enhancing cognitive performance. Our findings reported a significant reduction in agmatine levels in the hippocampus and prefrontal cortex in SMG conditions. Agmatine administration and its modulation normalized neurotransmitter imbalances, especially by restoring the reduced levels of gamma-aminobutyric acid, dopamine, and serotonin, along with a reduction of elevated levels of glutamate in SMG conditions. Moreover, agmatine decreased reactive oxygen species production, enhanced hippocampal antioxidant enzyme activities, suppressed pro-inflammatory cytokines (TNF-α, IL-6), and improved IL-10 and brain-derived neurotrophic factor levels in HU rats. Moreover, agmatine and its endogenous modulation preserved neuronal cells of the hippocampus and prefrontal cortex. In conclusion, the present study suggests that agmatine administration and modulation of endogenous agmatine levels effectively mitigate SMG-induced neurological dysregulation through neuroprotection and neuromodulation. Understanding the neurobiological mechanisms underlying these effects opens up new possibilities for creating novel interventions targeting agmatinergic signaling in spaceflight conditions and associated complications. Show less