Cerebral Erythropoietin Prevents Sex-Dependent Disruption of Respiratory Control Induced by Early Life Stress

Injuries that occur early in life are often at the root of adult illness. Neonatal maternal separation (NMS) is a form of early life stress that has persistent and sex-specific effects on the development of neural networks, including those that regulate breathing. The release of stress hormones during a critical period of development contributes to the deleterious consequences of NMS, but the role of increased corticosterone (CORT) in NMS-induced respiratory disturbance is unknown. Because erythropoietin (EPO) is a potent neuroprotectant that prevents conditions associated with hyperactivation of the stress neuroaxis in a sex-specific manner, we hypothesized that EPO reduces the sex-specific alteration of respiratory regulation induced by NMS in adult mice. Animals were either raised under standard conditions (controls) or exposed to NMS 3 h/day from postnatal days 3–12. We tested the efficacy of EPO in preventing the effects of NMS by comparing wild-type mice with transgenic mice that overexpress EPO only in the brain (Tg21). In 7-days-old pups, NMS augmented CORT levels ~2.5-fold by comparison with controls but only in males; this response was reduced in Tg21 mice. Respiratory function was assessed using whole-body plethysmography. Apneas were detected during sleep; the responsiveness to stimuli was measured by exposing mice to hypoxia (10% O2; 15 min) and hypercapnia (5% CO2; 10 min). In wild-type, NMS increased the number of apneas and the hypercapnic ventilatory response (HcVR) only in males; with no effect on Tg21. In wild-type males, the incidence of apneas was positively correlated with HcVR and inversely related to the tachypneic response to hypoxia. We conclude that neural EPO reduces early life stress-induced respiratory disturbances observed in males.

The Implication of Low Dose Dimethyl Sulfoxide on Mitochondrial Function and Oxidative Damage in Cultured Cardiac and Cancer Cells

Although numerous studies have demonstrated the biological and multifaceted nature of dimethyl sulfoxide (DMSO) across different in vitro models, the direct effect of “non-toxic” low DMSO doses on cardiac and cancer cells has not been clearly explored. In the present study, H9c2 cardiomyoblasts and MCF-7 breast cancer cells were treated with varying concentrations of DMSO (0.001–3.7%) for 6 days. Here, DMSO doses < 0.5% enhanced the cardiomyoblasts respiratory control ratio and cellular viability relative to the control cells. However, 3.7% DMSO exposure enhanced the rate of apoptosis, which was driven by mitochondrial dysfunction and oxidative stress in the cardiomyoblasts. Additionally, in the cancer cells, DMSO (≥0.009) led to a reduction in the cell’s maximal respiratory capacity and ATP-linked respiration and turnover. As a result, the reduced bioenergetics accelerated ROS production whilst increasing early and late apoptosis in these cells. Surprisingly, 0.001% DMSO exposure led to a significant increase in the cancer cells proliferative activity. The latter, therefore, suggests that the use of DMSO, as a solvent or therapeutic compound, should be applied with caution in the cancer cells. Paradoxically, in the cardiomyoblasts, the application of DMSO (≤0.5%) demonstrated no cytotoxic or overt therapeutic benefits.

New method to measure interbreath intervals in infants for the assessment of apnoea and respiration

BackgroundRespiratory disorders, including apnoea, are common in preterm infants due to their immature respiratory control compared with term-born infants. However, our inability to accurately measure respiratory rate in hospitalised infants results in unreported episodes of apnoea and an incomplete picture of respiratory activity.MethodsWe develop, validate and use a novel algorithm to identify interbreath intervals (IBIs) and apnoeas in preterm infants. In 42 preterm infants (1600 hours of recordings), we assess IBIs from the chest electrical impedance pneumograph using an adaptive amplitude threshold for the detection of breaths. The algorithm is refined by comparing its accuracy with clinically observed breaths and pauses in breathing. We develop an automated classifier to differentiate periods of true apnoea from artefactually low amplitude signal. We assess the performance of this algorithm in the detection of morphine-induced respiratory depression. Finally, we use the algorithm to investigate whether retinopathy of prematurity (ROP) screening alters the IBI distribution.ResultsIndividual breaths were detected with a false-positive rate of 13% and a false-negative rate of 12%. The classifier identified true apnoeas with an accuracy of 93%. As expected, morphine caused a significant shift in the IBI distribution towards longer IBIs. Following ROP screening, there was a significant increase in pauses in breathing that lasted more than 10 s (t-statistic=1.82, p=0.023). This was not reflected by changes in the monitor-derived respiratory rate and no episodes of apnoea were recorded in the medical records.ConclusionsWe show that our algorithm offers an improved method for the identification of IBIs and apnoeas in preterm infants. Following ROP screening, increased respiratory instability can occur even in the absence of clinically significant apnoeas. Accurate assessment of infant respiratory activity is essential to inform clinical practice.

Respiratory disorders of Parkinson's Disease

Parkinson's disease (PD) is characterized by the progressive loss of dopaminergic neurons in the substantia nigra, mainly affecting people over 60 years of age. Patients develop both classic symptoms (tremors, muscle rigidity, bradykinesia and postural instability) and nonclassical symptoms (orthostatic hypotension, neuropsychiatric deficiency, sleep disturbances and respiratory disorders). Thus, patients with PD can have a significantly impaired quality of life, especially when they do not have multi-modality therapeutic follow-up. The respiratory alterations associated with this syndrome are the main cause of mortality in PD. They can be classified as peripheral when caused by disorders of the upper airways or muscles involved in breathing and as central when triggered by functional deficits of important neurons located in the brainstem and involved in respiratory control. Currently, there is little research describing these disorders, and therefore, there is no well-established knowledge about the subject, making the treatment of patients with respiratory symptoms difficult. In this review, the history of the pathology and data about the respiratory changes in PD obtained thus far will be addressed.

Respiration modulates oscillatory neural network activity at rest

Despite recent advances in understanding how respiration affects neural signalling to influence perception, cognition, and behaviour, it is yet unclear to what extent breathing modulates brain oscillations at rest. We acquired respiration and resting state magnetoencephalography (MEG) data from human participants to investigate if, where, and how respiration cyclically modulates oscillatory amplitudes (2 to 150 Hz). Using measures of phase–amplitude coupling, we show respiration-modulated brain oscillations (RMBOs) across all major frequency bands. Sources of these modulations spanned a widespread network of cortical and subcortical brain areas with distinct spectrotemporal modulation profiles. Globally, delta and gamma band modulations varied with distance to the head centre, with stronger modulations at distal (versus central) cortical sites. Overall, we provide the first comprehensive mapping of RMBOs across the entire brain, highlighting respiration–brain coupling as a fundamental mechanism to shape neural processing within canonical resting state and respiratory control networks (RCNs).

Sleep Pathophysiology

Sleep is a natural, reversible, and periodic behavioral state characterized by perceptual inattention and decreased responsiveness to external stimuli. The processes governing sleep, sleep-wake transitions, and maintenance of wakefulness are mediated by complex physiologic mechanisms, the primary neurobiological substrates of which include the neocortex, basal forebrain, thalamus, hypothalamus, pontine tegmentum, and brainstem monoaminergic nuclei. Moreover, the integrity of brainstem autonomic respiratory control networks becomes critical in the maintenance of ventilation during sleep. Pathologic insults to these systems may result in a broad constellation of clinical deficits.

Nandrolone Decanoate supplementation promotes AMPK activation and divergent brain connectivity rearrangements in adult and aged mice.

Abnormalities in energetic and proteic homeostasis during ageing relate to neurodegenerative diseases. The mitochondria are a hub of oxidative metabolism, influencing autophagic flux. Ageing can lead to a functional disruption of these systems, leading to neuroenergetic and proteotoxic imbalance. Lower levels of testosterone have been proposed as a mechanism accelerating functional decline during ageing. In this study we investigated whether nandrolone decanoate (ND), an analog of testosterone, in aged animals improves mitochondrial bioenergetics and autophagy. Albino CF1 mice of 3 and 18 months of age, were separated in 4 groups that received daily subcutaneous injections for 15 days of either ND (15mg/kg), or vehicle. Were performed baseline and 14th day 18FDG uptake analysis, through positron emission tomography scan. High resolution respirometry was performed to assess functionally mitochondrial respiratory states and respiratory control ratio (RCR) in synaptossomes fractions. Also, hypothalamic immunocontent of AMPK, pAMPKT172, Beclin-1 and BCL-2 LC3 was assessed. Results demonstrate that aged animals did not display alterations nor in 18FDG uptake, neither in mitochondrial respiratory states. Also, aged mice displayed reduced pAMPKT172/ AMPK ratio, and increased LC3-II compared to adult controls. Curiously, ND in aged mice did neither increase 18FDG uptake, nor alter mitochondrial states. Albeit, ND increased pAMPKT172/ AMPK ratio, LC3-II turnover, as well as increased RCR. This suggest that ageing does not culminate necessarily in bioenergetics alterations in brain, although biomarkers of energetic status and autophagy are reduced. ND improved bioenergetic efficiency and autophagy in aged mice. These benefits are probably mediated by reprogramation of AMPK signalling.

Effect of Melatonin Administration on Mitochondrial Activity and Oxidative Stress Markers in Patients with Parkinson’s Disease

Mitochondrial dysfunction and oxidative stress are extensively linked to Parkinson’s disease (PD) pathogenesis. Melatonin is a pleiotropic molecule with antioxidant and neuroprotective effects. The aim of this study was to evaluate the effect of melatonin on oxidative stress markers, mitochondrial complex 1 activity, and mitochondrial respiratory control ratio in patients with PD. A double-blind, cross-over, placebo-controlled randomized clinical trial study was conducted in 26 patients who received either 25 mg of melatonin or placebo at noon and 30 min before bedtime for three months. At the end of the trial, in patients who received melatonin, we detected a significant diminution of lipoperoxides, nitric oxide metabolites, and carbonyl groups in plasma samples from PD patients compared with the placebo group. Conversely, catalase activity was increased significantly in comparison with the placebo group. Compared with the placebo group, the melatonin group showed significant increases of mitochondrial complex 1 activity and respiratory control ratio. The fluidity of the membranes was similar in the melatonin group and the placebo group at baseline and after three months of treatment. In conclusion, melatonin administration was effective in reducing the levels of oxidative stress markers and restoring the rate of complex I activity and respiratory control ratio without modifying membrane fluidity. This suggests that melatonin could play a role in the treatment of PD.