A perspective on "cure" for Rett syndrome

The reversal of the Rett syndrome disease process in the Mecp2 mouse model of Guy et al. (2007) has motivated families and researchers to work on this condition. The reversibility in adult mice suggests that there is potentially much to be gained from rational treatments applied to patients of any age. However, it may be difficult to strike the right balance between enthusiasm on the one hand and realism on the other. One effect of this has been a fragmentation of the “Rett syndrome community” with some groups giving priority to work aimed at a cure while fewer resources are devoted to medical or therapy-based interventions to enhance the quality of life of affected patients or provide support for their families. Several possible therapeutic approaches are under development that, it is claimed and hoped, may lead to a “cure” for patients with Rett syndrome. While all have a rationale, there are potential obstacles to each being both safe and effective. Furthermore, any strategy that succeeded in restoring normal levels of MECP2 gene expression throughout the brain carries potential pitfalls, so that it will be of crucial importance to introduce any clinical trials of such therapies with great care. Expectations of families for a radical, rational treatment should not be inflated beyond a cautious optimism. This is particularly because affected patients with us now may not be able to reap the full benefits of a “cure”. Thus, interventions aimed at enhancing the quality of life of affected patients should not be forgone and their importance should not be minimised

Delayed Ventricular Repolarization and Sodium Channel Current Modification in a Mouse Model of Rett Syndrome

Rett syndrome (RTT) is a severe developmental disorder that is strongly linked to mutations in the MECP2 gene. RTT has been associated with sudden unexplained death and ECG QT interval prolongation. There are mixed reports regarding QT prolongation in mouse models of RTT, with some evidence that loss of Mecp2 function enhances cardiac late Na current, I(Na,Late). The present study was undertaken in order to investigate both ECG and ventricular AP characteristics in the Mecp2(Null/Y) male murine RTT model and to interrogate both fast I(Na) and I(Na,Late) in myocytes from the model. ECG recordings from 8–10-week-old Mecp2(Null/Y) male mice revealed prolongation of the QT and rate corrected QT (QTc) intervals and QRS widening compared to wild-type (WT) controls. Action potentials (APs) from Mecp2(Null/Y) myocytes exhibited longer APD(75) and APD(90) values, increased triangulation and instability. I(Na,Late) was also significantly larger in Mecp2(Null/Y) than WT myocytes and was insensitive to the Nav1.8 inhibitor A-803467. Selective recordings of fast I(Na) revealed a decrease in peak current amplitude without significant voltage shifts in activation or inactivation V(0.5). Fast I(Na) ‘window current’ was reduced in RTT myocytes; small but significant alterations of inactivation and reactivation time-courses were detected. Effects of two I(Na,Late) inhibitors, ranolazine and GS-6615 (eleclazine), were investigated. Treatment with 30 µM ranolazine produced similar levels of inhibition of I(Na,Late) in WT and Mecp2(Null/Y) myocytes, but produced ventricular AP prolongation not abbreviation. In contrast, 10 µM GS-6615 both inhibited I(Na,Late) and shortened ventricular AP duration. The observed changes in I(Na) and I(Na,Late) can account for the corresponding ECG changes in this RTT model. GS-6615 merits further investigation as a potential treatment for QT prolongation in RTT

Carotid sinus denervation (CSD) ameliorates renovascular hypertension in adult Wistar rats

The peripheral chemoreflex is known to be hyper-responsive in both spontaneously hypertensive (SHR) and Goldblatt hypertensive (2 kidney 1 clip; 2K1C) rats. We have previously shown that carotid sinus nerve denervation (CSD) reduces arterial blood pressure (ABP) in SHR. Here, we show that CSD ameliorates 2K1C hypertension and reveal potential underlying mechanisms. Adult Wistar rats were instrumented to record ABP via telemetry, then underwent CSD (n = 9) or sham CSD (n = 9) five weeks after renal artery clipping, versus normal Wistar (n = 5). After 21 days renal function was assessed, and tissue collected to assess sympathetic postganglionic intracellular calcium transients ([Ca(2+) ]i ) and immune cell infiltrates. Hypertensive 2K1C rats showed a profound elevation in ABP (Wistar: 98 ± 4 mmHg vs. 2K1C: 147 ± 8 mmHg; P < 0.001), coupled with impairments in renal function and baroreflex sensitivity, increased neuro-inflammatory markers and enhanced [Ca(2+) ]I in stellate neurons (P < 0.05). CSD reduced ABP in 2K1C+CSD rats and prevented the further progressive increase in ABP seen in 2K1C+sham CSD rats, with a between-group difference of 14 ± 2 mmHg by Week 3 (P < 0.01), accompanied by improvements in both baroreflex control and spectral indicators of cardiac sympatho-vagal balance. Furthermore, CSD improved protein and albuminuria, decreased [Ca(2+) ]i evoked responses from stellate neurons, and reduced indicators of brainstem inflammation. In summary, CSD in 2K1C rats reduces the hypertensive burden and improves renal function. This may be mediated by improvements in autonomic balance, functional remodelling of post-ganglionic neurones and reduced inflammation. Our results suggest that the peripheral chemoreflex may be considered as a potential therapeutic target for controlling renovascular hypertension

Carotid body dysregulation contributes to Long COVID symptoms

Patients with long COVID suffer from breathlessness during exercise, leading to exercise intolerance. We know that SARSCoV-2, the virus that causes COVID-19, can infect carotid bodies which is a small sensory organ that sends signals to the brain for regulating breathing and blood pressure. This is called the carotid chemoreflex. However, itis not clear if SARS-CoV-2 infection affects carotid chemoreflex. Here, we examine whether the normal functioning of carotid chemoreflex is disrupted in non-hospitalised patients with long COVID and if this is linked to excessive breathing during exercise. Our study shows that carotid chemoreflex is more sensitive in long COVID patients, who areotherwise healthy. The carotid bodies could be a good therapeutic target for treating breathlessness in patients with long COVID

Comparison of the effects of fentanyls and other μ opioid receptor agonists on the electrical activity of respiratory muscles in the rat

Introduction: Deaths due to overdose of fentanyls result primarily from depression of respiration. These potent opioids can also produce muscle rigidity in the diaphragm and the chest muscles, a phenomenon known as Wooden Chest Syndrome, which further limits ventilation.Methods: We have compared the depression of ventilation by fentanyl and morphine by directly measuring their ability to induce muscle rigidity using EMG recording from diaphragm and external and internal intercostal muscles, in the rat working heart-brainstem preparation.Results: At equipotent bradypnea-inducing concentrations fentanyl produced a greater increase in expiratory EMG amplitude than morphine in all three muscles examined. In order to understand whether this effect of fentanyl was a unique property of the phenylpiperidine chemical structure, or due to fentanyl’s high agonist intrinsic efficacy or its lipophilicity, we compared a variety of agonists with different properties at concentrations that were equipotent at producing bradypnea. We compared carfentanil and alfentanil (phenylpiperidines with relatively high efficacy and high to medium lipophilicity, respectively), norbuprenorphine (orvinolmorphinan with high efficacy and lipophilicity) and levorphanol (morphinan with relatively low efficacy and high lipophilicity).Discussion: We observed that, agonists with higher intrinsic efficacy were more likely to increase expiratory EMG amplitude (i.e., produce chest rigidity) than agonists with lower efficacy. Whereas lipophilicity and chemical structure did not appear to correlate with the ability to induce chest rigidity

Brainstem respiratory networks:building blocks and microcircuits

Breathing movements in mammals are driven by rhythmic neural activity generated within spatially and functionally organized brainstem neural circuits comprising the respiratory central pattern generator (CPG). This rhythmic activity provides homeostatic regulation of gases in blood and tissues and integrates breathing with other motor acts. We review new insights into the spatial–functional organization of key neural microcircuits of this CPG from recent multidisciplinary experimental and computational studies. The emerging view is that the microcircuit organization within the CPG allows the generation of multiple rhythmic breathing patterns and adaptive switching between them, depending on physiological or pathophysiological conditions. These insights open the possibility for site- and mechanism-specific interventions to treat various disorders of the neural control of breathing