Approches thérapeutiques des troubles du sommeil et des rythmes chez l’enfant avec TSA

Sleep disturbances are extremely common (40–86%) in children and adolescents, especially those with autism spectrum disorders (ASD) and are often among the first symptoms identified by parents at a very early stage of their child's development. These abnormalities are among the main parental concerns when having a child with ASD and have a significant impact on the quality of life of patients, their parents, and more broadly their siblings. Sleep disorders are essentially abnormalities of the sleep-wake rhythm – primarily sleep onset insomnia or nocturnal awakenings (with difficulty falling back to sleep). These disturbances can be accompanied by other sleep disorders, requiring notably a systematic elimination of the presence of a sleep apnea or restless legs syndrome – to ensure a personalized and efficient therapeutic approach. Physiologically, the determinants of these sleep disorders are poorly understood, even though several studies point to a significant decrease in melatonin synthesis in people with ASD. Melatonin is a hormone that facilitates falling asleep and maintaining sleep and is also involved in the endogenous synchronization of internal biological clocks. However, the causal factors of this decrease in melatonin synthesis are largely unknown, involving to a small extent the genes involved in melatonin synthesis pathway. The treatment of sleep disorders is relatively systematic: after eliminating other specific sleep disorders associated with the complaint of insomnia, as well as other possible associated comorbidities (such as seizures), a global and graduated therapeutic approach must be put in place. This treatment will be non-pharmacological as a first line, then pharmacological as a second line. A number of non-pharmacological treatment strategies for sleep disorders in typically developing children and adolescents, as well as those with ASD, have been shown to be effective. This treatment requires a combination of: 1) parental education to promote sleep development; 2) setting up bedtime rituals adapted to the child's age and particularities; 3) specific behavioral strategies including bedtime fading, gradual extinction and positive reinforcement of adapted behaviors. It is very essential that the parents are accompanied throughout this therapy. Sleep hygiene and behavioral care must also take into consideration the important role of the zeitgebers of sleep-wake rhythms, i.e. the external environmental factors involved in the synchronization of the biological clocks: regular exposure to light at adapted times, regular meal and wake-up times, social activities and times for going to school. The evidence for the effectiveness of behavioral interventions in the treatment of behavioral insomnia in the typical developmental child is strong, since 94% of children show clinically significant improvements in nighttime sleepiness and waking. By contrast, only about 25% of children with ASD are improved by an approach combining sleep hygiene and behavioral therapy. Melatonin has a special and prominent place in the drug management of sleep disorders associated with ASD. Several clinical trials have shown that melatonin is effective in treating sleep disorders in patients with ASD. This work led to the European Medicines Agency (EMA) granting marketing authorization in September 2018 for a sustained-release paediatric melatonin molecule (Slenyto®). This synthetic molecule is a prolonged release melatonin (PRM) which mimics the physiological pharmacokinetic and secretory characteristics of endogenous melatonin, having a very short blood half-life and prolonged secretion for several hours during the night. A recent study evaluated the efficacy and safety of pediatric PRM (mini-tablets) in 125 children, aged 2 to 17.5 years with mainly ASD. After 15 days on placebo, the children were randomized into two parallel groups, PRM or placebo in a double-blind design for 13 weeks. At endpoint, total sleep time was increased by an average of 57.5 minutes on PRM and only 9.14 minutes on placebo (P = 0.034). This difference between the two groups was already significant after three weeks of treatment (P = 0.006). Sleep latency was also improved in the PRM group (?39.6 minutes) compared to placebo (?12.51 minutes) (P = 0.01). Consolidated sleep duration (uninterrupted by awakenings) was improved by 77.9 minutes for the PRM group and only 25.4 minutes for the placebo group (P < 0.001). PRM was well tolerated, the most frequent side effects being headache and daytime drowsiness at the same level with PRM or placebo. In addition, the acceptability by the children for swallowing the mini-tablets was excellent (100% compliance). The efficacy and tolerability of PRM was maintained over the medium and long term in the open phase, over a total study duration of 2 years.     

Melatonin and Metformin Failed to Modify the Effect of Dacarbazine in Melanoma

Lessons Learned

• Melatonin did not increase the efficacy of systemic chemotherapy in melanoma.
• Metformin did not increase the efficacy of systemic chemotherapy in melanoma.

     

Circadian and circannual timescales interact to generate seasonal changes in immune function

Annual changes in day length enhance or suppress diverse aspects of immune function, giving rise to seasonal cycles of illness and mortality. The daily light–dark cycle also entrains circadian rhythms in immunity. Most published reports on immunological seasonality rely on measurements or interventions performed only at one point in the day. Because there can be no perfect matching of circadian phase across photoperiods of different duration, the manner in which these timescales interact to affect immunity is not understood. We examined whether photoperiodic changes in immune function reflect phenotypic changes that persist throughout the daily cycle, or merely reflect photoperiodic shifts in the circadian phase alignment of immunological rhythms. Diurnal rhythms in blood leukocyte trafficking, infection induced sickness responses, and delayed-type hypersensitivity skin inflammatory responses were examined at high-frequency sampling intervals (every 3 h) in Siberian hamsters (Phodopus sungorus) following immunological adaptation to summer or winter photoperiods. Photoperiod profoundly enhanced or suppressed immune function, in a trait-specific manner, and we were unable to identify a phase alignment of diurnal waveforms which eliminated these enhancing and suppressing effects of photoperiod. These results support the hypothesis that seasonal timescales affect immunity via mechanisms independent of circadian entrainment of the immunological circadian waveform.     

Melatonin Treatment Ameliorates Hyperhomocysteinemia-Induced Impairment of Erectile Function in a Rat Model

BackgroundHyperhomocysteinemia (HHcy) has been reported to be strongly correlated with the occurrence of erectile dysfunction (ED), but the mechanisms are not fully understood. Moreover, whether melatonin could be a potential treatment of HHcy-induced ED needs to be elucidated.AimThe aim of this study was to investigate the effects of melatonin on HHcy-induced ED and the potential mechanisms via modulating oxidative stress and apoptosis.MethodsThe Sprague-Dawley (SD) rat model of HHcy was induced by 7% methionine (Met)-rich diets. 36 male SD rats were randomly distributed into 3 groups (n = 12 per group): control group, 7% Met group, and 7% Met + melatonin (Mel; 10 mg/kg, intraperitoneal injection) treatment group. After 4 weeks, the erectile function of all rats was evaluated by electrical stimulation of the cavernous nerve. Histologic and molecular alterations of the corpus cavernosum were also analyzed by immunofluorescence, immunohistochemistry, enzyme-linked immunosorbent assay, Western blotting, and polymerase chain reaction.OutcomesHHcy-induced ED rat models were successfully established, and Mel could preserve erectile function mainly through inhibiting oxidative stress via the Erk1/2/Nrf2/HO-1 signaling pathway and suppression of apoptosis.ResultsErectile function was significantly reduced in the rats with HHcy compared with that in the control group and was ameliorated in the HHcy rats treated with Mel. Compared with the control group, the rats in the HHcy group showed the following: (1) higher levels of total plasma homocysteine; (2) fewer neuronal nitric oxide synthase-positive cells in the corpus cavernous; (3) higher levels of reactive oxygen species and malondialdehyde, higher expression levels of nicotinamide adenine dinucleotide phosphate oxidase, and lower activities of superoxide dismutase, indicating an overactivated oxidative stress; (4) lower expression levels of Erk1/2/Nrf2/HO-1 signaling pathway components; and (5) higher levels of apoptosis, as determined by the expression levels of Bax, Bcl-2, and caspase 3. Mel treatment improved the erectile response, as well as histologic and molecular alterations.Clinical TranslationOur study on a rodent model of HHcy provided evidence that Mel could be a potential therapeutic method for HHcy-related ED.ConclusionsMel treatment improves erectile function in rats with HHcy probably by potential antioxidative stress activity. This finding provides evidence for a potential new therapy for HHcy-induced ED.Tang Z, Song J, Yu, Z, et al. Melatonin Treatment Ameliorates Hyperhomocysteinemia-Induced Impairment of Erectile Function in a Rat Model. J Sex Med 2019;16:1506–1517.     

Pinealectomy Does Not Affect the Healing of Experimental Colonic Anastomoses

Gastrointestinal system anastomoses, especially colonic anastomoses, have significant morbidity and mortality despite recent technical improvements. Besides regulating the circadian rhythm, the pineal gland and its main neurohormone product melatonin have widespread actions in the organism. The purpose of this study was to investigate the effects of pinealectomy on the healing of colonic anastomoses. One hundred male albino Wistar rats were used in this study. The rats were separated into three groups: control, pinealectomy, and sham groups. In the control group, only colonic resection and anastomoses were performed. Following pinealectomy, colonic anastomosis was performed 2 weeks later on one half and 2 months later on the other half of the pinealectomy group. Only craniotomy was performed on the sham group, and the rats were separated and evaluated like the pinealectomy group. Colonic anastomoses were evaluated on postanastomotic day 3 and 7 by measuring the bursting pressure and the hydroxyproline levels in the anastomotic segments. There was no difference in the bursting pressure measurements between the groups on both postoperative day 3 and 7. Although hydroxyproline levels were different between groups on both postanastomotic days 3 and 7, it has been observed that neither normal nor anastomotic hydroxyproline levels influenced the anastomotic bursting pressure measurements. The percent deviation from the normal values was compared in the anastomotic segments, and no differences were found regarding the bursting pressure and hydroxyproline levels. It was concluded that pinealectomy has no effect on the healing of colonic anastomoses.     

Effects of Exogenous Melatonin on Myoglobinuric Acute Renal Failure in the Rats

Free oxygen radicals and nitric oxide (NO) play a crucial role in the pathogenesis of myoglobinuric acute renal failure (ARF). In this study, we aimed to investigate the effect of melatonin, a potent free radical scavenger, on the myoglobinuric ARF formed by injecting hypertonic glycerol intramuscularly (im). The rats were randomly divided into 4 Groups. Rats in Group 1 were given saline and those in Groups 2, 3, and 4 were injected with glycerol (10 mL/kg) im. Concomitant and 24 hours after glycerol injection Group 3 (5 mg/kg) and Group 4 (10 mg/kg) were administrated melatonin intraperitoneally. Forty‐eight hours after the glycerol injection, the blood and kidneys of the rats were taken under anesthesia. Kidney morphology and the levels of urea, creatinine and nitric oxide metabolites (NO_x) in the plasma and the enzyme activities of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) and the level of malondialdehyde (MDA) in the kidney were determined. In both groups of melatonin administration, there was no protective effect of melatonin. Moreover, melatonin significantly decreased the level of NO. As a result, we suggest that the decreasing effect of melatonin on NO, which is a strong vasodilatator, may further increase the renal ischemia in this model. Thus, melatonin may have worsening rather than beneficial effects on myoglobinuric ARF.