Orexins, also known as hypocretins, are two neuropeptides secreted from orexin-containing neurons, mainly in the lateral hypothalamus (LH). Orexins orchestrate their effects by binding and activating two G-protein-coupled receptors (GPCRs), orexin receptor type 1 (OX1R) and type 2 (OX2R). Orexin/receptor pathways play vital regulatory roles in many physiological processes, especially feeding behavior, sleep-wake rhythm, reward and addiction and energy balance. Furthermore several reports showed that orexin/receptor pathways are involved in pathological processes of neurological diseases such as narcolepsy, depression, ischemic stroke, drug addiction and Alzheimer's disease (AD). This review article summarizes the expression patterns, physiological functions and potential molecular mechanisms of the orexin/receptor system in neurological diseases, providing an overall framework for considering these pathways from the standpoints of basic research and clinical treatment of neurological diseases.

/pdf/the-orexin-receptor-system-molecular-mechanism-and-77yr5i3hk6.pdf

The Orexin/Receptor System: Molecular Mechanism and Therapeutic Potential for Neurological Diseases.

Mood disorders are amongst the most prevalent and severe disorders worldwide, with a tendency to be recurrent and disabling. Although multiple mechanisms have been hypothesized to be involved in their pathogenesis, just a few integrative theoretical frameworks have been proposed and have yet to integrate comprehensively all available findings. As such, a comprehensive framework would be quite useful from a clinical and therapeutic point of view in order to identify elements to evaluate and target in the clinical practice. Because conditions of sleep loss, which include reduced sleep duration and insomnia, are constant alterations in mood disorders, the aim of this paper was to review the literature on their potential role in the pathogenesis of mood disorders and to propose a novel theoretical model. According to this hypothesis, sleep should be considered the main regulator of several systems and processes whose dysregulation is involved in the pathogenesis of mood disorders. The model may help explain why sleep disturbances are so strikingly linked to mood disorders, and underscores the need to evaluate, assess and target sleep disturbances in clinical practice, as a priority, in order to prevent and treat mood disorders.

https://onlinelibrary.wiley.com/doi/epdf/10.1111/jsr.12841

The key role of insomnia and sleep loss in the dysregulation of multiple systems involved in mood disorders: A proposed model

Multiple Acyl-CoA dehydrogenation deficiency (MADD) is an autosomal recessive disorder of fatty acid oxidation and amino-acid metabolism. Most patients with late-onset MADD are well responsive to treatment with riboflavin, which is also termed as riboflavin-responsive MADD (RR-MADD). In this study, we summarized the clinical profiles and genetic features of 13 Chinese patients with RR-MADD and reanalyzed the existing data on RR-MADD patients in Mainland China. In a cohort comprising 13 patients, all were seen to present with severe muscular symptoms occasionally accompanied with mild involvements of extramuscular organs. A total of 18 mutations (13 reported and 5 novel) of the ETFDH gene were identified in this series of patients. Exon deletion/duplication was not found in all patients. ETF:QO expression from the muscle specimens was significantly decreased in all patients. At the time of this study the total number of RR-MADD cases had reached 148 in Mainland China since 2009. The muscle symptoms in Mainland China were similar to those in other regions. However, the common extramuscular symptoms were fatty liver and recurrent vomiting in mainland Chinese patients rather than encephalopathy found in Caucasian patients. A total of 68 mutations had been identified in 148 patients with RR-MADD. The c.250G>A had a high mutation frequency in Southern China, whereas c.770A>G and c.1227A>C were more geographically widespread hot spot mutations in Mainland China.

Riboflavin-responsive multiple Acyl-CoA dehydrogenation deficiency in 13 cases, and a literature review in mainland Chinese patients

Study Objectives: To assess potential effects of lemborexant on next-morning driving performance in adult and elderly healthy volunteers. Methods: Randomized, double-blind, double-dummy, placebo and active-controlled, four period incomplete crossover study in 48 healthy volunteers (22 females), 23-78 years old. Participants were treated at bedtime for 8 consecutive nights with 2 of 3 dose levels of lemborexant (2.5, 5, or 10 mg), zopiclone 7.5 mg (on the first and last night with placebo on intervening nights), or placebo. Driving performance was assessed in the morning on day 2 and 9 using a standardized highway driving test in normal traffic, measuring standard deviation of lateral position (SDLP). Drug-placebo differences in SDLP > 2.4 cm were considered to reflect clinically meaningful driving impairment. Results: Mean drug-placebo differences in SDLP following lemborexant 2.5, 5, and 10 mg on day 2 and 9 were 0.74 cm or less. The upper bound of the 95% confidence intervals (CIs) for lemborexant treatment groups were all below 2.4 cm and the 95% CIs included zero, indicating that the effects were neither clinically meaningful nor statistically significant. Symmetry analysis further supported the lack of clinically meaningful impairment with lemborexant. Conclusions: When assessed starting ~9 h after lemborexant administration at bedtime the previous night, there was no statistically significant or clinically meaningful effect on driving performance in healthy adults and elderly, as assessed by either mean differences in SDLP relative to placebo or symmetry analysis. In this study, lemborexant at doses up to 10 mg was well-tolerated.

On-the-road driving performance the morning after bedtime administration of lemborexant in healthy adult and elderly volunteers

Short sleep duration and poor sleep quality are associated with cardiovascular risk, and sympathetic nervous system (SNS) dysfunction appears to be a key contributor. The present review will characterize sympathetic function across several sleep disorders and insufficiencies in humans, including sleep deprivation, insomnia, narcolepsy, and obstructive sleep apnea (OSA). We will focus on direct assessments of sympathetic activation, e.g., plasma norepinephrine and muscle sympathetic nerve activity, but include heart rate variability (HRV) when direct assessments are lacking. The review also highlights sex as a key biological variable. Experimental models of total sleep deprivation and sleep restriction are converging to support several epidemiological studies reporting an association between short sleep duration and hypertension, especially in women. A systemic increase of SNS activity via plasma norepinephrine is present with insomnia and has also been confirmed with direct, regionally specific evidence from microneurographic studies. Narcolepsy is characterized by autonomic dysfunction via both HRV and microneurographic studies but with opposing conclusions regarding SNS activation. Robust sympathoexcitation is well documented in OSA and is related to baroreflex and chemoreflex dysfunction. Treatment of OSA with continuous positive airway pressure results in sympathoinhibition. In summary, sleep disorders and insufficiencies are often characterized by sympathoexcitation and/or sympathetic/baroreflex dysfunction, with several studies suggesting women may be at heightened risk. 

Sympathetic neural responses to sleep disorders and insufficiencies

Increased plasma orexin-A levels in patients with insomnia disorder are not associated with prepro-orexin or orexin receptor gene polymorphisms

Novel mutation of SLC20A2 in a Chinese family with primary familial brain calcification

Abnormal sleep architecture and white matter hyperintensities (WMHs) may be involved in cognitive impairment. There is little evidence on the connections between WMHs and chronic insomnia disorder (CID). Therefore, we evaluated the severity of WMHs and polysomnography parameters as well as cognitive tests to explore the underlying connections. There was no significant difference in sex, age, or educational attainment (years) between the two groups. The data showed significant decreases in total sleep time, sleep efficiency, and percentage of time spent in stage nonrapid eye movement sleep 3 in the CID group, but this group also showed prolonged sleep latency and increased percentages of time spent in stages nonrapid eye movement sleep 1 and nonrapid eye movement sleep 2 and wake after sleep onset. Moreover, chronic insomniacs showed poor performance on the attention, intelligence, and memory tests, as well as visual recognition and visual regeneration. Importantly, WMHs were observed to be associated with sleep latency, percentage of time spent in stage nonrapid eye movement sleep 1, and percentage of time spent in stage nonrapid eye movement sleep 3. In conclusion, our findings suggest that there are certain underlying correlations between WMHs and sleep architecture. Abnormal sleep architecture and WMHs could be involved in the impairment of cognitive function in CID. However, it remains unclear whether WMHs are a pre-existing abnormality or a consequence of CID.

White matter hyperintensity and cognitive impairments in chronic insomniacs.

Obstructive sleep apnea is a highly prevalent but under-recognized disorder that causes neurocognitive deficits such as spatial memory and learning deficits. These deficits are frequently accompanied by an increase in orexin-A, which has been shown to be involved in learning and memory as well as in neuronal apoptosis in brain areas involved in cognition, such as the hippocampus. The aim of this work was to study the possible harmful effects of orexin-A on intermittent hypoxemia-induced hippocampal neuronal damage and to investigate the potential underlying molecular mechanisms and signaling pathways in vitro. We established a hypoxia model in cultured rat hippocampal neurons and evaluated the effects of orexin-A by testing the apoptosis rate of the hippocampal neurons. Further studies using the extracellular signal-regulated kinase 1/2 inhibitor U0126, siRNA-PLCβ1, and siRNA-PLCβ4 were carried out to evaluate the mechanisms by which orexin-A contributes toward impairment of hippocampal neurons. The results showed that orexin-A increases intermittent hypoxemia-induced hippocampal neurons damage by overphosphorylating extracellular signal-regulated kinase 1/2 through the OXR-PLCβ1 pathway.

Orexin-A aggravates the impairment of hippocampal neurons caused by intermittent hypoxemia by the OXR-PLCβ1-ERK1/2 pathway.

Encephalopathy associated with propofol infusion syndrome: A case report.

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