Orexin A and Orexin B

Insomnia, a highly prevalent disorder, can be detrimental to patients' overall health and worsen existing comorbidities. Patients may have acute episodes of insomnia related to a traumatic event, but more commonly insomnia occurs chronically. While proper sleep hygiene and behavioral therapy play important roles in the nonpharmacologic management of short-term and chronic insomnia, medications may also be required. Historically, insomnia has been treated with agents such as benzodiazepines, nonbenzodiazepine receptor agonists, and melatonin agonists. Dual orexin receptor antagonists represent a new class of medications for the treatment of insomnia, which block the binding of wakefulness-promoting neuropeptides orexin A and orexin B to their respective receptor sites. Suvorexant (Belsomra) is the first dual orexin receptor antagonist to be approved in the US and Japan and has demonstrated efficacy in decreasing time to sleep onset and increasing total sleep time. Its unique mechanism of action, data to support efficacy and safety over 12 months of use, and relative lack of withdrawal effects when discontinued may represent an alternative for patients with chronic insomnia who cannot tolerate or do not receive benefit from more traditional sleep agents. Suvorexant is effective and well tolerated, but precautions exist for certain patient populations, including females, obese patients, and those with respiratory disease. Suvorexant has only been studied vs placebo, and hence it is unknown how it directly compares with other medications approved by the US Food and Drug Administration for insomnia. Suvorexant is not likely to replace benzodiazepines or nonbenzodiazepine receptor antagonists as a first-line sleep agent but does represent a novel option for the treatment of patients with chronic insomnia.

This study aimed to explore the clinical characteristics and alteration of orexinergic level in cerebrospinal fluid (CSF) and the volumes of brain grey and white matters, and investigate the roles of orexinergic level on the association between brain atrophy and depression in Alzheimer's disease (AD) patients. The demographic variables of 156 participants were collected. Orexinergic level in CSF and the volumes of brain grey and white matters were evaluated. The correlations of orexinergic level in CSF with depression and brain volume in AD patients were analyzed. The mediating effect of orexinergic level in CSF on the association between brain atrophy and depression in AD patients was investigated. The joint predictive value of orexinergic level in CSF and brain volume for depression in AD patients was established. AD with depression patients showed significantly elevated levels of orexin A and orexin B in CSF; orexin A level in CSF was positively correlated with HAMD score in AD patients. The elevated orexin A level in CSF mediated 49.6% of total association between the decreased grey matter volume of right dorsal medial thalamic nucleus and depression, and 50.3% of total association between the reduced white matter volume of left amygdala and depression. Combinations of above parameters could predict depression in AD patients with a significantly high area under the curve (AUC = 0.841). Therefore, the elevated orexin A level in CSF mediates its effect on the atrophy of the right dorsal medial thalamic nucleus and the white matter of the left amygdala, eventually alleviating depression in AD.

BACKGROUND: Orexin dysfunction has previously been demonstrated to be associated with depression. However, no studies reported the different effects of orexin A/B on depression with and without childhood trauma (CT). In this study，we assessed the correlation between expression of orexin A/B and depression severity in major depressive disorder (MDD) patients and healthy controls. METHODS: A total of 97 MDD patients and 51 healthy controls were recruited in this study. According to the total scores of childhood trauma questionnaire (CTQ), the MDD patients were further divided into two subgroups, MDD with CT and MDD without CT. The 17-item Hamilton Depression Scale (HAMD-17), and plasma orexin A and orexin B concentrations were measured in all participants using enzyme-linked immunosorbent assay. RESULTS: Orexin B plasma levels were significantly higher in MDD patients with CT and without CT than that in the healthy control group (P < 0.05), whereas there was no statistical difference between the two depression groups. After adjusting age and BMI for covariates, the LASSO regression revealed significant association between the plasma orexin B levels and the total scores of HAMD (β = 3.348), CTQ (β = 2.005). There was no difference in plasma orexin A levels among three groups (P > 0.05). CONCLUSIONS: Although peripheral orexin B levels are associated with the depression, rather than orexin A, CT appear to play a role in the association between orexin B levels and depression. China Clinical Trial Registration Center (Registration No.: ChiCTR2000039692).

The orexin system consists of two G-protein-coupled receptors, the orexin 1 and orexin 2 receptors, widely expressed in diverse regions of the brain, and two peptide agonists, orexin A and orexin B, which are produced in a small assembly of neurons in the lateral hypothalamus. The orexin system plays an important role in the maintenance of wakefulness. Several compounds (almorexant, SB-649868, suvorexant) have been in advanced clinical trials for treating primary insomnia. ACT-462206 is a new, potent, and selective dual orexin receptor antagonist (DORA) that inhibits the stimulating effects of the orexin peptides at both the orexin 1 and 2 receptors. It decreases wakefulness and increases non-rapid eye movement (non-REM) and REM sleep while maintaining natural sleep architectures in rat and dog electroencephalography/electromyography (EEG/EMG) experiments. ACT-462206 shows anxiolytic-like properties in rats without affecting cognition and motor function. It is therefore a potential candidate for the treatment of insomnia.

The neuropeptides orexin A and B (also known as hypocretins) play an important role in many physiological and behavioral activities. Orexins are ligands of two closely related G-protein-coupled receptors, that are the named orexin 1 and orexin 2 receptors. To clearly identify the minimal ligand sequences required for receptor activation, we synthesized and analyzed different centrally, C- and N-terminally truncated analogues of orexins A and B. Furthermore, we used the shortest active analogue to screen for important amino acid residues by l-alanine and l-proline replacement scans. For orexin A, only full-length peptides were able to show the same activity as orexin A, but interestingly, reduced orexin A and natural orexin A, which contains the two disulfide bonds, had the same activity. The shortest highly active orexin B analogue was orexin B 6-28. In addition, we identified orexin A 2-33 as the first analogue with orexin 1 receptor preference and orexin B 10-28, [A27]orexin B 6-28, and [P11]orexin B 6-28 as being highly potent orexin 2 receptor selective (>1000-fold) peptides.

BACKGROUND: Maternal elevated glucocorticoid levels during pregnancy can affect the developing fetus, permanently altering the structure and function of its brain throughout life. Excessive action of these hormones is known to contribute to psychiatric disorders, including depression. MATERIALS: The study was performed in a rat model of depression based on prenatal administration of dexamethasone (DEX) in late pregnancy (0.1 mg/kg, days 14-21). We evaluated the effects of prenatal DEX treatment on the cognition and bioenergetic signaling pathways in the brain of adult male rats, in the frontal cortex and hippocampus, and in response to stress in adulthood, using behavioral and biochemical test batteries. RESULTS: We revealed cognitive deficits in rats prenatally treated with DEX. At the molecular level, a decrease in the orexin A and orexin B levels and downregulation of the AMPK-SIRT1-PGC1α transduction pathway in the frontal cortex of these animals were observed. In the hippocampus, a decreased expression of orexin B was found and changes in the MR/GR ratio were demonstrated. Furthermore, an increase in HDAC5 level triggered by the prenatal DEX treatment in both brain structures and a decrease in MeCP2 level in the hippocampus were reported. CONCLUSIONS: Our study demonstrated that prenatal DEX treatment is associated with cognitive dysfunction and alterations in various proteins leading to metabolic changes in the frontal cortex, while in the hippocampus adaptation mechanisms were activated. The presented results imply that different pathophysiological metabolic processes may be involved in depression development, which may be useful in the search for novel therapies.