Role Of Orexin Research Articles

Contribution of hypothalamic orexin (hypocretin) circuits to pathologies of motivation.

The orexin (also known as hypocretin) system, consisting of neuropeptides orexin-A and orexin-B, was discovered over 25 years ago and was immediately identified as a central regulator of sleep and wakefulness. These peptides interact with two G-protein coupled receptors, orexin 1 (OX1) and orexin 2 (OX2) receptors which are capable of coupling to all heterotrimeric G-protein subfamilies, but primarily transduce increases in calcium signalling. Orexin neurons are regulated by a variety of transmitter systems and environmental stimuli that signal reward availability, including food and drug related cues. Orexin neurons are also activated by anticipation, stress, cues predicting motivationally relevant information, including those predicting drugs of abuse, and engage neuromodulatory systems, including dopamine neurons of the ventral tegmental area (VTA) to respond to these signals. As such, orexin neurons have been characterized as motivational activators that coordinate a range of functions, including feeding and arousal, that allow the individual to respond to motivationally relevant information, critical for survival. This review focuses on the role of orexins in appetitive motivation and highlights a role for these neuropeptides in pathologies characterized by inappropriately high levels of motivated arousal (overeating, anxiety and substance use disorders) versus those in which motivation is impaired (depression).

The role of orexin in Parkinson's disease.

Emerging evidence has implicated the orexin system in non-motor pathogenesis of Parkinson's disease. It has also been suggested the orexin system is involved in the modulation of motor control, further implicating the orexin system in Parkinson's disease. Parkinson's disease is the second most common neurodegenerative disease with millions of people suffering worldwide with motor and non-motor symptoms, significantly affecting their quality of life. Treatments are based solely on symptomatic management and no cure currently exists. The orexin system has the potential to be a treatment target in Parkinson's disease, particularly in the non-motor stage. In this review, the most current evidence on the orexin system in Parkinson's disease and its potential role in motor and non-motor symptoms of the disease is summarized. This review begins with a brief overview of Parkinson's disease, animal models of the disease, and the orexin system. This leads into discussion of the possible roles of orexin neurons in Parkinson's disease and levels of orexin in the cerebral spinal fluid and plasma in Parkinson's disease and animal models of the disease. The role of orexin is then discussed in relation to symptoms of the disease including motor control, sleep, cognitive impairment, psychological behaviors, and the gastrointestinal system. The neuroprotective effects of orexin are also summarized in preclinical models of the disease.

The role of orexin in fatigue and sleep quality in patients with primary Sjögren's syndrome.

Sleep disorders and fatigue are prevalent symptoms affecting primary Sjögren's syndrome (pSS) patients. This study aimed to assess the sleep quality of pSS patients as well as its relationship to fatigue and orexin level. This is across-sectional study evaluating fatigue in pSS using the Fatigue Severity Scale (FSS). Sleep quality was evaluated using the Pittsburg Sleep Quality Index (PSQI). The European Alliance of Associations for Rheumatology (EULAR) Sjögren's Syndrome Disease Activity Index (ESSDAI) and EULAR Sjögren's Syndrome Patient-Reported Index (ESSPRI) were calculated. Forty-one patients met the sample criteria and were involved in the final report. They were all females, with amean (± SD) age and median disease duration of 40.87 ± 10.84 and 36 (6-180) months, respectively. The mean ESSDAI was 0.92 ± 1.3, while the mean ESSPRI was 5.8 ± 2.13. Based on the FSS, 32 (78.04%) patients had apositive test with amean score of 5.07 ± 1.54. The total PSQI score showed that 60.97% had poor sleep, and the orexin level was lower in patients with pSS than in healthy controls. There was no correlation between orexin level and the presence of fatigue nor the PSQI score. In conclusion, serum orexin levels were lower in patients with pSS than healthy controls, It could be related to impairments in sleep and fatigue in patients with pSS.

Involvement of orexin type-2 receptors in genetic absence epilepsy rats.

Orexin is a neuropeptide neurotransmitter that regulates the sleep/wake cycle produced by the lateral hypothalamus neurons. Recent studies have shown the involvement of orexin system in epilepsy. Limited data is available about the possible role of orexins in the pathophysiology of absence seizures. This study aims to understand the role of orexinergic signaling through the orexin-type 2 receptor (OX2R) in the pathophysiology of absence epilepsy. The pharmacological effect of a selective OX2R agonist, YNT-185 on spike-and-wave-discharges (SWDs) and the OX2R receptor protein levels in the cortex and thalamus in adult GAERS were investigated. The effect of intracerebroventricular (ICV) (100, 300, and 600 nmol/10 μL), intrathalamic (30 and 40 nmol/500 nL), and intracortical (40 nmol/500 nL) microinjections of YNT-185 on the duration and number of spontaneous SWDs were evaluated in adult GAERS. The percentage of slow-wave sleep (SWS) and spectral characteristics of background EEG were analyzed after the ICV application of 600 nmol YNT-185. The level of OX2R expression in the somatosensory cortex and projecting thalamic nuclei of adult GAERS were examined by Western blot and compared with the non-epileptic Wistar rats. We showed that ICV administration of YNT-185 suppressed the cumulative duration of SWDs in GAERS compared to the saline-administered control group (p < 0.05). However, intrathalamic and intracortical microinjections of YNT-185 did not show a significant effect on SWDs. ICV microinjections of YNT-185 affect sleep states by increasing the percentage of SWS and showed a significant treatment effect on the 1-4 Hz delta frequency band power during the 1-2 h post-injection period where YNT-185 significantly decreased the SWDs. OXR2 protein levels were significantly reduced in the cortex and thalamus of GAERS when compared to Wistar rats. This study investigated the efficacy of YNT-185 for the first time on absence epilepsy in GAERS and revealed a suppressive effect of OX2R agonist on SWDs as evidenced by the significantly reduced expression of OX2R in the cortex and thalamus. YNT-185 effect on SWDs could be attributed to its regulation of wake/sleep states. The results constitute a step toward understanding the effectiveness of orexin neuropeptides on absence seizures in GAERS and might be targeted by therapeutic intervention for absence epilepsy.

Orexin receptors regulate hippocampal sharp wave-ripple complexes in ex vivo slices

Orexin is a neuromodulatory peptide produced by lateral hypothalamic orexin neurons and binds to G-protein-coupled orexin-1 receptor and orexin-2 receptors. Whether orexin modulates learning and memory is not fully understood. Orexin has biphasic effects on learning and memory: promoting learning and memory at homeostatic levels and inhibiting at supra- and sub-homeostatic levels. Hippocampal sharp wave-ripples encode memory information and are essential for memory consolidation and retrieval. The role of orexin on sharp wave-ripples in hippocampal CA1 remains unknown. Here, we used multi-electrode array recordings in acute ex vivo hippocampal slices to determine the effects of orexin receptor antagonists on sharp wave-ripples. Bath-application of either the orexin-1 receptor antagonist N-(2-Methyl-6-benzoxazolyl)-N'-1,5-naphthyridin-4-yl urea (SB-334867) or the orexin-2 receptor antagonist N-Ethyl-2-[(6-methoxy-3-pyridinyl)[(2-methylphenyl)sulfonyl]amino]-N-(3-pyridinylmethyl)-acetamide (EMPA) reduced sharp wave and ripple incidence, sharp wave amplitude, and sharp wave duration. SB-334867 and EMPA effects on sharp wave amplitude and duration were equivalent, whereas EMPA exhibited a greater reduction of sharp wave and ripple incidence. EMPA also increased ripple duration, whereas SB-334867 had no effect. Inhibition of both orexin receptors with a dual orexin receptor antagonist N-[1,1'-Biphenyl]-2-yl-1-[2-[(1-methyl-1H-benzimidazol-2-yl)thio]acetyl-2-pyrrolidinedicarboxamide (TCS-1102) had effects similar to EMPA, however, sharp wave amplitude and duration were unaffected. Region-specific expression of orexin receptors suggests orexin may regulate sharp wave generation in CA3, dentate gyrus-mediated sharp wave modification, sharp wave propagation to CA1, and local ripple emergence in CA1. Our study indicates an orexin contribution to hippocampal sharp wave-ripple complexes and suggests a mechanism by which sub-homeostatic concentrations of orexin may inhibit learning and memory function.

Engagement of the brain orexin system in activity-based anorexia behaviour in mice

While excessive physical activity is common amongst anorexia nervosa (AN) patients, contributing to their low body weight, little is known about the underlying biology and effective treatments targeting the hyperactivity are lacking. Given the role of orexin in arousal, physical activity and energy expenditure, we sought to investigate i) the extent to which orexin neurons are activated during severe anorectic state in the activity-based anorexia (ABA) mouse model, and ii) if the dual orexin receptor antagonist suvorexant can reduce physical activity during ABA. The Fos-TRAP2 technique enable us to visually capture active neurons (Fos expressing) during severe anorectic state in the ABA mouse model, and by immunohistochemistry, determine the extent to which these active neurons are orexin positive. In addition, suvorexant was administered peripherally to ABA mice and running activity was monitored. We found that a large population of orexin neurons in the hypothalamus are activated by ABA and that peripheral administration of suvorexant decreases food anticipatory activity in these mice. We conclude that orexin may be a suitable target to treat hyperactivity in AN and recommend further studies to examine the efficacy of suvorexant in aiding AN patients to control their drive for hyperactivity.

Localization and expression of Orexin B (OXB) and its type 2 receptor (OX2R) in mouse testis during postnatal development

The orexins (OXs) were first reported in hypothalamus of rat, and they play an important role in diverse physiological actions. The OXs consist of orexin A (OXA) and orexin B (OXB) peptides and their actions are mediated via two G-protein-coupled receptors, orexin 1 receptor (OX1R) and orexin 2 receptor (OX2R), respectively. Presence of OXA and OX1R has been also reported in peripheral organs like reproductive tissues. These findings, therefore, highlight a possible role of OXs and their receptors in male reproductive health. Though, expression and localization of OXB and OX2R in the testis and their role in spermatogenesis are not finally clarified. Herein, we elucidated the localization and the patterns of expression of OXB and OX2R in Parkes mice testes during postnatal development. Results suggest that the precursor prepro-orexin (PPO), OXB and OX2R are expressed at the transcript and protein levels in mouse testis throughout the postnatal development. Immunostaining further showed the localization of OXB and OX2R both in interstitium and tubular compartments of the testis. On 7 day postpartum (7 dpp), only spermatogonia showed immunoreactivity of OXB and OX2R, while at 14, 28, 42 and 90 dpp, immunolocalization of OXB and OX2R were noted in the seminiferous tubules, especially in leptotene, pachytene spermatocytes, round and elongating spermatids, and in Leydig cells and Sertoli cells. The immunoreactivity of OXB and OX2R appeared to be stage-specific in adult mouse testis. The results suggest the expression of OXB and OX2R in mouse testis and their possible regulatory role in spermatogenesis and steroidogenesis.

Antagonization of OX1 Receptor Potentiates CB2 Receptor Function in Microglia from APPSw/Ind Mice Model.

Microdialysis assays demonstrated a possible role of orexin in the regulation of amyloid beta peptide (Aß) levels in the hippocampal interstitial fluid in the APP transgenic model. CB2R is overexpressed in activated microglia, showing a neuroprotective effect. These two receptors may interact, forming CB2-OX1-Hets and becoming a new target to combat Alzheimer's disease. Aims: Demonstrate the potential role of CB2-OX1-Hets expression and function in microglia from animal models of Alzheimer's disease. Receptor heteromer expression was detected by immunocytochemistry, bioluminescence resonance energy transfer (BRET) and proximity ligation assay (PLA) in transfected HEK-293T cells and microglia primary cultures. Quantitation of signal transduction events in a heterologous system and in microglia cells was performed using the AlphaScreen® SureFire® kit, western blot, the GCaMP6 calcium sensor and the Lance Ultra cAMP kit (PerkinElmer). The formation of CB2-OX1 receptor complexes in transfected HEK-293T cells has been demonstrated. The tetrameric complex is constituted by one CB2R homodimer, one OX1R homodimer and two G proteins, a Gi and a Gq. The use of TAT interfering peptides showed that the CB2-OX1 receptor complex interface is TM4-TM5. At the functional level it has been observed that the OX1R antagonist, SB334867, potentiates the action induced by CB2R agonist JWH133. This effect is observed in transfected HEK-293T cells and microglia, and it is stronger in the Alzheimer's disease (AD) animal model APPSw/Ind where the expression of the complex assessed by the proximity ligation assay indicates an increase in the number of complexes compared to resting microglia. The CB2-OX1 receptor complex is overexpressed in microglia from AD animal models where OX1R antagonists potentiate the neuroprotective actions of CB2R activation. Taken together, these results point to OX1R antagonists as drugs with therapeutic potential to combat AD. Data access statement: Raw data will be provided by the corresponding author upon reasonable requirement.

Effect of orexin and its antagonist on the organization of emotional and exploratory behavior of rats in a model of psychic trauma

BACKGROUND: A number of recent studies have revealed the role of orexins in regulating emotional behavior and emotional memory. The rationale for this role of orexin regulation is the close bi-directional interaction of orexin neurons with emotional structures of the brain, such as the bed nucleus of the stria terminalis, locus ceruleus, central and dorsomedial amygdala, hippocampus, medial prefrontal cortex. There is experimental and clinical evidence that an endogenous or induced deficiency of orexin effects accelerates the elimination of traumatic memory.&#x0D; AIM: To study the effect of the OX1R Orexin Receptor Antagonist SB408124 and orexin on the emotional and exploratory behavior of animals after predator-induced stress.&#x0D; MATERIALS AND METHODS: The experiments were made with 36 male Wistar rats, divided into 4 groups of 8 animals. Animals of 3 groups were exposed to single simulation of post-traumatic stress disorder by exposition with the indian python and subsequent death of one rat as a result of predator activity. The rats of 2 experimental groups received SB408124 OX1R antagonist in a dose of 20 l of 0.1% solution and Orexin A in the same dose intranasally. The other animals received physiological solution in a dose of 20 l intranasally. Behavior tests was made 7 days after the modeling of psychotrauma. A panel of behavioral tests was used: an elevated X-maze, an open field test, and an residentintruder test. The obtained data were statistically processed using the Student t-test and ANOVA dispersion analysis. The differences were considered statistically significant at p 0.01.&#x0D; RESULTS: Orexin antagonist SB408124 showed anxiolytic effects. SB408124 showed anxiolytic properties in stressed rats. It restored the time spent in the light arm of the elevated X-maze to the intact level. In the open field test SB408124 increased (p 0.01) the orientation behavior and reduced the frequency of freezing in stressed animals. Orexin A suppressed (p 0,01) locomotor activity of animals in the open field. In the residentintruder test in stressed animals SB408124 restored suppressed communication activity (p 0,01). Orexin A reduced communicative behavior and increased aggression of animals.&#x0D; CONCLUSIONS: The work shows a moderate anxiolytic action of SB408124 in the post-traumatic stress model in rats.

Neuroanatomical Basis for the Orexinergic Modulation of Anesthesia Arousal and Pain Control.

Hypothalamic orexin (hypocretin) neurons play crucial roles in arousal control. Their involvement in anesthesia and analgesia remains to be better understood. In order to enhance our view on the neuroanatomy, we systematically mapped the projections of orexin neurons with confocal microscope and light sheet microscope. We specifically expressed optogenetic opsins tagged with fluorescence markers in orexin neurons through adeno-associated viral infection in the mouse brain. The imaging results revealed fine details and novel features of the orexin projections throughout the brain, particularly related to the nuclei regulating arousal and pain. We then optogenetically activated orexin neurons in the lateral hypothalamus to study the effects on anesthesia-related behaviors. cFos staining showed that optogenetic stimulation can activate orexin neurons in the ChR2-mCherry group, but not the control mCherry group (62.86 ± 3.923% vs. 7.9 ± 2.072%; P < 0.0001). In behavior assays, optogenetic stimulation in the ChR2-mCherry group consistently elicited robust arousal from light isoflurane anesthesia (9.429 ± 3.804 s vs. 238.2 ± 17.42 s; P < 0.0001), shortened the emergence time after deep isoflurane anesthesia (109.5 ± 13.59 s vs. 213.8 ± 21.77 s; P = 0.0023), and increased the paw withdrawal latency in a hotplate test (11.45 ± 1.185 s vs. 8.767 ± 0.7775; P = 0.0317). The structural details of orexin fibers established the neuroanatomic basis for studying the role of orexin in anesthesia and analgesia.

Lateral hypothalamic self-stimulation with threshold current intensity induces emotional overeating in self-deprivation paradigm in well-fed rats: Role of orexin and dopaminergic systems of the brain

BACKGROUND: Emotional overeating in forms of соmpulsive overeating, or bulimia nervosa, and binge eating disorder (ВED) is underlying the basis of eating disorders. In particular, binge eating disorder is included in ICD-10 as a form of nonchemical dependence.&#x0D; AIM: The participation of the orexin and dopamine systems of the brain was studied in conditions of food self-deprivation caused by self-stimulation of the lateral hypothalamus.&#x0D; METHODS: To reproduce the self-stimulation of the lateral hypothalamus, male Wistar rats were trained to press the pedal in Skinner box. After training, rats received a food deprivation, a feeder was placed in the Skinner box, and a conditioned reflex on food reinforcement was developed in rats for 5 days. The food self-deprivation reaction was observed in these rats with a stimulating current intensity of 10% and above the threshold for self-stimulation.&#x0D; RESULTS: Hungry animals pressed the pedal forhypothalamic self-stimulation and did not distract to the feeding trough. Food reactions were observed only when using the threshold current. Then rats received a free access to food, but the animals, pressing the pedal for self-stimulation, continued food intakes for many times and eat up to 60 seeds in 10 minutes of the experiment. Dopamine receptor D2/D3 antagonist sulpiride at doses of 5 and 20 mg/kg ip and orexin receptor antagonists OX1RSB-408124 and OX2R TCS 29 0.5 mg/ml, 20 l intranasally were used. Sulpiride administration in fed rats decreased both the eating behavior and the reinforcing properties of electrical stimulation in food self-deprivation testing. At the same time, SB-408124 administration induced a decrease in the number of seeds eaten, but the number of pedal presses increased. Administration of OX2R TCS 29 had no effect.&#x0D; CONCLUSIONS: The conclusion was made about the selectivity of the orexin A OX1RSB-408124 antagonist for emotional eating forms compared with the D2/D3 receptor antagonist dopamine sulpiride.

Orexin one receptors within the basolateral amygdala are involved in the modulation of cognitive deficits associated with a migraine-like state in rats

ABSTRACT Objectives This study explored the possible role of orexin one receptors (Orx1R) in the basolateral amygdala (BLA) on the modulation of nitroglycerin (NTG)-induced migraine-like symptoms. In addition, pain-induced subsequent alteration in learning and memory competence was evaluated in the adult male Wistar rats. Methods The rats were given NTG (5 mg/kg, i.p.) every two days (for nine-day) to induce a migraine-like state. The migraine animals were treated with intra-BLA infusion of an Orx1R antagonist SB 334,867 (10, 20, and 40 nM/rat) or its vehicle DMSO. The NTG-induced migraine symptoms were recorded for 90 min. Spatial and passive avoidance performances were assessed by Morris water maze (MWM) and shuttle box tasks, respectively. Results In comparison with control, NTG produced significant migraine-like symptoms characterized by a decrease in cage climbing and an increase in head-scratching, freezing, and facial grooming behavior. Intra-BLA infusion of SB 334,867 (40 nM/rat) significantly decreased cage climbing and increased facial grooming responses in NTG-treated rats. Moreover, all administrated doses of SB 334,867 increased NTG-evoked head-scratching and freezing behavior. Besides, NTG impaired learning and memory performances in both tests, which were exaggerated by post-injection of SB 334,867 (40 nM/rat). Conclusions Overall, the data provided an emerging role for the orexin system within BLA in the modulation of cognitive decline comorbid with migraine in rats.

Orexin facilitates the hypoxic ventilatory response in rats

Orexin is a hypothalamic neuropeptide involved in a variety of functions including arousal, body temperature regulation, and feeding. Orexin neurons are active in wakefulness (or the dark phase in rats) and mostly silent in sleep (light phase), implying the effects of orexin are greater in wakefulness and/or dark phase. Recent evidence implicates orexin in the control of cardiorespiratory function, including the respiratory response to CO2 and blood pressure regulation. Whether orexin influences normal breathing in a state-dependent manner is unresolved. In addition, although the role of orexin in the hypercapnic ventilatory response is well established, its effects on the acute hypoxic ventilatory response (HVR) has not been investigated. We hypothesized that orexin receptor blockade would lead to hypoventilation in wakefulness but not sleep and would reduce the HVR. To test these hypotheses, we conducted two separate experiments, both of which were performed in the light phase. First, we used whole-body plethysmography to measure the ventilation of adult rats in room air. Rats were implanted with EEG and EMG electrodes to determine vigilance state, which was confirmed by applying Fast Fourier Transform on the EEG signals. After a 1hr baseline period, we injected i.p. either suvorexant (an OxR1 and OxR2 antagonist, 20 mg/kg i.p.) or vehicle (100% DMSO, i.p.) and allowed the rats to freely behave for 4 hours in the chamber while breathing room air. Separate groups of rats, also instrumented with EEG and EMG electrodes, were exposed to graded hypoxia (15%, 13%, 11%, and 9% O2) following administration of either 20 mg/kg i.p. suvorexant or vehicle. We found that, irrespective of state of vigilance, OxR1 and OxR2 blockade had no effect on baseline breathing, but significantly reduced the HVR (treatment × O2 level: p=0.03). The effect on the HVR was especially evident at 13% and 11% O2 when the response was reduced by ~30%. We show that orexin facilitates the HVR in the light phase, even though the orexin neurons are silent. Whether orexin has a larger effect on the HVR during the dark phase, when orexin neurons are active, has yet to be determined.

Causes and Consequences of Chronic Sleep Deficiency and the Role of Orexin.

Sleep is one of the pillars of health. Experimental models of acute sleep loss, of chronic partial sleep deprivation, and of sleep fragmentation in healthy sleepers are helpful models of sleep deficiency produced by insufficient sleep duration, sleep timing, and sleep disorders. Sleep deficiency is associated with changes in markers associated with risk for disease. These include metabolic, inflammatory, and autonomic markers of risk. In addition, sleep disruption and sleep deficits lead to mood instability, lack of positive outlook, and impaired neurobehavioral functioning. On a population level, insufficient sleep is associated with increased risk for hypertension and diabetes. Sleep disturbance is very common, and about half the population will report that they have experienced insomnia at some time in their lives. Approximately 10% of the population describe daytime impairment due to sleep disturbance at night, consistent with a diagnosis of insomnia disorder. The hypothalamic neuropeptides, orexin-A and orexin-B, act through G-protein-coupled receptors (orexin-1 and orexin-2 receptors). Dual and selective orexin-2 receptor antagonists have shown efficacy in inducing sleep in men and women with insomnia disorder by accelerating sleep onset and improving sleep efficiency and total sleep time. Further study comparing these medications, in short- and longer-term use models, is recommended. Greater understanding of comparative effects on mood, neurobehavioral, and physiological systems will help determine the extent of clinical utility of dual versus selective orexin receptor antagonists.

Association of orexin/hypocretin receptor gene (HCRTR1) with reward sensitivity, and interaction with gender

Orexins/hypocretins maintain wakefulness, increase appetite and participate in the coordination of stress response. We have recently provided evidence on the role of orexins in aggression, showing the association of the HCRTR1 genotype.(rs2271933 G > A; leading to amino acid substitution Ile408Val) with aggressiveness or breach of law in four independent cohorts. Aggressive behaviour can be reward driven and hence we have examined the association of HCRTR1 rs2271933 genotype with different aspects of reward sensitivity in the birth cohort representative Estonian Children Personality Behaviour and Health Study. HCRTR1 genotype was associated with reward sensitivity in a gender dependent manner. Male HCRTR1 A/A homozygotes had higher Openness to Rewards and the overall reward sensitivity score while, in contrast, female A/A homozygotes scored lower than G-allele carriers in Openness to Rewards. In the total sample, aggressiveness correlated positively with reward sensitivity, but this was on account of Insatiability by Reward. In contrast, the HCRTR1 A/A homozygotes had a positive association of aggressiveness and Openness to Rewards. Experience of stressful life events had a small but significant increasing effect on both aspects of reward sensitivity, and correlated in an anomalous way with reward sensitivity in the HCRTR1 A/A homozygotes. Conclusively, the higher aggressiveness of HCRTR1 A/A homozygotes appears based on a qualitative difference in sensitivity to rewards, in the form that suggests their lower ability to prevent responses to challenges being converted into overt aggression.

Appetite control: hormones or diet strategies?

Appetite control results from metabolic, behavioral, and environmental factors that influence hunger and the desire to eat. We summarize the latest advances in the hormonal and nutritional strategies to control appetite and reduce hunger. The fed-hunger-state is regulated by central and peripheric hormones, which modulate energy balance. Leptin, insulin, ghrelin, peptide YY (PYY), and other gut-derived peptides represent the main appetite controllers. The role of orexins, obestatin, and liver-expressed antimicrobial peptide 2 has been uncovered recently. New insights have demonstrated the role of hippocampal activity as a possible mechanism of action. Glucagon-like peptide 1 (GLP1) receptor agonists are well known agents controlling appetite. Association of GLP1 receptor agonist, PYY, or glucose-dependent insulinotropic polypeptide agonists have been tested as new approaches. Appetite-control hormones have also risen as factors involved in the efficacy of bariatric procedures. High-protein, ketogenic diet, and intermittent fasting have been described as nutritional strategies to reduce appetite, although the physiological mechanism and long-term safety remains unclear. Appetite control has been an important target for the treatment of obesity and associated disorders. New studies have demonstrated promising adoption of dietary approaches, hormone-based drugs, and bariatric surgery to control energy intake. Further research will establish a significant association, benefits, and safety of these new therapies.

Orexin and Alzheimer's Disease: A New Perspective.

Orexin’s role in human cognition has recently been emphasized and emerging evidences indicate its close relationship with Alzheimer’s disease (AD). This review aimed to demonstrate recent research on the relationship between orexin and AD. Orexin’s role in stress regulation and memory is discussed, with significant findings related to sexual disparities in stress response, with potential clinical implications pertaining to AD pathology. There are controversies regarding the orexin levels in AD patients, but the role of orexin in the trajectory of AD is still emphasized in recent literatures. Orexin is also accentuated in the context of tau pathology, and orexin as a potential therapeutic target for AD is frequently discussed. Future directions with regard to the relationship between orexin and AD are suggested: 1) consideration for AD trajectory in the measurement of orexin levels, 2) the need for objective measure such as polysomnography and actigraphy, 3) the need for close observation of cognitive profiles of orexin-deficient narcolepsy patients, 4) the need for validation studies by neuroimaging 5) the need for taking account sexual disparities in orexinergic activiation, and 6) consideration for orexin’s role as a stress regulator. The aforementioned new perspectives could help unravel the relationship between orexin and AD.

Effects of Prenatal Stress on the Formation of the Orexinergic System of the Hypothalamus in Rats

The effects of prenatal stress (PNS) on the formation of the orexinergic and dopaminergic systems of the brain were studied in 14- and 30-day-old rat pups born to females subjected to sleep deprivation (6 h/day) using the “small areas” method from day 13 to day 19 of pregnancy. The open fi eld test showed impairments to motor development in 14-day-old PNS rat pups. Immunohistochemical studies of brain sections showed that the hypothalamus contained a signifi cantly larger quantity of orexin A in neurons in the periforniceal area, while high-performance liquid chromatography demonstrated increases in the dopamine level and its rate of metabolism as compared with control rat pups born to intact females. Western blotting results provided evidence of a decrease in the striatal level of the GABA-sythesizing enzyme (GAD65) and an increase in the level of tyrosine hydroxylase (an enzyme involved in dopamine synthesis) phosphorylated at serine-40 as compared with controls. By day 30 of life measures of motor activity in PNS rat pups were no different from those in controls, though PNS rat pups had higher levels of anxiety and lower levels of exploratory activity. The results of morphological and biochemical studies also provided evidence that there were no differences between the study parameters in the hypothalamus and striatum in 30-day-old rat pups as compared with controls, which was confi rmed by results from electrophysiological studies indicating that there were no differences in the organization of the sleep-waking cycle in 30-day-old PNS and control rat pups. We discuss here the morphofunctional interactions of the orexinergic and dopaminergic systems of the brain in the early postnatal period of development of the body and the role of orexins in the compensatory mechanisms of the brain.

The role of orexin A in pathophysiological mechanisms of sleep disorder in postmenopausal women

Aim. To conduct a comparative analysis of serum orexin A levels in women of different age periods with and without sleep disorder and vasomotor symptoms. To evaluate the dynamics of orexin A levels under menopausal hormone therapy.&#x0D; Materials and methods. The study included 50 postmenopausal women and 30 women of reproductive age with a regular menstrual cycle. Using block randomization, patients are divided into 3 groups: group 1 (main group), n=25, -STRAW+ 10 (+1b and +1c), patients with sleep disorder and vasomotor symptoms; group 2 (comparison group), n=25, STRAW+ 10 (+1b and +1c), patients with vasomotor symptoms without sleep disorder; group 3 (control group), n=30, STRAW+ 10 (-4), women of reproductive age without sleep disorder. Group 1 patients were given menopausal hormone therapy. A comparative analysis was carried out using the questionnaire for assessing menopausal symptoms severity by the Greene Scale (the Greene Climacteric Scale) and Rating Scale for subjective sleep characteristics. After 12 weeks of treatment, a control examination was performed.&#x0D; Results. In group 1 women, the serum orexin A levels were significantly higher compared to the women without the symptoms. The link between the orexin A levels and menopause syndrome severity was established. A significant decrease in the menopausal symptoms severity after 12 weeks of menopausal hormone therapy was shown. It was accompanied by a 1,3-fold decrease in orexin A levels.&#x0D; Conclusions. The obtained data indicate the possible role of orexin A and the orexin neuropeptide system in the pathogenesis of sleep disorder and vasomotor symptoms in postmenopausal women.

Orexins and the brain reinforcing systems

The purpose of the review was to analyze the neurochemical and neurophysiological mechanisms of the orexin system and the role of orexin in body functions and behavior. The focus is on the participation of orexin in the mechanisms of reinforcement and the formation of addictive behavior. At the beginning of the review a history of the first works on the field of orexin and its receptors are described. Hypothalamic orexin-producing cells and effects on brain functions are described. The effects of orexins and their receptors on eating behavior, wakefulness and positive reinforcement are described. Then, the effects of orexins on narcolepsy was analyzed. The participation of orexins in the mechanisms of reinforcement and dependence and the key role of orexins in the development of addictive behaviors is described. The special role of orexin in the formation of ethanol dependence is shown. Next, the issue of the action of orexins under stress was considered. Orexins have been shown to play an important role in the regulation of the nervous and humoral mechanisms mediating the formation of emotional memory associated with negative experience. It is concluded that orexin can modulate the estimation of stress and probability for reaching stimulus. In this regard, orexin antagonists can be considered as possible promising means of preventing and treating disorders of the anxiety-phobic spectrum, as well as disorders associated with the use of addictive drugs caused by stress and environmental stimuli.