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Dual orexin receptor antagonist (DORA-22) minimally alters EEG frequency as a function of sleep. Area under/over the electroencephalogram (EEG) spectral frequency () as a function of decreases in active wake () for each sleep/wake state (different panes). Inverted triangle (▾) indicates low dose, square (▪) indicates mid dose, and triangle (▴) indicates high dose. Symbols represent average decrease in active wake (x axis)±standard error of mean (SEM), and average area under/over the EEG frequency curve outside of the±5% dosing effect area (y axis)±SEM.Download Power Point slide (202 KB)
Source publication
Dual orexin receptor antagonists (DORAs) induce sleep by blocking orexin 1 and orexin 2 receptor-mediated activities responsible for regulating wakefulness. DORAs represent a potential alternative mechanism to the current standard of care that includes the γ-aminobutyric acid (GABA)A receptor positive allosteric modulators, eszopiclone and zolpidem...
Context in source publication
Context 1
... correlation between the magnitude of compound- induced EEG spectral changes within each sleep stage and sleep-promoting efficacy (as measured by decreases in active wake) was calculated to better quantify the difference between agents. Eszopiclone and zolpidem produced a strong relationship between changes in EEG spectral frequency (y axis) and decreases in active wake time (x axis) across all sleep/wake states ( Figure 5). DORA-22, however, exhibited no correlation between changes in the EEG spectral frequency and decreases in active wake time except in REM sleep, which was associated with a decrease in the lower frequencies and an increase in the higher frequencies at the high dose. ...
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The ability to awaken from sleep in response to important stimuli is a critical feature of normal sleep, as is maintaining sleep continuity in the presence of irrelevant background noise. Dual orexin receptor antagonists (DORAs) effectively promote sleep across species by targeting the evolutionarily conserved wake-promoting orexin signaling pathwa...
Citations
... DORAs exhibit a distinct action mechanism from GABA modulators, leading to differences in efficacy and side effects. Firstly, whereas GABA modulators alter both sleep stages and the brain's activity network during specific sleep stages, DORAs induce somnolence consistent with normal sleep [30]. The possible explanation for this is that, while GABA modulators alter cortical activity, DORAs inhibit the activity of orexin peptides. ...
Insomnia, commonly treated with benzodiazepine (BZD) receptor agonists, presents challenges due to associated serious side effects such as abuse and dependence. To address these concerns, many researches have been conducted to develop and advance both pharmacological and non-pharmacological interventions. Dual orexin receptor antagonists (DORAs), which include suvorexant, daridorexant and lemborexant, have recently been approved by United States Food and Drug Administration (US FDA) as a novel pharmacotherapeutic alternative. Unlike BZD receptor agonists that act as positive allosteric modulators of the gamma-aminobutyric acid type A subunit alpha 1 receptor, DORAs function by binding to both orexin receptor types 1 and 2, and inhibiting the action of the wake-promoting orexin neuropeptide. These drugs induce normal sleep without sleep stage change, do not impair attention and memory performance, and facilitate easier awakening. However, more real-world safety information is needed. Selective orexin-2 receptor antagonists (2-SORAs) is under clinical developments. This review provides an overview of the mechanism of action in relation to insomnia, pharmacokinetics, efficacy and safety information of DORAs and SORA. According to insomnia management guidelines, the first-line treatment for chronic insomnia is cognitive behavioral therapy for insomnia (CBT-I). Although it has proven effective in improving sleep-related quality of life, it has several restrictions limitations due to a face-to-face format. Recently, prescription digital therapy such as Somryst® was approved by US FDA. Somryst®, a smartphone app-based CBT-I, demonstrated meaningful responses in patients. However, digital limitations may impact scalability. Overall, these developments offer promising alternatives for insomnia treatment, emphasizing safety, efficacy, and accessibility.
... Male and female rTg4510 transgenic mice and WT littermate controls were used as previously described Santacruz et al., 2005). rTg4510 mice were generated in house by crossing Tg , MK-1064 (Gotter et al., 2016;Roecker et al., 2014) and zolpidem (Fox et al., 2013;Steiner et al., 2011) were selected based on literature and preliminary data in-house, and for the OX receptor WT (n = 16; 7 males, 9 females); rTg4510 (n = 13; 7 males, 6 females). ...
Background and Purpose
Transgenic mouse models of tauopathy display prominent sleep/wake disturbances which manifest primarily as a hyperarousal phenotype during the active phase, suggesting that tau pathology contributes to sleep/wake changes. However, no study has yet investigated the effect of sleep‐promoting compounds in these models. Such information has implications for the use of hypnotics as potential therapeutic tools in tauopathy‐related disorders.
Experimental Approach
This study examined polysomnographic recordings in 6‐6.5‐month‐old male and female rTg4510 mice following acute administration of suvorexant (50 mg·kg⁻¹), MK‐1064 (30 mg·kg⁻¹) or zolpidem (10 mg·kg⁻¹), administered at the commencement of the active phase.
Key Results
Suvorexant, a dual OX receptor antagonist, promoted REM sleep in rTg4510 mice, without affecting wake or NREM sleep. MK‐1064, a selective OX2 receptor antagonist, reduced wake and increased NREM and total sleep time. MK‐1064 normalised the hyperarousal phenotype of male rTg4510 mice, whereas female rTg4510 mice exhibited a more transient response. Zolpidem, a GABAA receptor positive allosteric modulator, decreased wake and increased NREM sleep in both male and female rTg4510 mice. Of the three compounds, the OX2 receptor antagonist MK‐1064 promoted and normalised physiologically normal sleep, especially in male rTg4510 mice.
Conclusions and Implications
Our findings indicate that hyperphosphorylated tau accumulation and associated hyperarousal does not significantly alter the responses of tauopathy mouse models to hypnotics. However, the sex differences observed in the sleep/wake response of rTg4510 mice to MK‐1064, but not suvorexant or zolpidem, raise questions about therapeutic implications for the use of OX2 receptor antagonists in human neurodegenerative disorders.
... In contrast, recent findings suggest that zolpidem improves memory in humans (Niknazar et al., 2015;Zhang et al., 2020). Rodent studies looked at the effect of eszopiclone on cortical oscillations but not ripples (Xi and Chase, 2008;Hambrecht-Wiedbusch et al., 2010;Huang et al., 2010;Methippara et al., 2010;Fox et al., 2013), and there are few studies of zolpidem in rodents (Ponomarenko et al., 2004;Koniaris et al., 2011;Berdyyeva et al., 2014). We hypothesized that the contrasting effects of these drugs on memory consolidation were due to differential effects in hippocampal function. ...
Clinical populations have memory deficits linked to sleep oscillations that can potentially be treated with sleep medications. Eszopiclone and zolpidem (two non-benzodiazepine hypnotics) both enhance sleep spindles. Zolpidem improved sleep-dependent memory consolidation in humans, but eszopiclone did not. These divergent results may reflect that the two drugs have different effects on hippocampal ripple oscillations, which correspond to the reactivation of neuronal ensembles that represent previous waking activity and contribute to memory consolidation. We used extracellular recordings in the CA1 region of rats and systemic dosing of eszopiclone and zolpidem to test the hypothesis that these two drugs differentially affect hippocampal ripples and spike activity. We report evidence that eszopiclone makes ripples sparser, while zolpidem increases ripple density. In addition, eszopiclone led to a drastic decrease in spike firing, both in putative pyramidal cells and interneurons, while zolpidem did not substantially alter spiking. These results provide an explanation of the different effects of eszopiclone and zolpidem on memory in human studies and suggest that sleep medications can be used to regulate hippocampal ripple oscillations, which are causally linked to sleep-dependent memory consolidation.
... The proportional increase of both non-REM and REM sleep and therewith the preservation of the overall sleep architecture is a unique characteristic of DORAs and differs from that of classical positive GABA-A receptor modulators that skew sleep architecture towards stage N2 of non-REM sleep and a decrease in REM sleep (Bettica et al. 2012;Brisbare-Roch et al. 2007;Brunner et al. 1991;Fox et al. 2013;Lundahl et al. 2012;Tannenbaum et al. 2016). The preclinical data translated clinically as daridorexant improves sleep onset and sleep maintenance in adult and elderly patients with insomnia Zammit et al. 2020). ...
Dual orexin receptor antagonists (DORAs) represent a novel type of sleep medication that provide an alternative to the traditionally used positive allosteric gamma-aminobutyric acid (GABA)-A receptor modulators. Daridorexant is a new DORA that exhibited in phase 3 trials in insomnia not only a beneficial effect on sleep variables, measured objectively and assessed subjectively, but also an improvement in daytime functioning. Daridorexant was discovered through a tailored research program aimed at identifying an optimized sleep-promoting molecule with pharmacokinetic properties appropriate for covering the whole night while avoiding next-morning residual activity at efficacious doses. By specific binding to both orexin receptors, daridorexant inhibits the actions of the wake-promoting orexin (also called hypocretin) neuropeptides. This mechanism avoids a more widespread inhibition of neuronal pathways and associated side effects that are intrinsic to positive allosteric GABA-A receptor modulators. Here, we review the general pharmacology of daridorexant, based on nonclinical pharmacology studies of daridorexant, unpublished or already described, or based on work with other DORAs. Some unique features of daridorexant will be highlighted, such as the promotion of natural and surmountable sleep, the preservation of memory and cognition, the absence of tolerance development or risk of physical dependence, and how it can benefit daytime functioning.
... These included eszopiclone, which is an agonist/positive allosteric modulator of GABRA3. Studies have shown the interactions between eszopiclone and GABA receptors [42,43]. However, despite these novel ndings, this study did have some limitations. ...
Background: Colorectal cancer (CRC) is the third most common malignancy in the world and metastasis is responsible for a major proportion of the cancer-related deaths in CRC patients.
Aims: To construct machine learning models for predicting lymph node and distant metastases in colorectal cancer and analyze biological functions features of metastasis-related genes.
Methods: RNA-seq and miRNA-seq data as well as corresponding clinical data from colon adenocarcinoma (COAD) and rectum adenocarcinoma (READ) were obtained from The Cancer Genome Atlas (TCGA) database. The differentially expressed RNAs (DE-RNAs) in non-LNM (N0) and LNM (N1/N2) as well as non-distant metastases (M0) and distant metastases (M1) were analyzed. Six machine learning models including logistic regression (LR), random forest (RF), support vector machine (SVM), Catboost, gradient boosting decision tree (GBDT), and artificial neural network (NN) were constructed to predict cancer metastasis and the feature genes of the optimal model were further analyzed by functional enrichment, protein-protein interaction (PPI) network, and drug-target analyses.
Results: Differential RNA expression profiles of LNM and non-LNM as well as M0 vs. M1 were observed in both COAD and READ samples. NN model was determined to be the optimal model for predicting distant metastases, while Catboost and LR models were the optimal models for predicting LNM in COAD and READ samples, respectively. PPI analysis indicated that KIR2DL4, chemokine-related genes CXCL9/10/11/13 and CCL25, and gamma-aminobutyric acid (GABA) receptor genes (GABRR1, GABRB2 and GABRA3) were key genes in metastasis. In addition, atorvastatin and eszopiclone were identified as potential therapeutic agents as they target these genes.
Conclusions: We constructed six machine learning models for predicting colorectal cancer metastases and identify the optimal model. We analyzed biological functions features of metastasis-related RNAs in colorectal cancer.
... 57,58 There is no evidence for cognitive impairment or addiction potential; on the contrary, orexin receptor antagonism appears a viable approach to treat drug dependence, and appears otherwise safe. [59][60][61][62][63] The fact that DORAs exclusively stimulate REM sleep could be an advantage in disorders where REM sleep is primarily affected, e.g. Alzheimer's disease 64-67 : suvorexant's recent phase III data in AD patients looks highly promising. ...
Insomnia and, more generally, lack of sleep are on the rise. Traditionally treated by classical hypnotics, such as benzodiazepines and Z drugs, which both act on the GABAA receptor, and other modalities, including nondrug therapies, such as cognitive behavioural therapy, there is a range of new hypnotics which are being developed or have recently received market approval. Suvorexant and the like target the orexin/hypocretin system: they should have less side effects in terms of drug–drug interactions with e.g. alcohol, less memory impairment and dependence potential compared to classical hypnotics.
... Currently, the most commonly prescribed hypnotic agents are γ-aminobutyric acid (GABA) agonists, which enhance the function of the major inhibitory neurotransmitter GABA by binding to the allosteric benzodiazepine site on GABA A receptors. Electroencephalographic (EEG) power spectral analyses have revealed a decrease in low-frequency (0.25 to 7.02 Hz) activity and an increase in high-frequency activity (14.04 to 21.84 Hz) in non-rapid eye movement (NREM) sleep with the administration of these GABA A receptor agonists (8,9). As a consequence of the widespread expression of GABA A receptors in the central nervous system, GABA A receptor agonists can inhibit neurons throughout the brain and spinal cord, including those not involved in the induction and maintenance of sleep (10,11). ...
... Currently, the most commonly prescribed hypnotic agents are γ-aminobutyric acid (GABA) agonists, which enhance the function of the major inhibitory neurotransmitter GABA by binding to the allosteric benzodiazepine site on GABA A receptors. Electroencephalographic (EEG) power spectral analyses have revealed a decrease in low-frequency (0.25 to 7.02 Hz) activity and an increase in high-frequency activity (14.04 to 21.84 Hz) in non-rapid eye movement (NREM) sleep with the administration of these GABA A receptor agonists (8,9). As a consequence of the widespread expression of GABA A receptors in the central nervous system, GABA A receptor agonists can inhibit neurons throughout the brain and spinal cord, including those not involved in the induction and maintenance of sleep (10,11). ...
Significance
Insomnia is a common symptom representing an important health burden. Widely prescribed hypnotic agents enhance the function of γ-aminobutyric acid (GABA), a major inhibitory neurotransmitter. The ability to arouse and respond to unexpected stimuli is a feature of normal sleep, and one of the concerns of this class of hypnotic agents is that patients may become physically and/or cognitively impaired while the drug is in effect. As a new approach for the treatment of insomnia, orexin receptor antagonists have been recently approved, which specifically inhibit the orexin-mediated wake-promoting system, supposedly without affecting the whole brain. We found that, compared with the GABA receptor agonist brotizolam, the orexin receptor antagonist suvorexant induced less impairment in body balance after taking the medicine.
... For example, GABA-targeting compounds improve the sleep profile, largely by enhancement of NREM sleep. [15][16][17] Insomnia treatment with GABA-targeting compounds at effective doses, though, may impair motor and cognitive function, including learning and memory. [18][19][20][21][22][23][24][25][26] For example, treatment with such hypnotics may impair synaptic plasticity and sleep dependent memory consolidation. ...
Insomnia-related sleep disruption can contribute to impaired learning and memory. Treatment of insomnia should ideally improve the sleep profile while minimally impacting mnemonic function, yet many hypnotic drugs (e.g., benzodiazepines) are known to impair memory. Here, we used a rat model of insomnia to determine if the novel hypnotic drug DORA-22, a dual orexin receptor antagonist, improves mild stress-induced insomnia with minimal effect on memory. Animals were first trained to remember the location of a hidden platform (acquisition) in the Morris Water Maze, then administered DORA-22 (10, 30, or 100mg/kg doses) or vehicle control. Animals were then subjected to a rodent insomnia model involving two exposures to dirty cages over a six-hour time period (at timepoints 0 and 3 hours), followed immediately by a probe trial in which memory of the water maze platform location was evaluated. DORA-22 treatment improved the insomnia-related sleep disruption - wake was attenuated and NREM sleep was normalized. REM sleep amounts were enhanced compared to vehicle treatment for one dose (30mg/kg). In the first hour of insomnia model exposure, DORA-22 promoted the number and average duration of NREM sleep spindles, which have been previously proposed to play a role in memory consolidation (all doses). Water maze measures revealed probe trial performance improvement for select doses of DORA-22, including increased time spent in the platform quadrant (10 and 30 mg/kg); and time spent in platform location and number of platform crossings (10mg/kg only). In conclusion, DORA-22 treatment improved insomnia-related sleep disruption and memory consolidation deficits.
... ***p < .001 theta activity expressed typically during REM sleep by increasing theta power and decreasing its frequency both in rodents [53] and humans [54]. Our work further shows that antagonizing Orx 1 and Orx 2 receptors affects only the pathological beta activity by decreasing its power without changing other brain waves. ...
Huntington’s disease (HD) is associated with sleep and circadian disturbances in addition to hallmark motor and cognitive impairments. Electrophysiological studies on HD mouse models have revealed an aberrant oscillatory activity at the beta frequency, during sleep, that is associated with HD pathology. Moreover, HD animal models display an abnormal sleep–wake cycle and sleep fragmentation. In this study, we investigated a potential involvement of the orexinergic system dysfunctioning in sleep–wake and circadian disturbances and abnormal network (i.e., beta) activity in the R6/1 mouse model. We found that the age at which orexin activity starts to deviate from normal activity pattern coincides with that of sleep disturbances as well as the beta activity. We also found that acute administration of Suvorexant, an orexin 1 and orexin 2 receptor antagonist, was sufficient to decrease the beta power significantly and to improve sleep in R6/1 mice. In addition, a 5-day treatment paradigm alleviated cognitive deficits and induced a gain of body weight in female HD mice. These results suggest that restoring normal activity of the orexinergic system could be an efficient therapeutic solution for sleep and behavioral disturbances in HD.
