Chronic orexin-1 receptor blockage attenuates depressive behaviors and provokes PSD-95 expression in a rat model of depression

Mirblouk, Batoul; Rohampour, Kambiz; Rostampour, Mohammad; Jafari, Adele; Taleghani, Behrooz Khakpour

doi:10.1016/j.bbr.2022.114123

Cited by 11 publications

(5 citation statements)

References 43 publications

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“…168 Very recently, chronic administration of the 1-SORA SB-334867 proved to decrease depressive-like behavior in a rat model of depression, demonstrating that OX1-R is also involved in this disorder. 169 Overall, these studies support that both OX-R subtypes might play importantroles in anxiety-and depressive-like behaviors, depending on the brain region considered.…”

Section: Mood Disordersmentioning

confidence: 64%

“…Contrarily, the DORA filorexant did not show significant efficacy in patients with MDD, but the results of this Phase 2 clinical trial should be interpreted with caution, due to the limitations concerning the insufficient statistical power and the enrollment criteria 168 . Very recently, chronic administration of the 1‐SORA SB‐334867 proved to decrease depressive‐like behavior in a rat model of depression, demonstrating that OX1‐R is also involved in this disorder 169 . Overall, these studies support that both OX‐R subtypes might play importantroles in anxiety‐ and depressive‐like behaviors, depending on the brain region considered.…”

Section: Pharmacological Potential Of Dual or Subtype‐selective Ox‐r ...mentioning

confidence: 85%

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Targeting orexin receptors: Recent advances in the development of subtype selective or dual ligands for the treatment of neuropsychiatric disorders

Bonifazi

Bello

Giorgioni

et al. 2023

Medicinal Research Reviews

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Orexin‐A and orexin‐B, also named hypocretin‐1 and hypocretin‐2, are two hypothalamic neuropeptides highly conserved across mammalian species. Their effects are mediated by two distinct G protein‐coupled receptors, namely orexin receptor type 1 (OX1‐R) and type 2 (OX2‐R), which share 64% amino acid identity. Given the wide expression of OX‐Rs in different central nervous system and peripheral areas and the several pathophysiological functions in which they are involved, including sleep‐wake cycle regulation (mainly mediated by OX2‐R), emotion, panic‐like behaviors, anxiety/stress, food intake, and energy homeostasis (mainly mediated by OX1‐R), both subtypes represent targets of interest for many structure–activity relationship (SAR) campaigns carried out by pharmaceutical companies and academies. However, before 2017 the research was predominantly directed towards dual‐orexin ligands, and limited chemotypes were investigated. Analytical characterizations, including resolved structures for both OX1‐R and OX2‐R in complex with agonists and antagonists, have improved the understanding of the molecular basis of receptor recognition and are assets for medicinal chemists in the design of subtype‐selective ligands. This review is focused on the medicinal chemistry aspects of small molecules acting as dual or subtype selective OX1‐R/OX2‐R agonists and antagonists belonging to different chemotypes and developed in the last years, including radiolabeled OX‐R ligands for molecular imaging. Moreover, the pharmacological effects of the most studied ligands in different neuropsychiatric diseases, such as sleep, mood, substance use, and eating disorders, as well as pain, have been discussed. Poly‐pharmacology applications and multitarget ligands have also been considered.

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Section: Mood Disordersmentioning

confidence: 64%

Section: Pharmacological Potential Of Dual or Subtype‐selective Ox‐r ...mentioning

confidence: 85%

Targeting orexin receptors: Recent advances in the development of subtype selective or dual ligands for the treatment of neuropsychiatric disorders

Bonifazi

Bello

Giorgioni

et al. 2023

Medicinal Research Reviews

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“…Currently, selective agonists and antagonists of orexin receptors have been tested in preclinical studies for their potential effects on insomnia, narcolepsy, obesity, addiction, anxiety, depression, dementia, and so on [ 9 ]. Especially for OX1Rs, their involvement in the regulation of autonomic responses, reward, motivation, mood, and memory further justifies and encourages their thorough investigation [ 45 , 46 , 47 ]. However, species-specific differences in the expression of orexin receptors [ 15 ] highlight the need for accurate information regarding the human brain, in order to better predict the effect of selective OX1R agonists and antagonists on patients.…”

Section: Discussionmentioning

confidence: 99%

Cellular Localization of Orexin 1 Receptor in Human Hypothalamus and Morphological Analysis of Neurons Expressing the Receptor

Vraka

Mytilinaios²,

Katsenos

et al. 2023

Biomolecules

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The orexin system is related to food behavior, energy balance, wakefulness and the reward system. It consists of the neuropeptides orexin A and B, and their receptors, orexin 1 receptor (OX1R) and orexin 2 receptor (OX2R). OX1R has selective affinity for orexin A, and is implicated in multiple functions, such as reward, emotions, and autonomic regulation. This study provides information about the OX1R distribution in human hypothalamus. The human hypothalamus, despite its small size, demonstrates a remarkable complexity in terms of cell populations and cellular morphology. Numerous studies have focused on various neurotransmitters and neuropeptides in the hypothalamus, both in animals and humans, however, there is limited experimental data on the morphological characteristics of neurons. The immunohistochemical analysis of the human hypothalamus revealed that OX1R is mainly found in the lateral hypothalamic area, the lateral preoptic nucleus, the supraoptic nucleus, the dorsomedial nucleus, the ventromedial nucleus, and the paraventricular nucleus. The rest of the hypothalamic nuclei do not express the receptor, except for a very low number of neurons in the mammillary bodies. After identifying the nuclei and neuronal groups that were immunopositive for OX1R, a morphological and morphometric analysis of those neurons was conducted using the Golgi method. The analysis revealed that the neurons in the lateral hypothalamic area were uniform in terms of their morphological characteristics, often forming small groups of three to four neurons. A high proportion of neurons in this area (over 80%) expressed the OX1R, with particularly high expression in the lateral tuberal nucleus (over 95% of neurons). These results were analyzed, and shown to represent, at the cellular level, the distribution of OX1R, and we discuss the regulatory role of orexin A in the intra-hypothalamic areas, such as its special role in the plasticity of neurons, as well as in neuronal networks of the human hypothalamus.

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“…Orexin-A, a hypothalamic neuropeptide, modulates appetite, the sleep-wake cycle, stress response, and reward processing 78 . Chronic antagonism of orexin receptors mitigates depressive-like behaviors in rodents 79 . In humans, orexin receptor antagonists improve sleep outcomes in individuals with insomnia 80,81 .…”

Section: Discussionmentioning

confidence: 99%

Plasma Inflammation and Plasticity Biomarkers Associated with Future Suicidal Ideation and Depression Severity in Mood Disorders: A Six-Month Prospective Study

Lengvenyte

Cognasse²,

Hamzeh‐Cognasse³

et al. 2023

Preprint

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Discerning potential associations between plasma biomarkers and the evolution of suicidal ideation (SI) in mood disorders could advance our understanding of disease progression. We evaluated a cohort of 149 mood disorder patients, assessing 32 plasma soluble proteins implicated in neuroplasticity and inflammation at baseline and six-month follow-up. The primary outcome was the occurrence of suicidal ideation during the six-month follow-up. Secondary outcomes included the presence of suicidal ideation and depression severity at six-month follow-up. We employed Principal Component Analysis and Elastic Net regression for feature extraction and selection. Selected markers were then examined in covariate-adjusted regression models. Our results showed that high baseline levels of interferon-γ and a pro-inflammatory principal component score were linked to the occurrence of SI during follow-up. At the six-month point, SI presence was associated with elevated interferon-γ, interleukin-1β, and diminished serotonin levels, with the latter connection dissipating post-adjustment. High interferon-γ, and low orexin-A at baseline were associated with increased depression severity at follow-up, with specific associations between interferon-γ and anxious symptoms, and orexin-A and atypical depressive symptoms. These findings identify elevated interferon-γ, interleukin-1β, and reduced orexin-A as potential biomarkers associated with the occurrence of SI and severity of depression in mood disorders over six months. With further validation in larger cohorts, these insights could enable more personalized risk assessment and intervention strategies, representing a step forward in improving therapeutic outcomes.

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Chronic orexin-1 receptor blockage attenuates depressive behaviors and provokes PSD-95 expression in a rat model of depression

Cited by 11 publications

References 43 publications

Targeting orexin receptors: Recent advances in the development of subtype selective or dual ligands for the treatment of neuropsychiatric disorders

Targeting orexin receptors: Recent advances in the development of subtype selective or dual ligands for the treatment of neuropsychiatric disorders

Cellular Localization of Orexin 1 Receptor in Human Hypothalamus and Morphological Analysis of Neurons Expressing the Receptor

Plasma Inflammation and Plasticity Biomarkers Associated with Future Suicidal Ideation and Depression Severity in Mood Disorders: A Six-Month Prospective Study

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