Chenyu Zhuang, Yuhan Cao, Jiayu Lu, Yifan Zhou, Yanqing Liu, Yan Li
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Changes in OX concentrations strongly correlate with cognitive decline, and this correlation varies with disease progression. OX regulates essential molecular mechanisms, including neuronal survival, synaptic plasticity, neural network integrity, and circadian rhythm stability-processes impaired as cognitive deficits intensify. These findings emphasize OX's critical and context-dependent role in cellular resilience and cognitive function.</p><p><strong>Conclusions: </strong>OX system emerges as a multifaceted therapeutic target for dementia-related cognitive impairment. Its effects vary across disease stages, initially offering neuroprotection but later contributing to pathology. Moreover, OX's involvement in circadian rhythm regulation complicates its clinical utility, as disruptions exacerbate cognitive deficits. These opposing functions highlight the need for tailored, stage-specific interventions to maximize cognitive benefits while minimizing adverse signaling.</p>","PeriodicalId":20783,"journal":{"name":"Psychopharmacology","volume":" ","pages":"2161-2179"},"PeriodicalIF":3.3000,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"The orexin/hypocretin system in dementia-related neurological disorders: a double-edged sword in cognitive impairment.\",\"authors\":\"Chenyu Zhuang, Yuhan Cao, Jiayu Lu, Yifan Zhou, Yanqing Liu, Yan Li\",\"doi\":\"10.1007/s00213-025-06839-2\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Rationale: </strong>The orexin (OX) system plays a crucial role in regulating cognitive functions. Dysregulation of this system has been implicated in several dementia-related neurological disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD) and dementia with Lewy bodies (DLB).</p><p><strong>Objectives: </strong>This review aims to synthesize current research on the involvement of the OX system in dementia-related neurological diseases, focusing on its effects on cognitive function and its potential as a therapeutic target.</p><p><strong>Results: </strong>The OX system, encompassing hypothalamic neuropeptides and receptors (OX1R and OX2R), exhibits dysregulation in neurodegenerative diseases associated with dementia. Changes in OX concentrations strongly correlate with cognitive decline, and this correlation varies with disease progression. OX regulates essential molecular mechanisms, including neuronal survival, synaptic plasticity, neural network integrity, and circadian rhythm stability-processes impaired as cognitive deficits intensify. These findings emphasize OX's critical and context-dependent role in cellular resilience and cognitive function.</p><p><strong>Conclusions: </strong>OX system emerges as a multifaceted therapeutic target for dementia-related cognitive impairment. Its effects vary across disease stages, initially offering neuroprotection but later contributing to pathology. Moreover, OX's involvement in circadian rhythm regulation complicates its clinical utility, as disruptions exacerbate cognitive deficits. These opposing functions highlight the need for tailored, stage-specific interventions to maximize cognitive benefits while minimizing adverse signaling.</p>\",\"PeriodicalId\":20783,\"journal\":{\"name\":\"Psychopharmacology\",\"volume\":\" \",\"pages\":\"2161-2179\"},\"PeriodicalIF\":3.3000,\"publicationDate\":\"2025-10-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Psychopharmacology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1007/s00213-025-06839-2\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2025/6/16 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q2\",\"JCRName\":\"NEUROSCIENCES\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Psychopharmacology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1007/s00213-025-06839-2","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/6/16 0:00:00","PubModel":"Epub","JCR":"Q2","JCRName":"NEUROSCIENCES","Score":null,"Total":0}
The orexin/hypocretin system in dementia-related neurological disorders: a double-edged sword in cognitive impairment.
Rationale: The orexin (OX) system plays a crucial role in regulating cognitive functions. Dysregulation of this system has been implicated in several dementia-related neurological disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD) and dementia with Lewy bodies (DLB).
Objectives: This review aims to synthesize current research on the involvement of the OX system in dementia-related neurological diseases, focusing on its effects on cognitive function and its potential as a therapeutic target.
Results: The OX system, encompassing hypothalamic neuropeptides and receptors (OX1R and OX2R), exhibits dysregulation in neurodegenerative diseases associated with dementia. Changes in OX concentrations strongly correlate with cognitive decline, and this correlation varies with disease progression. OX regulates essential molecular mechanisms, including neuronal survival, synaptic plasticity, neural network integrity, and circadian rhythm stability-processes impaired as cognitive deficits intensify. These findings emphasize OX's critical and context-dependent role in cellular resilience and cognitive function.
Conclusions: OX system emerges as a multifaceted therapeutic target for dementia-related cognitive impairment. Its effects vary across disease stages, initially offering neuroprotection but later contributing to pathology. Moreover, OX's involvement in circadian rhythm regulation complicates its clinical utility, as disruptions exacerbate cognitive deficits. These opposing functions highlight the need for tailored, stage-specific interventions to maximize cognitive benefits while minimizing adverse signaling.
期刊介绍：
Official Journal of the European Behavioural Pharmacology Society (EBPS)
Psychopharmacology is an international journal that covers the broad topic of elucidating mechanisms by which drugs affect behavior. The scope of the journal encompasses the following fields:
Human Psychopharmacology: Experimental
This section includes manuscripts describing the effects of drugs on mood, behavior, cognition and physiology in humans. The journal encourages submissions that involve brain imaging, genetics, neuroendocrinology, and developmental topics. Usually manuscripts in this section describe studies conducted under controlled conditions, but occasionally descriptive or observational studies are also considered.
Human Psychopharmacology: Clinical and Translational
This section comprises studies addressing the broad intersection of drugs and psychiatric illness. This includes not only clinical trials and studies of drug usage and metabolism, drug surveillance, and pharmacoepidemiology, but also work utilizing the entire range of clinically relevant methodologies, including neuroimaging, pharmacogenetics, cognitive science, biomarkers, and others. Work directed toward the translation of preclinical to clinical knowledge is especially encouraged. The key feature of submissions to this section is that they involve a focus on clinical aspects.
Preclinical psychopharmacology: Behavioral and Neural
This section considers reports on the effects of compounds with defined chemical structures on any aspect of behavior, in particular when correlated with neurochemical effects, in species other than humans. Manuscripts containing neuroscientific techniques in combination with behavior are welcome. We encourage reports of studies that provide insight into the mechanisms of drug action, at the behavioral and molecular levels.
Preclinical Psychopharmacology: Translational
This section considers manuscripts that enhance the confidence in a central mechanism that could be of therapeutic value for psychiatric or neurological patients, using disease-relevant preclinical models and tests, or that report on preclinical manipulations and challenges that have the potential to be translated to the clinic. Studies aiming at the refinement of preclinical models based upon clinical findings (back-translation) will also be considered. The journal particularly encourages submissions that integrate measures of target tissue exposure, activity on the molecular target and/or modulation of the targeted biochemical pathways.
Preclinical Psychopharmacology: Molecular, Genetic and Epigenetic
This section focuses on the molecular and cellular actions of neuropharmacological agents / drugs, and the identification / validation of drug targets affecting the CNS in health and disease. We particularly encourage studies that provide insight into the mechanisms of drug action at the molecular level. Manuscripts containing evidence for genetic or epigenetic effects on neurochemistry or behavior are welcome.
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