Zhuang Chenyu, Cao Yuhan, Lu Jiayu, Zhou Yifan, Liu Yanqing, Li Yan
Medical College, Yangzhou University, Yangzhou, 225009, PR China.
The Key Laboratory of Syndrome Differentiation and Treatment of Gastric, Cancer of the State Administration of Traditional Chinese Medicine, Yangzhou, 225009, PR China.
Psychopharmacology (Berl). 2025 Jun 16. doi: 10.1007/s00213-025-06839-2.
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).
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.
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.
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.
食欲素（OX）系统在调节认知功能中起关键作用。该系统的失调与多种痴呆相关的神经疾病有关，包括阿尔茨海默病（AD）、帕金森病（PD）、亨廷顿病（HD）和路易体痴呆（DLB）。
本综述旨在综合当前关于OX系统参与痴呆相关神经疾病的研究，重点关注其对认知功能的影响及其作为治疗靶点的潜力。
OX系统包括下丘脑神经肽和受体（OX1R和OX2R），在与痴呆相关的神经退行性疾病中表现出失调。OX浓度的变化与认知能力下降密切相关，且这种相关性随疾病进展而变化。OX调节包括神经元存活、突触可塑性、神经网络完整性和昼夜节律稳定性等重要分子机制，这些过程会随着认知缺陷加剧而受损。这些发现强调了OX在细胞弹性和认知功能中关键且依赖于背景的作用。
OX系统成为痴呆相关认知障碍的多方面治疗靶点。其作用在疾病不同阶段有所不同，最初提供神经保护，但后期会导致病理变化。此外，OX参与昼夜节律调节使其临床应用复杂化，因为节律紊乱会加剧认知缺陷。这些相反的功能凸显了需要进行量身定制的、针对特定阶段的干预措施，以在最大程度提高认知益处的同时最小化不良信号。
