Jacobson Laura H, Hoyer Daniel, de Lecea Luis
The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Victoria, Australia.
Department of Biochemistry and Pharmacology, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, Victoria, Australia.
J Intern Med. 2022 May;291(5):533-556. doi: 10.1111/joim.13406. Epub 2022 Jan 19.
The hypocretins (Hcrts), also known as orexins, are two neuropeptides produced exclusively in the lateral hypothalamus. They act on two specific receptors that are widely distributed across the brain and involved in a myriad of neurophysiological functions that include sleep, arousal, feeding, reward, fear, anxiety and cognition. Hcrt cell loss in humans leads to narcolepsy with cataplexy (narcolepsy type 1), a disorder characterized by intrusions of sleep into wakefulness, demonstrating that the Hcrt system is nonredundant and essential for sleep/wake stability. The causal link between Hcrts and arousal/wakefulness stabilisation has led to the development of a new class of drugs, Hcrt receptor antagonists to treat insomnia, based on the assumption that blocking orexin-induced arousal will facilitate sleep. This has been clinically validated: currently, two Hcrt receptor antagonists are approved to treat insomnia (suvorexant and lemborexant), with a New Drug Application recently submitted to the US Food and Drug Administration for a third drug (daridorexant). Other therapeutic applications under investigation include reduction of cravings in substance-use disorders and prevention of neurodegenerative disorders such as Alzheimer's disease, given the apparent bidirectional relationship between poor sleep and worsening of the disease. Circuit neuroscience findings suggest that the Hcrt system is a hub that integrates diverse inputs modulating arousal (e.g., circadian rhythms, metabolic status, positive and negative emotions) and conveys this information to multiple output regions. This neuronal architecture explains the wealth of physiological functions associated with Hcrts and highlights the potential of the Hcrt system as a therapeutic target for a number of disorders. We discuss present and future possible applications of drugs targeting the Hcrt system for the treatment of circuit-related neuropsychiatric and neurodegenerative conditions.
下丘脑泌素（Hcrts），也被称为食欲素，是仅在下丘脑外侧产生的两种神经肽。它们作用于两种特定受体，这些受体广泛分布于大脑中，并参与无数神经生理功能，包括睡眠、觉醒、进食、奖赏、恐惧、焦虑和认知。人类下丘脑泌素细胞缺失会导致发作性睡病伴猝倒（1型发作性睡病），这是一种以睡眠侵入清醒状态为特征的疾病，表明下丘脑泌素系统是不可或缺的，对睡眠/觉醒稳定性至关重要。下丘脑泌素与觉醒/清醒稳定之间的因果联系导致了一类新型药物——下丘脑泌素受体拮抗剂的开发，用于治疗失眠，其依据是阻断食欲素诱导的觉醒将有助于睡眠。这已在临床上得到验证：目前，两种下丘脑泌素受体拮抗剂已被批准用于治疗失眠（苏沃雷生和伦博雷生），最近还有一种新药（达利雷生）已向美国食品药品监督管理局提交新药申请。正在研究的其他治疗应用包括减少物质使用障碍中的渴望以及预防神经退行性疾病，如阿尔茨海默病，因为睡眠不佳与疾病恶化之间存在明显的双向关系。神经回路神经科学研究结果表明，下丘脑泌素系统是一个枢纽，整合了调节觉醒的各种输入（如昼夜节律、代谢状态、正负情绪），并将这些信息传递到多个输出区域。这种神经元结构解释了与下丘脑泌素相关的丰富生理功能，并突出了下丘脑泌素系统作为多种疾病治疗靶点的潜力。我们讨论了针对下丘脑泌素系统的药物在治疗与神经回路相关的神经精神和神经退行性疾病方面目前及未来可能的应用。
