Article
Clinical Neurology
Maija Orjatsalo, Eemil Partinen, Gerd Wallukat, Anniina Alakuijala, Markku Partinen
Summary: The study found that patients with narcolepsy type 1 carry autoimmune antibodies that may be related to symptoms such as cataplexy, hallucinations, pain, and autonomic dysfunction. Positive autoantibodies against M2 muscarinic receptors, nociception receptors, and beta 2 adrenergic receptors may exacerbate the progression of the disease.
Article
Multidisciplinary Sciences
Rebecca Evans, Haruhide Kimura, Robert Alexander, Ceri H. Davies, Helene Faessel, Deborah S. Hartman, Takashi Ishikawa, Emiliangelo Ratti, Kohei Shimizu, Motohisa Suzuki, Shinichiro Tanaka, Hiroshi Yukitake, Yves Dauvilliers, Emmanuel Mignot
Summary: Narcolepsy is a sleep disorder that can be classified into type 1 and type 2. The drug danavorexton shows promising results in treating narcolepsy by targeting both orexin 1 and orexin 2 receptors.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Review
Clinical Neurology
Maria P. Mogavero, Alessandro Silvani, Giuseppe Lanza, Lourdes M. DelRosso, Luigi Ferini-Strambi, Raffaele Ferri
Summary: After describing orexins and their roles in sleep and medical disorders, the article discusses the clinical evidence on the effects of DORAs and SORAs on insomnia to provide recommendations for further assessment in personalized and precision medicine. Trials with orexin receptor antagonists have shown potential as a valid therapeutic option for insomnia in various medical conditions, but more studies are needed to determine the most suitable options for different patient populations.
NATURE AND SCIENCE OF SLEEP
(2023)
Article
Biochemistry & Molecular Biology
Melissa Girard, Steve Dagenais Bellefeuille, Emilie Eiselt, Guillaume Arguin, Jean-Michel Longpre, Philippe Sarret, Fernand-Pierre Gendron
Summary: This study found that endosomal trafficking plays an important role in G protein-coupled receptor (GPCR) signaling. UDP selectively activates GPCR P2Y6 as a signaling molecule. The study found that MRS2693 and UDP have different effects on the internalization of the P2Y6 receptor, with MRS2693 inducing P2Y6 internalization through an independent caveolin-dependent mechanism. This study provides insights for the development of bias ligands that can influence P2Y6 signaling.
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH
(2023)
Article
Cell Biology
Andrew S. Huhn, Patrick H. Finan, Charlene E. Gamaldo, Alexis S. Hammond, Annie Umbricht, Cecilia L. Bergeria, Eric C. Strain, Kelly E. Dunn
Summary: This study examined the use of a dual-orexin receptor antagonist in opioid withdrawal and found that it may have potential benefits for improving sleep and withdrawal outcomes.
SCIENCE TRANSLATIONAL MEDICINE
(2022)
Article
Behavioral Sciences
Takashi Ishikawa, Hiroe Hara, Ayumi Kawano, Haruhide Kimura
Summary: Narcolepsy type 1 (NT1) is a neurological disorder characterized by excessive daytime sleepiness and other symptoms. The novel drug danavorexton is being evaluated for its potential in treating NT1. Preclinical studies have shown that danavorexton promotes wakefulness, reduces fragmentation of wakefulness, and suppresses weight gain in a mouse model of NT1. These findings provide valuable insights into the pathophysiology of NT1 and the potential therapeutic effects of OX2R agonists.
PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR
(2022)
Article
Clinical Neurology
Brendan P. Lucey, Haiyan Liu, Cristina D. Toedebusch, David Freund, Tiara Redrick, Samir L. Chahin, Kwasi G. Mawuenyega, James G. Bollinger, Vitaliy Ovod, Nicolas R. Barthelemy, Randall J. Bateman
Summary: In this study, it was found that suvorexant, a dual orexin receptor antagonist, acutely decreased tau phosphorylation and amyloid-beta concentrations in the central nervous system. This suggests that suvorexant may have potential as a repurposed drug for the prevention of Alzheimer's disease.
ANNALS OF NEUROLOGY
(2023)
Review
Pharmacology & Pharmacy
Marieke Vringer, Birgitte Rahbek Kornum
Summary: Narcolepsy type 1 and type 2 are characterized by excessive daytime sleepiness and reduced quality of life, with current treatments focused on improving daytime sleepiness and reducing cataplexy. Targeting Hcrt receptors shows promise in alleviating symptoms, but careful consideration of potential side effects is required. Immunotherapies may target the core pathophysiology of narcolepsy, but further research is needed to identify the optimal therapeutic target.
EXPERT OPINION ON THERAPEUTIC TARGETS
(2021)
Article
Pharmacology & Pharmacy
Hiroshi Tsuneki, Masanori Sugiyama, Kiyofumi Sato, Hisakatsu Ito, Sanaka Nagai, Kanta Kon, Tsutomu Wada, Nao Kobayashi, Takuya Okada, Naoki Toyooka, Masashi Kawasaki, Toshihiro Ito, Ryota Otsubo, Daisuke Okuzaki, Teruhito Yasui, Toshiyasu Sasaoka
Summary: The drug lemborexant, used to treat insomnia, has been found to have a positive effect on sleep and glucose metabolism in individuals with type 2 diabetes. In experiments, lemborexant increased sleep duration and improved glucose tolerance in db/db mice. This improvement did not affect body weight or insulin secretion.
EUROPEAN JOURNAL OF PHARMACOLOGY
(2023)
Article
Neurosciences
Hye Ji J. Kim, Ayat Zagzoog, Anna Maria Smolyakova, Udoka C. Ezeaka, Michael J. Benko, Teagan Holt, Robert B. Laprairie
Summary: The endocannabinoid and orexin neuromodulatory systems play key roles in regulating sleep, appetite, pain processing, and emotional behaviors related to reward. They co-localize in the brain regions and physically interact as heterodimers, particularly in the ventral striatum. Male mice show greater effects following combined treatment with cannabinoid receptor agonist and orexin receptor antagonist.
FRONTIERS IN NEUROSCIENCE
(2021)
Review
Clinical Neurology
Laura Palagini, Pierre A. Geoffroy, Matteo Balestrieri, Mario Miniati, Giovanni Biggio, Claudio Liguori, Danilo Menicucci, Luigi Ferini-Strambi, Lino Nobili, Dieter Riemann, Angelo Gemignani
Summary: Insomnia disorder is associated with hyperarousal, stress, and emotion dysregulation. The orexinergic system plays a key role in sleep, arousal, and stress modulation, making it of interest for insomnia treatment. Research suggests that overactivation of the orexinergic system may contribute to disrupted sleep and insomnia in response to stress. Dual orexin receptor antagonists (DORAs) may rebalance orexins and regulate sleep and stress-related systems, potentially reducing hyperarousal in insomnia. However, further research is needed to fully understand the role of the orexin system in insomnia and assess the effects of DORAs on sleep and stress regulation.
JOURNAL OF SLEEP RESEARCH
(2023)
Review
Psychiatry
Xin Wu, Tao Xue, Zhouqing Chen, Zhong Wang, Gang Chen
Summary: This review examines the use of orexin receptor antagonists (ORAs) in treating insomnia. Recent research focuses on comorbid insomnia with suvorexant, while lemborexant and daridorexant are still being studied for primary insomnia. Almorexant is mainly used in animal studies due to safety concerns. There is limited research on the sleep-promoting effects of filorexant. Seltorexant, a selective ORA, has not reached phase 3 yet. High-quality clinical trials are needed to compare authorized ORAs, investigate non-approved ORAs, and explore the pathophysiology of the orexin signaling system in insomnia.
CURRENT PSYCHIATRY REPORTS
(2022)
Review
Pharmacology & Pharmacy
Juliane Park, Kandon P. P. Render, Drew W. W. Cates
Summary: This article reviews the pharmacology, pharmacokinetics/pharmacodynamics, safety, and efficacy of daridorexant in patients with insomnia. Daridorexant demonstrates favorable tolerability and significant reductions in LPS and WASO in adult patients with insomnia.
ANNALS OF PHARMACOTHERAPY
(2023)
Article
Medicine, General & Internal
Craig Chepke, Rakesh Jain, Russell Rosenberg, Margaret Moline, Jane Yardley, Kate Pinner, Dinesh Kumar, Carlos Perdomo, Gleb Filippov, Norman Atkins, Manoj Malhotra
Summary: This analysis evaluated the effects of lemborexant, a dual orexin receptor antagonist, on reducing fatigue in patients with insomnia. The results showed that lemborexant significantly reduced subject-reported fatigue over a 6-month treatment period, and this reduction was sustained over 12 months. Improvements in fatigue were positively correlated with improvements in sleep onset and maintenance parameters.
POSTGRADUATE MEDICINE
(2022)
Article
Behavioral Sciences
Lu Wang, Yundan Pan, Chunyan Ye, Lizhe Guo, Sumei Luo, Sisi Dai, Na Chen, E. Wang
Summary: Orexin receptor antagonists can be widely used in adults and the elderly, with both short-term and long-term use being effective for primary insomnia. H1 antagonists are more effective in adults than in the elderly. Although benzodiazepines have a more obvious effect on sleep maintenance, it is best to reduce their use due to their side effects, especially for the elderly. As a food supplement, melatonin has little effect on adults, but it still has a certain effect on the elderly.
NEUROSCIENCE AND BIOBEHAVIORAL REVIEWS
(2021)
Article
Biochemistry & Molecular Biology
Richard J. Ward, John D. Pediani, Antoine G. Godin, Graeme Milligan
JOURNAL OF BIOLOGICAL CHEMISTRY
(2015)
Article
Biochemistry & Molecular Biology
Eugenia Sergeev, Anders Hojgaard Hansen, Sunil K. Pandey, Amanda E. MacKenzie, Brian D. Hudson, Trond Ulven, Graeme Milligan
JOURNAL OF BIOLOGICAL CHEMISTRY
(2016)
Article
Biochemistry & Molecular Biology
Elisa Alvarez-Curto, Asuka Inoue, Laura Jenkins, Sheikh Zahir Raihan, Rudi Prihandoko, Andrew B. Tobin, Graeme Milligan
JOURNAL OF BIOLOGICAL CHEMISTRY
(2016)
Article
Biochemistry & Molecular Biology
John D. Pediani, Richard J. Ward, Antoine G. Godin, Sara Marsango, Graeme Milligan
JOURNAL OF BIOLOGICAL CHEMISTRY
(2016)
Article
Biochemistry & Molecular Biology
Ying Liu, Hong Zeng, John D. Pediani, Richard J. Ward, Lu-Yao Chen, Nan Wu, Li Ma, Mei Tang, Yang Yang, Su An, Xiao-Xi Guo, Qian Hao, Tian-Rui Xu
Article
Immunology
Nurul A. S. Binti Mohd Amir, Amanda E. Mackenzie, Laura Jenkins, Karim Boustani, Marston C. Hillier, Tomoko Tsuchiya, Graeme Milligan, James E. Pease
JOURNAL OF IMMUNOLOGY
(2018)
Review
Neurosciences
Sara Marsango, Richard J. Ward, Elisa Alvarez-Curto, Graeme Milligan
Review
Pharmacology & Pharmacy
John D. Pediani, Richard J. Ward, Sara Marsango, Graeme Milligan
TRENDS IN PHARMACOLOGICAL SCIENCES
(2018)
Article
Multidisciplinary Sciences
Sara Marsango, Gianluigi Caltabiano, Mireia Jimemez-Roses, Mark J. Millan, John D. Pediani, Richard J. Ward, Graeme Milligan
SCIENTIFIC REPORTS
(2017)
Article
Biochemical Research Methods
Michael R. Stoneman, Gabriel Biener, Richard J. Ward, John D. Pediani, Dammar Badu, Annie Eis, Ionel Popa, Graeme Milligan, Valerica Raicu
Article
Biochemistry & Molecular Biology
Richard J. Ward, John D. Pediani, Sara Marsango, Richard Jolly, Michael R. Stoneman, Gabriel Biener, Tracy M. Handel, Valerica Raicu, Graeme Milligan
Summary: CXCR4, a chemokine-activated G protein-coupled receptor widely expressed in immune response cells, plays a role in cancer development, viral infection, and other processes. Research indicates that CXCR4 can exist as a mixture of monomers, dimers, and higher-order oligomers, with different antagonists affecting its oligomerization state differently.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2021)
Article
Cell Biology
Andy Shaw, Stewart Jeromson, Kenneth R. Watterson, John D. Pediani, Iain J. Gallagher, Tim Whalley, Gillian Dreczkowski, Naomi Brooks, Stuart D. Galloway, D. Lee Hamilton
AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY
(2017)
Article
Biochemistry & Molecular Biology
Richard J. Ward, John D. Pediani, Kaleeckal G. Harikumar, Laurence J. Miller, Graeme Milligan
BIOCHEMICAL JOURNAL
(2017)
Review
Pharmacology & Pharmacy
Graeme Milligan
BRITISH JOURNAL OF PHARMACOLOGY
(2018)