Microglia are the first line of defense at the level of the central nervous system (CNS). Phenotypic change in microglia can be regulated by various factors, including the orexin system. Neuroinflammation is an inflammatory process mediated by cytokines, by the lack of interaction between neurotransmitters and their specific receptors, caused by systemic tissue damage or, more often, associated with direct damage to the CNS. Chronic activation of microglia could lead to long-term neurodegenerative diseases. This review aims to explore how tocopherol (vitamin E) and the orexin system may play a role in the prevention and treatment of microglia inflammation and, consequently, in neurodegenerative diseases thanks to its antioxidant properties. The results of animal and in vitro studies provide evidence to support the use of tocopherol for a reduction in microglia inflammation as well as a greater activation of the orexinergic system. Although there is much in vivo and in vitro evidence of vitamin E antioxidant and protective abilities, there are still conflicting results for its use as a treatment for neurodegenerative diseases that speculate that vitamin E, under certain conditions or genetic predispositions, can be pro-oxidant and harmful.
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http://dx.doi.org/10.3390/brainsci11081098 | DOI Listing |
Drug Alcohol Depend Rep
March 2025
Institute for Drug and Alcohol Studies, Virginia Commonwealth University, 203 East Cary Street, Richmond, VA 23219, USA.
Background: Evidence supports the common incidence of sleep disturbance in opioid use disorder (OUD) as a potential marker of disrupted orexin system functioning. This study evaluated the initial safety and tolerability of a challenge dose of lemborexant, a dual orexin antagonist, as an adjunct to buprenorphine/naloxone.
Methods: Patients (18-65 years old) with OUD receiving sublingual buprenorphine/naloxone, with a Pittsburgh Sleep Quality Index total score of 6 or higher, were recruited from outpatient clinics.
Int J Mol Sci
December 2024
A.V. Zhirmunsky National Scientific Center of Marine Biology, Far Eastern Branch, Russian Academy of Sciences, 690041 Vladivostok, Russia.
Sleep is the most important physiological function of all animals studied to date. Sleep disorders include narcolepsy, which is characterized by excessive daytime sleepiness, disruption of night sleep, and muscle weakness-cataplexy. Narcolepsy is known to be caused by the degeneration of orexin-synthesizing neurons (hypocretin (HCRT) neurons or orexin neurons) in the hypothalamus.
View Article and Find Full Text PDFExpert Opin Emerg Drugs
January 2025
Department of Psychiatry, University of Toronto, Toronto, ON, Canada.
Introduction: Preclinical and clinical pharmacologic evidence indicate that orexin systems are relevant to sleep-wake cycle regulation and dimensions of reward and cognition, providing the basis to hypothesizing that they may be effective as therapeutics in mental disorders. Due to the limited efficacy and tolerability profiles of existing treatments for Major Depressive Disorder (MDD), investigational compounds in novel treatment classes are needed; seltorexant, an orexin receptor antagonist, is a potential new treatment currently under investigation.
Areas Covered: Mechanisms implicated in MDD, including reward and sleep are first overviewed.
Toxicol Sci
January 2025
Takeda Development Center Americas, Inc, Cambridge, MA, USA.
The frequency of drug-induced liver injury (DILI) in clinical trials remains a challenge for drug developers despite advances in human hepatotoxicity models and improvements in reducing liver-related attrition in preclinical species. TAK-994, an oral orexin receptor 2 agonist, was withdrawn from phase II clinical trials due to the appearance of severe DILI. Here, we investigate the likely mechanism of TAK-994 DILI in hepatic cell culture systems examined cytotoxicity, mitochondrial toxicity, impact on drug transporter proteins, and covalent binding.
View Article and Find Full Text PDFProtein Expr Purif
January 2025
VIB-VUB Center for Structural Biology, VIB, Pleinlaan 2, Brussels, Belgium; Structural Biology Brussels, Vrije Universiteit Brussel (VUB), Pleinlaan 2, Brussels, Belgium. Electronic address:
Orexin receptors constitute a family of class A G-protein coupled receptors. There are two subtypes of orexin receptors, namely OX1R and OX2R. OX1R and OX2R are widely distributed in the central nervous system and are the targets for the peptide neurotransmitters orexin-A and orexin-B.
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