1,721,132 research outputs found
Melatonin, Melatonin Receptors and Sleep: Moving Beyond Traditional Views
Full text linkSleep, constituting approximately one-third of the human lifespan, is a crucial physiological process essential for physical and mental well-being. Normal sleep consists of an orderly progression through wakefulness, non-rapid eye movement (NREM) sleep, and rapid eye movement (REM) sleep, all of which are tightly regulated. Melatonin, often referred to as the “hormone of sleep,” plays a pivotal role as a regulator of the sleep/wake cycle and exerts its effects through high-affinity G-protein coupled receptors known as MT1 and MT2. Selective modulation of these receptors presents a promising therapeutic avenue for sleep disorders. This review examines research on the multifaceted role of melatonin in sleep regulation, focusing on selective ligands targeting MT1 and MT2 receptors, as well as studies involving MT1 and MT2 knockout mice. Contrary to common beliefs, growing evidence suggests that melatonin, through MT1 and MT2 receptors, might not only influence circadian aspects of sleep but likely, also modulate the homeostatic process of sleep and sleep architecture, or could be the molecule linking the homeostatic and circadian regulation of sleep. Furthermore, the distinct brain localization of MT1 and MT2 receptors, with MT1 receptors primarily regulating REM sleep and MT2 receptors regulating NREM sleep, is discussed. Collectively, sleep regulation extends beyond the circulating levels and circadian peak of melatonin; it also critically involves the expression, molecular activation, and regulatory functions of MT1 and MT2 receptors across various brain regions and nuclei involved in the regulation of sleep. This research underscores the importance of ongoing investigation into the selective roles of MT1 and MT2 receptors in sleep. Such research efforts are expected to pave the way for the development of targeted MT1 or MT2 receptors ligands, thereby optimizing therapeutic interventions for sleep disorders
Acute and Chronic Pain Preclinical Models to Study the Analgesic Properties of Melatonergic Compounds
No full textMelatonin (MLT) has been implicated in several pathophysiological states, including pain. MLT mostly activates two G protein-coupled receptors, MT1 and MT2. MLT displays analgesic properties in several animal paradigms of acute, inflammatory, and neuropathic pain. Although the analgesic mechanism of action of MLT is not yet completely elucidated, there is strong preclinical evidence suggesting the pharmacological potential of melatonergic compounds for treating pain. Importantly, MLT and melatonergic compounds seem to have a favorable toxicological profile than currently approved analgesic drugs. These compounds may thus deserve to be further developed as novel analgesic drugs, but this process relies on the use of appropriate and standardized experimental procedures. Therefore, in this chapter, we present the methodology to study the analgesic properties of MLT and melatonergic drugs in a preclinical model of chronic and acute pain. In addition to technical details of the surgical technique, details of anesthesia and perioperative care are also included
Distinct role of melatonin MT1 and MT2 receptors in sleep and anxiety: insights from melatonin receptor knockout mice
No full textTherapeutic modulation of the kynurenine pathway in severe mental illness and comorbidities: A potential role for serotonergic psychedelics
Full text linkMounting evidence points towards a crucial role of the kynurenine pathway (KP) in the altered gut-brain axis (GBA) balance in severe mental illness (SMI, namely depression, bipolar disorder, and schizophrenia) and cardiometabolic comorbidities. Preliminary evidence shows that serotonergic psychedelics and their analogues may hold therapeutic potential in addressing the altered KP in the dysregulated GBA in SMI and comorbidities. In fact, aside from their effects on mood, psychedelics elicit therapeutic improvement in preclinical models of obesity, metabolic syndrome, and vascular inflammation, which are highly comorbid with SMI. Here, we review the literature on the therapeutic modulation of the KP in the dysregulated GBA in SMI and comorbidities, and the potential application of psychedelics to address the altered KP in the brain and systemic dysfunction underlying SMI and comorbidities. Psychedelics might therapeutically modulate the KP in the altered GBA in SMI and comorbidities either directly, via altering the metabolic pathway by influencing the ratelimiting enzymes of the KP and affecting the levels of available tryptophan, or indirectly, by affecting the gut microbiome, gut metabolome, metabolism, and the immune system. Despite promising preliminary evidence, the mechanisms and outcomes of the KP modulation with psychedelics in SMI and systemic comorbidities remain largely unknown and require further investigation. Several concerns are discussed surrounding the potential side effects of this approach in specific cohorts of individuals with SMI and systemic comorbidities
Editorial: Neuropharmacological intervention for severe mental illness and suicide prevention
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Photothrombotic mouse models for the study of melatonin as a therapeutic tool after ischemic stroke
No full textMelatonin is a potent neuroprotective agent which has shown therapeutic effects in animal models of brain injury such as stroke. Currently, there are few effective treatments for the therapeutics of stroke, the second leading cause of death and a major cause of disability worldwide. As demonstrated by the high number of publications during the last two decades, there is growing interest in understanding how and if melatonin could be a possible drug for stroke in humans, given also its very low and limited toxicity. Here, we describe the detailed protocol for performing the photothrombotic model of stroke which involves the occlusion of small cerebral vessels caused by the photoactivation of the previously injected light-sensitive dye Rose Bengal. Importantly, this model allows for the study of cellular and molecular mechanisms underlying the pathophysiology of stroke and thus can be used for investigating the neuropharmacological role of melatonin and the melatonin system in stroke. In particular, future research is warranted to demonstrate how and if melatonin impacts neurodegeneration, neuroprotection, and neuro-regeneration occurring after the brain injury caused by the occlusion of cerebral vessels
Sex Differences in Responses to Antidepressant Augmentations in Treatment-Resistant Depression
Full text linkBACKGROUND: Women are nearly twice as likely as men to suffer from major depressive disorder. Yet, there is a dearth of studies comparing the clinical outcomes of women and men with treatment-resistant depression (TRD) treated with similar augmentation strategies. We aimed to evaluate the effects of the augmentation strategies in women and men at the McGill University Health Center. METHODS: We reviewed health records of 76 patients (42 women, 34 men) with TRD, treated with augmentation strategies including antidepressants (AD) with mood stabilizers (AD+MS), antipsychotics (AD+AP), or in combination (AD+AP+MS). Clinical outcomes were determined by comparing changes on the 17-item Hamilton Depression Rating Scale (HAMD-17), Montgomery-Åsberg Depression Rating Scale (MADRS), Quick Inventory of Depressive Symptomatology (QIDS-C16), and Clinical Global Impression rating scale (CGI-S) at the beginning and after 3 months of an unchanged treatment. Changes in individual items of the HAMD-17 were also compared between the groups. RESULTS: Women and men improved from beginning to 3 months on all scales (P < .001, η (p)(2) ≥ 0.68). There was also a significant sex × time interaction for all scales (P < .05, η (p)(2) ≥ 0.06), reflecting a greater improvement in women compared with men. Specifically, women exhibited greater improvement in early (P = .03, η (p)(2 = )0.08) and middle-of-the-night insomnia (P = .01, η (p)(2 = )0.09) as well as psychomotor retardation (P < .001 η (p)(2 = )0.16) and psychic (P = .02, η (p)(2 = )0.07) and somatic anxiety (P = .01, η (p)(2 = )0.10). CONCLUSIONS: The combination of AD+AP/MS generates a significantly greater clinical response in women compared with men with TRD, supporting the existence of distinct pharmacological profiles between sexes in our sample. Moreover, they emphasize the benefit of augmentation strategies in women, underscoring the benefit of addressing symptoms such as insomnia and anxiety with AP and MS
Centella asiatica (L.) urban from Nepal: Quali-quantitative analysis of samples from several sites, and selection of high terpene containing populations for cultivation
No full textCentella asiatica (L.) Urban is widely used in traditional medicine in many countries and in
the formulation of drugs and cosmetics, and is therefore suitable as a trade item for the
development of medicinal plants for the population of Nepal. The aim of this work was to select plant populations of C. asiatica with high contents of secondary metabolites growing in various localities in Nepal, and to enhance knowledge of the cultivation of this plant. Quali-quantitative analysis of bioactive triterpenes (asiaticoside and asiatic acid) and phenol derivatives (flavonoids and caffeoyl esters) was performed by HPLC-DAD-ELSD. The highest quantities of triterpenes and phenols were found in samples from the Gorkha and Chitwan districts. Regarding cultivated plants, soil fertilisation is critical, since over-rich soils affect secondary metabolite content. Plants growing in sand-rich soils produce more terpenes. This work provides indications on how to select high-terpene producing germplasm and recommendations for plant cultivation
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