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Insomnia and beyond - Exploring the therapeutic potential of orexin receptor antagonists

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889193301 Year: Pages: 219 DOI: 10.3389/978-2-88919-330-1 Language: English
Publisher: Frontiers Media SA
Subject: Psychiatry --- Therapeutics --- Neurology --- Medicine (General) --- Science (General)
Added to DOAB on : 2016-03-10 08:14:32
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Abstract

Orexin/hypocretin neuropeptides, produced by a few thousand neurons in the lateral hypothalamus, are of critical importance for the control of vigilance and arousal of vertebrates, from fish to amphibians, birds and mammals. Two orexin peptides, called orexin-A and orexin-B, exist in mammals. They bind with different affinities to two distinct, widely distributed, excitatory G-protein- coupled receptors, orexin receptor type 1 and type 2 (OXR-1/2). The discovery of an OXR mutation causing canine narcolepsy, the narcolepsy-like phenotype of orexin peptide knockout mice, and the orexin neuron loss associated with human narcoleptic patients laid the foundation for the discovery of small molecule OXR antagonists as novel treatments for sleep disorders. Proof of concept studies from Glaxo Smith Kline, Actelion Pharmaceuticals Ltd. and Merck have now consistently demonstrated the efficacy of dual OXR antagonists (DORAs) in promoting sleep in rodents, dogs, non-human primates and humans. Some of these antagonists have completed late stage clinical testing in primary insomnia. Orexin drug discovery programs have also been initiated by other large pharmaceutical companies including Hoffmann La Roche, Novartis, Eli Lilly and Johnson & Johnson. Orexins are increasingly recognized for orchestrating the activity of the organism’s arousal system with appetite, reward and stress processing pathways. Therefore, in addition to models of insomnia, pharmacological effects of DORAs have begun to be investigated in rodent models of addiction, depression and anxiety. The first clinical trials in diabetic neuropathy, migraine and depression have been initiated with Merck’s MK-6096 (www.clinicaltrials.gov). Whereas the pharmacology of DORAs is established for their effects on wakefulness, pharmacological effects of selective OXR-1 or OXR-2 antagonists (SORAs) have remained less clear. From an evolutionary point of view, the OXR-2 was expressed first in most vertebrate lineages, whereas the OXR-1 is believed to result from a gene duplication event, when mammals emerged. Yet, both receptors do not have redundant function. Their brain expression pattern, their intracellular signaling, as well as their affinity for orexin-A and orexin-B differs. During the past decade most preclinical research on selective OXR-1 antagonism was performed with SB-334867. Only in recent years, other selective OXR-1 and OXR-2 antagonists with optimized selectivity profiles and pharmacokinetic properties have been discovered, and phenotypes of OXR-1 and OXR-2 knockout mice were described. The present Research Topic (referred to in the Editorial as “special topics issue”) comprises submissions of original research manuscripts as well as reviews, directed towards the neuropharmacology of OXR antagonists. The submissions are preclinical papers dealing with dual and/or selective OXR antagonists that shed light on the differential contribution of endogenous orexin signaling through both OXRs for cellular, physiological and behavioral processes. Some manuscripts also report on convergence or divergence of DORA vs. SORA effects with phenotypes expressed by OXR-1 or OXR-2 knockout animals. Ultimately these findings may help further define the potential of DORAs and SORAs in particular therapeutic areas in insomnia and beyond insomnia.

Crosstalk between the osteogenic and neurogenic stem cell niches: how far are they from each other?

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889197774 Year: Pages: 102 DOI: 10.3389/978-2-88919-777-4 Language: English
Publisher: Frontiers Media SA
Subject: Neurology --- Science (General)
Added to DOAB on : 2016-04-07 11:22:02
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Somatic stem cells reside in definite compartments, known as “niches”, within developed organs and tissues, being able to renew themselves, differentiate and ensure tissue maintenance and repair. In contrast with the original dogmatic distinction between renewing and non-renewing tissues, somatic stem cells have been found in almost every human organ, including brain and heart. The adult bone marrow, in particular, houses a complex multifunctional niche comprising hemopoietic stem cells (HSCs) and mesenchymal stem cells (MSCs), that intensely interact. HSCs represent the common precursors of all mature blood cells. MSCs are instead able to differentiate along multiple mesodermal lineages and are believed to represent the key somatic stem cell within the skeletogenic niche, being conceptually able to produce any tissue included within a mature skeletal segment (bone, cartilage, blood vessels, adipose tissue, and supporting connective stroma). Despite this high plasticity, the claim that MSCs could be capable of transdifferentiation along non-mesodermal lineages, including neurons, has been strongly argued. Adult osteogenic and neurogenic niches display wide differences: embryo origin, microenvironment, progenitors’ lifespan, lineages of supporting cells. Although similar pathways may be involved, it is hard to believe that the osteogenic and neurogenic lineages can share functional features. The outbreaking research achievements in the field of regenerative medicine, along with the pressing need for effective innovative tools for the treatment of neurodegeneration and neurologic disorders, have been forcing experimental clinical applications, which, despite their scientific weakness, have recently stimulated the public opinion. Based on this contemporary background, this Research Topic wish to provide an in-depth revision of the state of the art on relevant scientific milestones addressing the differences and possible interconnections and overlaps, between the osteogenic and the neurogenic niches. Dissertations on both basic research and clinical aspects, along with ethical and regulatory issues on the use of somatic stem cells for in vivo transplantation, have been covered.

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