Choose an application

• Reference Manager
• EndNote
• RefWorks (Direct export to RefWorks)

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.

Neuroscience --- Addiction --- hypocretin --- Anxiety --- orexin --- orexin receptor antagonist --- Neuropeptide --- insomnia

Choose an application

• Reference Manager
• EndNote
• RefWorks (Direct export to RefWorks)

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.

Neuroscience --- Addiction --- hypocretin --- Anxiety --- orexin --- orexin receptor antagonist --- Neuropeptide --- insomnia --- Neuroscience --- Addiction --- hypocretin --- Anxiety --- orexin --- orexin receptor antagonist --- Neuropeptide --- insomnia

Choose an application

• Reference Manager
• EndNote
• RefWorks (Direct export to RefWorks)

The control of energy metabolism is a central event for cell, organ, and organism survival. There are many control levels in energy metabolism, although in this Special Issue, we concentrated on the neuroendocrine control which is operated through specialized neural circuits controlling both food intake and energy expenditure. Due to the explosion of obesity and associated diseases, the subject of this Special Issue is of particular interest today.

Medicine --- Neurosciences --- IGF1 --- IGF2 --- IGFBP2 --- high-fat diet --- obesity --- sex differences --- neuropeptides --- beige adipocyte --- white adipocyte --- brown adipocyte --- diabetes mellitus --- differentiation --- kisspeptin --- AgRP --- sheep --- reproduction --- LH --- genistein --- proopiomelanocortin --- arcuate nucleus --- rats --- endocrine disrupting chemicals --- bisphenol A --- diethylstilbestrol --- tributyltin --- neuropeptide Y --- pro-opiomelanocortin --- phytoestrogens --- endocrine disruptor --- dimorphism --- POMC --- orexin --- subfornical organ --- organum vasculosum of the lamina terminalis --- area postrema --- hypothalamus --- metabolism --- diabetes --- estrogens --- gut permeability/integrity --- insulin sensitivity --- Akkermansia --- gut microbiome --- lactate --- glycogen --- behavior --- learning --- astrocytes --- calcium signaling --- energy balance --- gliotransmission --- systemic metabolism --- amygdala --- kisspeptins --- food intake --- body weight --- intrauterine growth restriction --- macrosomia --- glucose tolerance --- abdominal adipocyte gene expression --- thrifty phenotype hypothesis

Choose an application

• Reference Manager
• EndNote
• RefWorks (Direct export to RefWorks)

The control of energy metabolism is a central event for cell, organ, and organism survival. There are many control levels in energy metabolism, although in this Special Issue, we concentrated on the neuroendocrine control which is operated through specialized neural circuits controlling both food intake and energy expenditure. Due to the explosion of obesity and associated diseases, the subject of this Special Issue is of particular interest today.

Medicine --- Neurosciences --- IGF1 --- IGF2 --- IGFBP2 --- high-fat diet --- obesity --- sex differences --- neuropeptides --- beige adipocyte --- white adipocyte --- brown adipocyte --- diabetes mellitus --- differentiation --- kisspeptin --- AgRP --- sheep --- reproduction --- LH --- genistein --- proopiomelanocortin --- arcuate nucleus --- rats --- endocrine disrupting chemicals --- bisphenol A --- diethylstilbestrol --- tributyltin --- neuropeptide Y --- pro-opiomelanocortin --- phytoestrogens --- endocrine disruptor --- dimorphism --- POMC --- orexin --- subfornical organ --- organum vasculosum of the lamina terminalis --- area postrema --- hypothalamus --- metabolism --- diabetes --- estrogens --- gut permeability/integrity --- insulin sensitivity --- Akkermansia --- gut microbiome --- lactate --- glycogen --- behavior --- learning --- astrocytes --- calcium signaling --- energy balance --- gliotransmission --- systemic metabolism --- amygdala --- kisspeptins --- food intake --- body weight --- intrauterine growth restriction --- macrosomia --- glucose tolerance --- abdominal adipocyte gene expression --- thrifty phenotype hypothesis --- IGF1 --- IGF2 --- IGFBP2 --- high-fat diet --- obesity --- sex differences --- neuropeptides --- beige adipocyte --- white adipocyte --- brown adipocyte --- diabetes mellitus --- differentiation --- kisspeptin --- AgRP --- sheep --- reproduction --- LH --- genistein --- proopiomelanocortin --- arcuate nucleus --- rats --- endocrine disrupting chemicals --- bisphenol A --- diethylstilbestrol --- tributyltin --- neuropeptide Y --- pro-opiomelanocortin --- phytoestrogens --- endocrine disruptor --- dimorphism --- POMC --- orexin --- subfornical organ --- organum vasculosum of the lamina terminalis --- area postrema --- hypothalamus --- metabolism --- diabetes --- estrogens --- gut permeability/integrity --- insulin sensitivity --- Akkermansia --- gut microbiome --- lactate --- glycogen --- behavior --- learning --- astrocytes --- calcium signaling --- energy balance --- gliotransmission --- systemic metabolism --- amygdala --- kisspeptins --- food intake --- body weight --- intrauterine growth restriction --- macrosomia --- glucose tolerance --- abdominal adipocyte gene expression --- thrifty phenotype hypothesis

Choose an application

• Reference Manager
• EndNote
• RefWorks (Direct export to RefWorks)

Positron emission tomography (PET) and single-photon emission computed tomography (SPECT) are in vivo molecular imaging methods which are widely used in nuclear medicine for diagnosis and treatment follow-up of many major diseases. These methods use target-specific molecules as probes, which are labeled with radionuclides of short half-lives that are synthesized prior to the imaging studies. These probes are called radiopharmaceuticals. The use of PET and SPECT for brain imaging is of special significance since the brain controls all the body’s functions by processing information from the whole body and the outside world. It is the source of thoughts, intelligence, memory, speech, creativity, emotion, sensory functions, motion control, and other important body functions. Protected by the skull and the blood–brain barrier, the brain is somehow a privileged organ with regard to nutrient supply, immune response, and accessibility for diagnostic and therapeutic measures. Invasive procedures are rather limited for the latter purposes. Therefore, noninvasive imaging with PET and SPECT has gained high importance for a great variety of brain diseases, including neurodegenerative diseases, motor dysfunctions, stroke, epilepsy, psychiatric diseases, and brain tumors. This Special Issue focuses on radiolabeled molecules that are used for these purposes, with special emphasis on neurodegenerative diseases and brain tumors.

SV2A --- SV2B --- SV2C --- microPET --- [18F]UCB-H --- epilepsy --- PBIF --- distribution volume --- blocking assay --- preclinical imaging --- Alzheimer’s disease (AD) --- network measure --- graph theory --- brain network --- positron emission tomography (PET) --- persistent homology --- Phosphodiesterase 2A (PDE2A) --- Positron Emission Tomography (PET) --- Benzoimidazotriazine (BIT) --- fluorinated --- Mouse Liver Microsomes (MLM) --- cyclic nucleotide phosphodiesterase --- PDE2A radioligand --- nitro-precursor --- fluorine-18 --- in vitro autoradiography --- PET imaging --- opioid receptors --- positron emission tomography --- radiotracers --- μOR-, δOR-, κOR- and ORL1-ligands --- movement disorders --- pain --- drug dependence --- GBM --- biomarkers --- Sigma 1 --- Sigma 2 --- PD-L1 --- PARP --- IDH --- Alzheimer’s disease --- Parkinson’s disease --- β-amyloid plaques --- neurofibrillary tangles --- α-synucleinopathy --- diagnostic imaging probes --- orexin receptors --- PET --- radiotracer --- imaging --- alpha 7 --- nicotinic acetylcholine receptors --- nAChR --- autoradiography --- amino acid --- FET --- FACBC --- FDOPA --- immunoPET --- molecular imaging --- glioma --- brain metastases --- adenosine A2A receptor --- rotenone-based mouse model --- [18F]FESCH --- two-step one-pot radiosynthesis