Histamine-1 receptor is not required as a downstream effector of orexin-2 receptor in maintenance of basal sleep/wake states

金沢大学医薬保健研究域医学系Aim: The effect of orexin on wakefulness has been suggested to be largely mediated by activation of histaminergic neurones in the tuberomammillary nucleus (TMN) via orexin receptor-2 (OX2R). However, orexin receptors in other regions of the brain might also play important roles in maintenance of wakefulness. To dissect the role of the histaminergic system as a downstream mediator of the orexin system in the regulation of sleep/wake states without compensation by the orexin receptor-1 (OX1R) mediated pathways, we analysed the phenotype of Histamine-1 receptor (H1R) and OX 1R double-deficient (H1R-/-;OX 1R-/-) mice. These mice lack OX1R-mediated pathways in addition to deficiency of H1R, which is thought to be the most important system in downstream of OX2R. Methods: We used H 1R deficient (H1R-/-) mice, H1R -/-;OX1R-/- mice, OX1R and OX 2R double-deficient (OX1R-/-;OX 2R-/-) mice, and wild type controls. Rapid eye movement (REM) sleep, non-REM (NREM) sleep and awake states were determined by polygraphic electroencephalographic/electromyographic recording. Results: No abnormality in sleep/wake states was observed in H1R-/- mice, consistent with previous studies. H1R-/-;OX 1R-/- mice also showed a sleep/wake phenotype comparable to that of wild type mice, while OX1R-/-; OX 2R-/- mice showed severe fragmentation of sleep/wake states. Conclusion: Our observations showed that regulation of the sleep/wake states is completely achieved by OX2R-expressing neurones without involving H1R-mediated pathways. The maintenance of basal physiological sleep/wake states is fully achieved without both H1 and OX1 receptors. Downstream pathways of OX2R other than the histaminergic system might play an important role in the maintenance of sleep/wake states. © 2009 Scandinavian Physiological Society

Enhanced Orexin Receptor-2 Signaling Prevents Diet-Induced Obesity and Improves Leptin Sensitivity

SummaryThe hypothalamic orexin neuropeptide acutely promotes appetite, yet orexin deficiency in humans and mice is associated with obesity. Prolonged effects of increased orexin signaling upon energy homeostasis have not been fully characterized. Here, we examine the metabolic effects of orexin gain of function utilizing genetic and pharmacologic techniques in mice. Transgenic orexin overexpression confers resistance to high-fat diet-induced obesity and insulin insensitivity by promoting energy expenditure and reducing consumption. Genetic studies indicate that orexin receptor-2 (OX2R), rather than OX1R signaling, predominantly mediates this phenotype. Likewise, prolonged central administration of an OX2R-selective peptide agonist inhibits diet-induced obesity. While orexin overexpression enhances the anorectic-catabolic effects of central leptin administration, obese leptin-deficient mice are completely resistant to the metabolic effects of orexin overexpression or OX2R agonist infusion. We conclude that enhanced orexin-OX2R signaling confers resistance to diet-induced features of the metabolic syndrome through negative energy homeostasis and improved leptin sensitivity

A scoring evaluation for the practical introduction of guideline‐directed medical therapy in heart failure patients

Abstract Aims The guideline‐directed medical therapy (GDMT) has been recommended for heart failure (HF) with reduced ejection fraction (HFrEF) based on the accumulating clinical evidence. However, it is difficult to implement all the trial‐proven medications for every patient in the real world. Methods and results A simple GDMT score was created, according to the combination of GDMT drugs (renin–angiotensin system inhibitors, beta‐blockers, mineralocorticoid receptor antagonists, and sodium–glucose transporter 2 inhibitors) administration and their dosage (0–9 points). Its impact on the prognosis of HF patients was investigated. Admitted HF patients [HFrEF and HF with mildly reduced ejection fraction (HFmrEF), n = 1054] were retrospectively analysed (excluding those with in‐hospital death and dialysis). A simple GDMT score ≥5, but not the number of medications, was significantly associated with a reduction of all‐cause death, HF readmission, and composite outcome (HF readmission and all‐cause death) (P < 0.001). Subgroup analysis showed that almost all groups with a simple GDMT score of 5 or higher had a better prognosis. Conclusions The developed simple GDMT score was associated with prognosis in HFrEF and HFmrEF patients. Even if all four drugs cannot be introduced for some reason, a regimen with a simple GDMT score ≥5 may lead to a prognosis in HF patients

Primary Lateral Sclerosis and Early Upper Motor Neuron Disease

ObjectivesThe goals of this study were to characterize clinical and electrophysiologic findings of subjects with upper motor neuron disease and to explore feasibility of clinical trials in this population.MethodsTwenty northeast amyotrophic lateral sclerosis consortium (northeast amyotrophic lateral sclerosis) sites performed chart reviews to identify active clinical pure upper motor neuron disease patients. Patients with hereditary spastic paraplegia or meeting revised El Escorial electrodiagnostic criteria for amyotrophic lateral sclerosis were excluded. Patients were classified into 2 groups according to the presence or absence of minor electromyography (EMG) abnormalities.ResultsTwo hundred thirty-three subjects with upper motor neuron disease were identified; 217 had available EMG data. Normal EMGs were seen in 140 subjects, and 77 had minor denervation. Mean disease duration was 84 (±80) months for the entire cohort with no difference seen between the 2 groups. No difference was seen in clinical symptoms, disability, or outcome measures between the 2 groups after correcting for multiple comparisons.ConclusionsMinor EMG abnormalities were not associated with phenotypic differences in a clinical upper motor neuron disease population. These findings suggest that subtle EMG abnormalities can not necessarily be used as a prognostic tool in patients with clinical upper motor neuron disease. This study also demonstrates the availability of a large number of patients with upper motor neuron diseases within the northeast amyotrophic lateral sclerosis network and suggests feasibility for conducting clinical trials in this population

Primary Lateral Sclerosis and Early Upper Motor Neuron Disease

ObjectivesThe goals of this study were to characterize clinical and electrophysiologic findings of subjects with upper motor neuron disease and to explore feasibility of clinical trials in this population.MethodsTwenty northeast amyotrophic lateral sclerosis consortium (northeast amyotrophic lateral sclerosis) sites performed chart reviews to identify active clinical pure upper motor neuron disease patients. Patients with hereditary spastic paraplegia or meeting revised El Escorial electrodiagnostic criteria for amyotrophic lateral sclerosis were excluded. Patients were classified into 2 groups according to the presence or absence of minor electromyography (EMG) abnormalities.ResultsTwo hundred thirty-three subjects with upper motor neuron disease were identified; 217 had available EMG data. Normal EMGs were seen in 140 subjects, and 77 had minor denervation. Mean disease duration was 84 (±80) months for the entire cohort with no difference seen between the 2 groups. No difference was seen in clinical symptoms, disability, or outcome measures between the 2 groups after correcting for multiple comparisons.ConclusionsMinor EMG abnormalities were not associated with phenotypic differences in a clinical upper motor neuron disease population. These findings suggest that subtle EMG abnormalities can not necessarily be used as a prognostic tool in patients with clinical upper motor neuron disease. This study also demonstrates the availability of a large number of patients with upper motor neuron diseases within the northeast amyotrophic lateral sclerosis network and suggests feasibility for conducting clinical trials in this population