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While zinc is known to be important for many biological processes in animals at a molecular and physiological level, new evidence indicates that it may also be involved in the regulation of sleep. Recent research has concluded that zinc serum concentration varies with the amount of sleep, while orally administered zinc increases the amount and the quality of sleep in mice and humans. In this review, we provide an exhaustive study of the literature connecting zinc and sleep, and try to evaluate which molecular mechanism is likely to be involved in this phenomenon. A better understanding should provide critical information not only about the way zinc is related to sleep but also about how sleep itself works and what its real function is.

Sleep control is ascribed to a two-process model, a widely accepted concept that posits homoeostatic drive and a circadian process as the major sleep-regulating factors. Cognitive and emotional factors also influence sleep–wake behaviour; however, the precise circuit mechanisms underlying their effects on sleep control are unknown. Previous studies suggest that adenosine has a role affecting behavioural arousal in the nucleus accumbens (NAc), a brain area critical for reinforcement and reward. Here, we show that chemogenetic or optogenetic activation of excitatory adenosine A2A receptor-expressing indirect pathway neurons in the core region of the NAc strongly induces slow-wave sleep. Chemogenetic inhibition of the NAc indirect pathway neurons prevents the sleep induction, but does not affect the homoeostatic sleep rebound. In addition, motivational stimuli inhibit the activity of ventral pallidum-projecting NAc indirect pathway neurons and suppress sleep. Our findings reveal a prominent contribution of this indirect pathway to sleep control associated with motivation.

Insomnia is the most common sleep complaint which occurs due to difficulty in falling asleep or maintaining it. Most of currently available drugs for insomnia develop dependency and/or adverse effects. Hence natural therapies could be an alternative choice of treatment for insomnia. The root or whole plant extract of Ashwagandha (Withania somnifera) has been used to induce sleep in Indian system of traditional home medicine, Ayurveda. However, its active somnogenic components remain unidentified. We investigated the effect of various components of Ashwagandha leaf on sleep regulation by oral administration in mice. We found that the alcoholic extract that contained high amount of active withanolides was ineffective to induce sleep in mice. However, the water extract which contain triethylene glycol as a major component induced significant amount of non-rapid eye movement sleep with slight change in rapid eye movement sleep. Commercially available triethylene glycol also increased non-rapid eye movement sleep in mice in a dose-dependent (10–30 mg/mouse) manner. These results clearly demonstrated that triethylene glycol is an active sleep-inducing component of Ashwagandha leaves and could potentially be useful for insomnia therapy.

Natural cannabinoids and their synthetic substitutes are the most widely used recreational drugs. Numerous clinical cases describe acute toxic symptoms and neurological consequences following inhalation of the mixture of synthetic cannabinoids known as \"Spice.\" Here we report that an intraperitoneal administration of the natural cannabinoid Δ9-tetrahydrocannabinol (10 mg/kg), one of the main constituent of marijuana, or the synthetic cannabinoid JWH-018 (2.5 mg/kg) triggered electrographic seizures in mice, recorded by electroencephalography and videography. Administration of JWH-018 (1.5, 2.5 and 5 mg/kg) increased seizure spikes dose-dependently. Pretreatment of mice with AM-251 (5 mg/kg), a cannabinoid receptor 1-selective antagonist, completely prevented cannabinoid-induced seizures. These data imply that abuse of cannabinoids can be dangerous and represents an emerging public health threat. Additionally, our data strongly suggest that AM-251 could be used as a crucial prophylactic therapy for cannabinoid-induced seizures or similar life-threatening conditions.

Pulmonary fibrosis is a progressive and fatal lung disease with limited therapeutic options. Although it is well known that lipid mediator prostaglandins are involved in the development of pulmonary fibrosis, the role of prostaglandin D2 (PGD2) remains unknown. Here, we investigated whether genetic disruption of hematopoietic PGD synthase (H-PGDS) affects the bleomycin-induced lung inflammation and pulmonary fibrosis in mouse. Compared with H-PGDS naïve (WT) mice, H-PGDS-deficient mice (H-PGDS-/-) represented increased collagen deposition in lungs 14 days after the bleomycin injection. The enhanced fibrotic response was accompanied by an increased mRNA expression of inflammatory mediators, including tumor necrosis factor-α, monocyte chemoattractant protein-1, and cyclooxygenase-2 on day 3. H-PGDS deficiency also increased vascular permeability on day 3 and infiltration of neutrophils and macrophages in lungs on day 3 and 7. Immunostaining showed that the neutrophils and macrophages expressed H-PGDS, and its mRNA expression was increased on day 3and 7 in WT lungs. These observations suggest that H-PGDS-derived PGD2 plays a protective role in bleomycin-induced lung inflammation and pulmonary fibrosis.

Octacosanol, a component of various food materials, possesses prominent biological activities and functions. It fights against cellular stress by increasing glutathione level and thus scavenging oxygen reactive species. However, its anti-stress activity and role in sleep induction remained elusive. We hypothesize that octacosanol can restore stress-affected sleep by mitigating stress. Cage change strategy was used to induce mild stress and sleep disturbance in mice, and effects of octacosanol administration on amount of sleep and stress were investigated. Results showed that octacosanol did not change rapid eye movement (REM) or non-REM (NREM) sleep compared to vehicle in normal mice. However, in cage change experiment, octacosanol induces significant increase in NREM sleep at doses of 100 and 200 mg/kg (75.7 ± 14.9 and 82.7 ± 9.3 min/5 h) compared to vehicle (21.2 ± 5.1 min/5 h), and decreased sleep latency. Octacosanol induced sleep by increasing number of sleep episodes and decreasing wake episode duration. Plasma corticosterone levels were significantly reduced after octacosanol (200 mg/kg) administration, suggesting a decrease in stress level. Octacosanol-induced changes in sleep-wake parameters in stressed-mice were comparable to the values in normal mice. Together, these data clearly showed that, though octacosanol does not alter normal sleep, it clearly alleviates stress and restore stress-affected sleep.

Prostaglandin D2 (PGD2) is a lipid mediator involved in sleep regulation and inflammation. PGD2 interacts with 2 types of G protein-coupled receptors, DP1 and DP2/CRTH2 (chemoattractant receptor homologous molecule expressed on T helper type 2 cells)/GPR44 to show a variety of biological effects. DP1 activation leads to Gs-mediated elevation of the intracellular cAMP level, whereas activation of DP2 decreases this level via the Gi pathway; and it also induces G protein-independent, arrestin-mediated cellular responses. Activation of DP2 by PGD2 causes the progression of inflammation via the recruitment of lymphocytes by enhancing the production of Th2-cytokines. Here we developed monoclonal antibodies (MAbs) against the extracellular domain of mouse DP2 by immunization of DP2-null mutant mice with DP2-overexpressing BAF3, murine interleukin-3 dependent pro-B cells, to reduce the generation of antibodies against the host cells by immunization of mice. Moreover, we immunized DP2-KO mice to prevent immunological tolerance to mDP2 protein. After cell ELISA, immunocytochemical, and Western blot analyses, we successfully obtained a novel monoclonal antibody, MAb-1D8, that specifically recognized native mouse DP2, but neither human DP2 nor denatured mouse DP2, by binding to a particular 3D receptor conformation formed by the N-terminus and extracellular loop 1, 2, and 3 of DP2. This antibody inhibited the binding of 0.5 nM [3H]PGD2 to mouse DP2 (IC50 = 46.3 ± 18.6 nM), showed antagonistic activity toward 15(R)-15-methyl PGD2-induced inhibition of 300 nM forskolin-activated cAMP production (IC50 = 16.9 ± 2.6 nM), and gave positive results for immunohistochemical staining of DP2-expressing CD4+ Th2 lymphocytes that had accumulated in the kidney of unilateral ureteral obstruction model mice. This monoclonal antibody will be very useful for in vitro and in vivo studies on DP2-mediated diseases.

Adenosine A(2A) receptors (A(2A) Rs) in the nucleus accumbens (Acb) have been demonstrated to play an important role in the arousal effect of adenosine receptor antagonist caffeine, and may be involved in physiological sleep. To better understand the functions of these receptors in sleep, projections of A(2A)R neurons were mapped utilizing adeno-associated virus (AAV) encoding humanized Renilla green fluorescent protein (hrGFP) as a tracer for long axonal pathways. The Cre-dependent AAV was injected into the core (AcbC) and shell (AcbSh) of the Acb in A(2A)R-Cre mice. Immunohistochemistry was then used to visualize hrGFP highlighting the perikarya of the A(2A)R neurons in the injection sites, and their axons in projection regions. The data revealed that A(2A)R neurons exhibit medium-sized and either round or elliptic perikarya with their processes within the Acb. Moreover, the projections from the Acb distributed to nuclei in the forebrain, diencephalon, and brainstem. In the forebrain, A(2A) R neurons from all Acb sub-regions jointly projected to the ventral pallidum, the nucleus of the diagonal band, and the substantia innominata. Heavy projections from the AcbC and the ventral AcbSh, and weaker projections from the medial AcbSh, were observed in the lateral hypothalamus and lateral preoptic area. In the brainstem, the Acb projections were found in the ventral tegmental area, while AcbC and ventral AcbSh also projected to the median raphe nucleus, the dorsal raphe nucleus, and the ventrolateral periaqueductal gray. The results supply a solid base for understanding the roles of the A(2A)R and A(2A)R neurons in the Acb, especially in the regulation of sleep.