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Serotonergic anorexigens are the primary pharmacologic risk factor associated with pulmonary arterial hypertension (PAH), and the resulting PAH is clinically indistinguishable from the heritable form of disease, associated with BMPR2 mutations. Both BMPR2 mutation and agonists to the serotonin receptor HTR2B have been shown to cause activation of SRC tyrosine kinase; conversely, antagonists to HTR2B inhibit SRC trafficking and downstream function. To test the hypothesis that a HTR2B antagonist can prevent BMRP2 mutation induced PAH by restricting aberrant SRC trafficking and downstream activity, we exposed BMPR2 mutant mice, which spontaneously develop PAH, to a HTR2B antagonist, SB204741, to block the SRC activation caused by BMPR2 mutation. SB204741 prevented the development of PAH in BMPR2 mutant mice, reduced recruitment of inflammatory cells to their lungs, and reduced muscularization of their blood vessels. By atomic force microscopy, we determined that BMPR2 mutant mice normally had a doubling of vessel stiffness, which was substantially normalized by HTR2B inhibition. SB204741 reduced SRC phosphorylation and downstream activity in BMPR2 mutant mice. Gene expression arrays indicate that the primary changes were in cytoskeletal and muscle contractility genes. These results were confirmed by gel contraction assays showing that HTR2B inhibition nearly normalizes the 400% increase in gel contraction normally seen in BMPR2 mutant smooth muscle cells. Heritable PAH results from increased SRC activation, cellular contraction, and vascular resistance, but antagonism of HTR2B prevents SRC phosphorylation, downstream activity, and PAH in BMPR2 mutant mice.
UNLABELLED - Mammalian orthoreoviruses (reoviruses) are nonenveloped double-stranded RNA viruses that infect most mammalian species, including humans. Reovirus binds to cell surface glycans, junctional adhesion molecule A (JAM-A), and the Nogo-1 receptor (depending on the cell type) and enters cells by receptor-mediated endocytosis. Within the endocytic compartment, reovirus undergoes stepwise disassembly, which is followed by release of the transcriptionally active viral core into the cytoplasm. In a small-molecule screen to identify host mediators of reovirus infection, we found that treatment of cells with 5-nonyloxytryptamine (5-NT), a prototype serotonin receptor agonist, diminished reovirus cytotoxicity. 5-NT also blocked reovirus infection. In contrast, treatment of cells with methiothepin mesylate, a serotonin antagonist, enhanced infection by reovirus. 5-NT did not alter cell surface expression of JAM-A or attachment of reovirus to cells. However, 5-NT altered the distribution of early endosomes with a concomitant impairment of reovirus transit to late endosomes and a delay in reovirus disassembly. Consistent with an inhibition of viral disassembly, 5-NT treatment did not alter infection by in vitro-generated infectious subvirion particles, which bind to JAM-A but bypass a requirement for proteolytic uncoating in endosomes to infect cells. We also found that treatment of cells with 5-NT decreased the infectivity of alphavirus chikungunya virus and coronavirus mouse hepatitis virus. These data suggest that serotonin receptor signaling influences cellular activities that regulate entry of diverse virus families and provides a new, potentially broad-spectrum target for antiviral drug development.
IMPORTANCE - Identification of well-characterized small molecules that modulate viral infection can accelerate development of antiviral therapeutics while also providing new tools to increase our understanding of the cellular processes that underlie virus-mediated cell injury. We conducted a small-molecule screen to identify compounds capable of inhibiting cytotoxicity caused by reovirus, a prototype double-stranded RNA virus. We found that 5-nonyloxytryptamine (5-NT) impairs reovirus infection by altering viral transport during cell entry. Remarkably, 5-NT also inhibits infection by an alphavirus and a coronavirus. The antiviral properties of 5-NT suggest that serotonin receptor signaling is an important regulator of infection by diverse virus families and illuminate a potential new drug target.
Copyright © 2015, American Society for Microbiology. All Rights Reserved.
Targeting serotonin (5-HT) bioavailability with selective 5-HT reuptake inhibitors (SSRIs) remains the most widely used treatment for mood disorders. However, their limited efficacy, delayed onset of action, and side effects restrict their clinical utility. Endogenous regulator of G-protein signaling (RGS) proteins have been implicated as key inhibitors of 5-HT(1A)Rs, whose activation is believed to underlie the beneficial effects of SSRIs, but the identity of the specific RGS proteins involved remains unknown. We identify RGS6 as the critical negative regulator of 5-HT(1A)R-dependent antidepressant actions. RGS6 is enriched in hippocampal and cortical neurons, 5-HT(1A)R-expressing cells implicated in mood disorders. RGS6(-/-) mice exhibit spontaneous anxiolytic and antidepressant behavior rapidly and completely reversibly by 5-HT(1A)R blockade. Effects of the SSRI fluvoxamine and 5-HT(1A)R agonist 8-OH-DPAT were also potentiated in RGS6(+/-) mice. The phenotype of RGS6(-/-) mice was associated with decreased CREB phosphorylation in the hippocampus and cortex, implicating enhanced Gα(i)-dependent adenylyl cyclase inhibition as a possible causative factor in the behavior observed in RGS6(-/-) animals. Our results demonstrate that by inhibiting serotonergic innervation of the cortical-limbic neuronal circuit, RGS6 exerts powerful anxiogenic and prodepressant actions. These findings indicate that RGS6 inhibition may represent a viable means to treat mood disorders or enhance the efficacy of serotonergic agents.
A selective 5-hydroxytryptamine (5-HT) 2A receptor antagonist sarpogrelate (SG) blocks serotonin-induced platelet aggregation. It has been used clinically for the treatment of peripheral arterial disease. SG might be able to improve chronic ischemia, which contributes to renal fibrosis progression by maintaining renal microcirculation. This study investigated whether SG suppresses renal fibrosis. C57BL/6 mice fed a 0.2% adenine-containing diet for 6 wk developed severe tubulointerstitial fibrosis with kidney dysfunction. Subsequent SG treatment (30 mg·kg(-1)·day(-1)) for 4 wk improved these changes significantly by increasing peritubular blood flow in the fibrotic area, as evaluated by intravital microscopy and decreasing fibrin deposition. Urinary L-type fatty acid-binding protein, up-regulated by renal hypoxia, was also reduced by SG. Additionally, results showed that mRNA expression of plasminogen activator inhibitor-1 (PAI-1), which is known to promote fibrosis by mediating and enhancing transforming growth factor (TGF)-β1 signaling, was suppressed by SG treatment in the kidney. In vitro experiments using cultured murine proximal tubular epithelial (mProx) cells revealed that incubation with TGF-β1 and 5-HT increased PAI-1 mRNA expression; SG significantly reduced it. In conclusion, SG reduces renal fibrosis not only by the antithrombotic effect of maintaining peritubular blood flow but also by suppressing PAI-1 expression in renal tubular cells.
Methamphetamine is a highly addictive psychostimulant drug of abuse, causing hyperthermia and neurotoxicity at high doses. Currently, there is no clinically proven pharmacotherapy to treat these effects of methamphetamine, necessitating identification of potential novel therapeutic targets. Earlier studies showed that methamphetamine binds to sigma (σ) receptors in the brain at physiologically relevant concentrations, where it "acts in part as an agonist." SN79 (6-acetyl-3-(4-(4-(4-florophenyl)piperazin-1-yl)butyl)benzo[d]oxazol-2(3H)-one) was synthesized as a putative σ receptor antagonist with nanomolar affinity and selectivity for σ receptors over 57 other binding sites. SN79 pretreatment afforded protection against methamphetamine-induced hyperthermia and striatal dopaminergic and serotonergic neurotoxicity in male, Swiss Webster mice (measured as depletions in striatal dopamine and serotonin levels, and reductions in striatal dopamine and serotonin transporter expression levels). In contrast, di-o-tolylguanidine (DTG), a well established σ receptor agonist, increased the lethal effects of methamphetamine, although it did not further exacerbate methamphetamine-induced hyperthermia. Together, the data implicate σ receptors in the direct modulation of some effects of methamphetamine such as lethality, while having a modulatory role which can mitigate other methamphetamine-induced effects such as hyperthermia and neurotoxicity.
Copyright © 2012 Elsevier B.V. and ECNP. All rights reserved.
Clinical observations have suggested that ritanserin, a 5-HT(2A/C) receptor antagonist may reduce motor deficits in persons with Parkinson's Disease (PD). To better understand the potential antiparkinsonian actions of ritanserin, we compared the effects of ritanserin with the selective 5-HT(2A) receptor antagonist M100907 and the selective 5-HT(2C) receptor antagonist SB 206553 on motor impairments in mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). MPTP-treated mice exhibited decreased performance on the beam-walking apparatus. These motor deficits were reversed by acute treatment with L-3,4-dihydroxyphenylalanine (levodopa). Both the mixed 5-HT(2A/C) antagonist ritanserin and the selective 5-HT(2A) antagonist M100907 improved motor performance on the beam-walking apparatus. In contrast, SB 206553 was ineffective in improving the motor deficits in MPTP-treated mice. These data suggest that 5-HT(2A) receptor antagonists may represent a novel approach to ameliorate motor symptoms of Parkinson's disease.
Published by Elsevier Ltd.
Recent studies have begun to elucidate the molecular mechanisms that promote the generation and progressive nature of atrial fibrillation. Evidence from both experimental and clinical investigations has implicated an important role for the renin-angiotensin-aldosterone system, inflammation, and oxidative stress, with data that suggest a potential beneficial effect for angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, aldosterone receptor antagonists, antiinflammatory agents, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins), and omega-3 polyunsaturated fatty acids. In addition, compounds that increase gap junctional conductance or that block 5-hydroxytryptamine-4 receptors have also shown promise in the experimental setting. Large-scale, prospective clinical trials will clarify the utility of these new therapeutic approaches to prevent atrial fibrillation in specific clinical settings.
BACKGROUND - Chemotherapy-induced nausea and vomiting (CINV) is one of the most distressing side effects of moderately or highly emetogenic chemotherapy. Diphenhydramine, lorazepam, and dexamethasone have been used individually to treat CINV. The objective of this study was to evaluate the safety and potential efficacy of those drugs administered via a patient controlled pump (BAD pump) to control CINV.
PROCEDURE - A retrospective chart review was conducted of all pediatric oncology patients who received the BAD pump. Emetic episodes, doses of rescue medications to treat breakthrough nausea or vomiting, and occurrence of adverse events were recorded. Complete response (CR) was defined as no emesis or rescue medications, partial response (PR) as emesis but no rescue medications, and failure (F) as rescue medications required.
RESULTS - Thirty patients received a total of 141 courses. Adverse events occurred in 4.2% of the courses; confusion (n = 2), depressed mood (n = 1), dysphoria (n = 1), agitation (n = 1), and restlessness (n = 1). All side effects resolved after decreasing the infusion rate, and the pump was not discontinued in any patients. Eighteen patients failed conventional prophylaxis and received BAD pump for identical subsequent chemotherapy cycles; they spent more days in CR with BAD pump than without it, 21 versus 45 days (P = .003) respectively. Patients receiving BAD pump had significantly shorter hospital stay with BAD pump than those not receiving it, 68 days versus 76 (P = .046).
CONCLUSIONS - BAD pump is well tolerated in pediatric patients receiving chemotherapy and may be more effective than conventional prophylaxis in controlling CINV in some patients.
(c) 2006 Wiley-Liss, Inc.
There have been conflicting reports as to whether olanzapine produces lower occupancy of striatal dopamine D(2)/D(3) receptor than typical antipsychotic drugs and preferential occupancy of extrastriatal dopamine D(2)/D(3) receptors. We performed [(18)F] fallypride PET studies in six schizophrenic subjects treated with olanzapine and six schizophrenic subjects treated with haloperidol to examine the occupancy of striatal and extrastriatal dopamine receptors by these antipsychotic drugs. [(18)F] setoperone PET studies were performed in seven olanzapine-treated subjects to determine 5-HT(2A) receptor occupancy. Occupancy of dopamine D(2)/D(3) receptors by olanzapine was not significantly different from that seen with haloperidol in the putamen, ventral striatum, medial thalamus, amygdala, or temporal cortex, that is, 67.5-78.2% occupancy; olanzapine produced no preferential occupancy of dopamine D(2)/D(3) receptors in the ventral striatum, medial thalamus, amygdala, or temporal cortex. There was, however, significantly lower occupancy of substantia nigra/VTA dopamine D(2)/D(3) receptors in olanzapine-treated compared to haloperidol-treated subjects, that is, 40.2 vs 59.3% (p=0.0014, corrected for multiple comparisons); in olanzapine-treated subjects, the substantia nigra/VTA was the only region with significantly lower dopamine D(2)/D(3) receptor occupancy than the putamen, that is, 40.2 vs 69.2% (p<0.001, corrected for multiple comparison). Occupancy of 5-HT(2A) receptors was 85-93% in the olanzapine- treated subjects. The results of this study demonstrated that olanzapine does not produce preferential occupancy of extrastriatal dopamine D(2)/D(3) receptors but does spare substantia nigra/VTA receptors. Sparing of substantia nigra/VTA dopamine D(2)/D(3) receptor occupancy may contribute to the low incidence of extrapyramidal side effects in olanzapine-treated patients.
Activation of the cerebral cortex is seen during hallucinations. The 5-HT(2A/C) agonist 1-[2,5-dimethoxy-4-iodophenyl]-2-aminopropane (DOI) is a potent hallucinogen that has been proposed to act by targeting 5-HT(2A) heteroceptors on thalamocortical neurons and eliciting release of glutamate from these cells, which in turn drives cortical neurons. We used in vivo microdialysis to determine if DOI increases extracellular glutamate levels. Systemic administration of DOI significantly increased extracellular glutamate levels in the somatosensory cortex of the freely-moving rat. Similarly, intracortical administration of DOI by reverse dialysis increased cortical extracellular glutamate levels. No consistent changes in either extracellular GABA or glycine levels were observed in response to DOI. The increase in glutamate levels elicited by intracortical DOI was blocked by treatment with the selective 5-HT(2A) antagonist MDL 100,907. These data are consistent with the hypothesis that 5-HT(2A) receptor-mediated regulation of glutamate release is the mechanism through which hallucinogens activate the cerebral cortex.