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Brain Research Jun 2016Traumatic brain injury (TBI) is a significant and enduring health care issue with limited treatment options. While several pre-clinical therapeutic approaches have led... (Review)
Review
Traumatic brain injury (TBI) is a significant and enduring health care issue with limited treatment options. While several pre-clinical therapeutic approaches have led to enhanced motor and/or cognitive performance, the benefits of these treatments have not translated to the clinic. One plausible explanation is that the therapies may not have been rigorously evaluated, thus rendering the bench-to-bedside leap premature and subsequently unsuccessful. An approach that has undergone considerable empirical research after TBI is pharmacological targeting of 5-HT1A receptors with agonists such as repinotan HCl, 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT), and buspirone. The goal of this review is to integrate and interpret the findings from a series of studies that evaluated the efficacy of 5-HT1A receptor agonists on functional, histological, and molecular outcome after acquired brain injury. The overwhelming consensus of this exhaustive review is that a decade of empirical evidence supports their use as an efficacious therapeutic strategy for brain trauma. This article is part of a Special Issue entitled SI:Brain injury and recovery.
Topics: Animals; Brain Injuries, Traumatic; Humans; Neuroprotective Agents; Receptor, Serotonin, 5-HT1A; Serotonin 5-HT1 Receptor Agonists
PubMed: 26612522
DOI: 10.1016/j.brainres.2015.11.026 -
Revista Da Associacao Medica Brasileira... 2011This paper reviews involvement of the serotonergic system in the control of food intake and satiety. It is of great interest to understand the relevance of this system... (Review)
Review
This paper reviews involvement of the serotonergic system in the control of food intake and satiety. It is of great interest to understand the relevance of this system for physiological control of energy balance and obesity. Over 35 years of research suggest that serotonin (5-HT) plays an important role in satiety. Thus, the serotonergic system has been a viable target for weight control. The 5-HT has control over hunger and satiety through different receptors with distinct functions. The 5-HT2C receptor may be more important in the relationship between food intake and energy balance. This review will discuss the mechanisms of the serotonergic system involved in the control of food intake and satiety.
Topics: Animals; Eating; Humans; Hunger; Hypothalamus; Neurotransmitter Agents; Obesity; Satiation; Serotonin; Serotonin 5-HT1 Receptor Agonists; Serotonin 5-HT2 Receptor Agonists; Serotonin Receptor Agonists
PubMed: 21390463
DOI: No ID Found -
CNS Neuroscience & Therapeutics Feb 20115-HT(1A) receptors have long been implicated in the pathogenesis and treatment of anxiety and depressive disorders. Recently, several lines of studies have revealed new... (Review)
Review
5-HT(1A) receptors have long been implicated in the pathogenesis and treatment of anxiety and depressive disorders. Recently, several lines of studies have revealed new insights into the therapeutic role of 5-HT(1A) receptors in treating schizophrenia and Parkinson's disease. Specifically, 5-HT(1A) receptors seem to be a promising target for alleviating antipsychotic-induced extrapyramidal side effects (EPS) and cognitive/affective disorders in schizophrenia. In the treatment of patients with Parkinson's disease, 5-HT(1A) agonists are expected to improve not only affective symptoms (e.g., anxiety and depression), but also the core parkinsonian symptoms as well as antiparkinsonian agents-induced side effects (e.g., L-DOPA-induced dyskinesia). Here, the therapeutic mechanisms mediated by 5-HT(1A) receptors in schizophrenia and Parkinson's disease are reviewed. This evidence should encourage discovery of new 5-HT(1A) ligands, which can resolve the unmet clinical needs in the current therapy.
Topics: Antipsychotic Agents; Basal Ganglia; Humans; Parkinson Disease; Receptor, Serotonin, 5-HT1A; Schizophrenia; Serotonin 5-HT1 Receptor Agonists; Serotonin 5-HT1 Receptor Antagonists
PubMed: 21091640
DOI: 10.1111/j.1755-5949.2010.00211.x -
Behavioural Brain Research Jun 2022Pharmacological activation of the serotonin (5-HT) 1B and 5-HT1A receptors has been shown to induce OCD-like perseverative circling and locomotor stereotypy in rodents....
Pharmacological activation of the serotonin (5-HT) 1B and 5-HT1A receptors has been shown to induce OCD-like perseverative circling and locomotor stereotypy in rodents. Although, several studies have examined how activation of these receptors facilitates these motor-associated OCD-like behaviors, it is not known how acute 5-HT1B and 5-HT1A activation impacts behavioral inflexibility, a common trait related to OCD. The current study examined how acute 5-HT1B/1A receptor agonist RU24969 treatment at 0.01, 0.1, and 1.0 mg/kg impacted behavioral flexibility in both female and male C57BL/6J mice. Behavioral flexibility was tested using a spatial reversal learning task, with probabilistic reward contingencies. In addition, locomotor activity and anxiety-like behaviors were also measured. RU24969 at 0.1 and 1.0 mg/kg impaired behavioral flexibility in both female and male C57BL/6J mice. RU24969 treatment at 1.0 mg/kg reduced locomotor activity in male mice, although RU24969 treatment did not significantly reduce locomotor activity in female mice. In the open field, 1.0 mg/kg elevated anxiety-like behavior in male mice only. Overall, these results demonstrate that acute 5-HT1B and 5-HT1A receptor activation leads to impairments in behavioral flexibility, a common trait associated with OCD.
Topics: Animals; Female; Male; Mice; Mice, Inbred C57BL; Receptor, Serotonin, 5-HT1A; Receptor, Serotonin, 5-HT1B; Receptors, Serotonin, 5-HT1; Serotonin; Serotonin 5-HT1 Receptor Agonists
PubMed: 35367298
DOI: 10.1016/j.bbr.2022.113865 -
CNS Neuroscience & Therapeutics 2009Vilazodone (EMD 68843; 5-{4-[4-(5-cyano-3-indolyl)-butyl]-1-piperazinyl}-benzofuran-2-carboxamide hydrochloride) is a combined serotonin specific reuptake inhibitor... (Review)
Review
Vilazodone (EMD 68843; 5-{4-[4-(5-cyano-3-indolyl)-butyl]-1-piperazinyl}-benzofuran-2-carboxamide hydrochloride) is a combined serotonin specific reuptake inhibitor (SSRI) and 5-HT1A receptor partial agonist currently under clinical evaluation for the treatment of major depression. This molecule was designed based on the premise that negative feedback circuitry, mediated via 5-HT1 receptors, limits the acute SSRI-induced enhancements in serotonergic neurotransmission. If the hypothesis is correct, combination of SSRI with 5-HT1A partial agonism should temporally enhance the neuroplastic adaptation and subsequently hasten therapeutic efficacy compared to current treatments. Preclinical in vitro evaluation has confirmed vilazodone's primary pharmacological profile both in clonal and native systems, that is, serotonin reuptake blockade and 5-HT1A partial agonism. However, in vivo and in contrast to combination of 8-OH-DPAT and paroxetine, vilazodone selectively enhanced serotonergic output in the prefrontal cortex of rats. Behavioral evaluations, in the ultrasonic vocalization model of anxiety in rats, demonstrated anxiolytic efficacy. In the forced swim test (a putative model of depression), vilazodone also showed efficacy but at a single dose only. In man, vilazodone abolished REM sleep and demonstrated clinical antidepressant efficacy equivalent to an SSRI. Ongoing clinical evaluations will hopefully reveal whether the founding hypothesis was valid and if vilazodone will produce a more rapid onset of antidepressant efficacy.
Topics: Animals; Antidepressive Agents; Benzofurans; Humans; Indoles; Mood Disorders; Piperazines; Receptor, Serotonin, 5-HT1A; Serotonin 5-HT1 Receptor Agonists; Serotonin Plasma Membrane Transport Proteins; Serotonin Receptor Agonists; Selective Serotonin Reuptake Inhibitors; Vilazodone Hydrochloride
PubMed: 19499624
DOI: 10.1111/j.1755-5949.2008.00067.x -
Journal of Neurology, Neurosurgery, and... Feb 1998
Topics: Acute Disease; Clinical Trials as Topic; Humans; Indoles; Migraine Disorders; Oxazoles; Oxazolidinones; Piperidines; Serotonin Receptor Agonists; Sumatriptan; Tryptamines
PubMed: 9489518
DOI: 10.1136/jnnp.64.2.143 -
CPT: Pharmacometrics & Systems... Oct 2021Ulotaront (SEP-363856) is a trace amine-associated receptor 1 agonist with 5-HT agonist activity in phase III development for the treatment of schizophrenia. The...
Ulotaront (SEP-363856) is a trace amine-associated receptor 1 agonist with 5-HT agonist activity in phase III development for the treatment of schizophrenia. The efficacy of ulotaront is not mediated by blockade of D or 5-HT receptors. The aim of this study was to evaluate the population pharmacokinetics (PopPKs) of ulotaront in adult subjects using pooled data from seven phase I studies, one phase II acute study, and one 6-month extension study. Single and multiple (up to 7 days) oral doses (5-150 mg/day) were studied in both healthy adult subjects (with intensive serial plasma sampling) and adult patients with schizophrenia (some with intensive and some with sparse plasma sampling). Ulotaront was well-absorbed and exhibited dose-proportionality in doses ranging from 10 to 100 mg, in mean maximum concentration, area under the concentration-time curve, and minimum concentration. Moderate interindividual variability was observed in concentration-time profiles. The estimated median time to maximal concentration was 2.8 h and the median effective half-life was 7 h, corresponding to an exposure accumulation ratio of 1.10 at steady-state with daily dosing. There was no indication of time-dependent changes in PKs after up to 12 weeks of daily dose administration. No clinically meaningful effects on ulotaront PK parameters were observed based on race, age, sex, formulation (capsule or tablet), or clinical status (healthy volunteer vs. patient with schizophrenia); body weight was the only meaningful covariate.
Topics: Adolescent; Adult; Female; Humans; Male; Middle Aged; Young Adult; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Healthy Volunteers; Pyrans; Receptor, Serotonin, 5-HT1A; Receptors, G-Protein-Coupled; Schizophrenia; Serotonin 5-HT1 Receptor Agonists
PubMed: 34292664
DOI: 10.1002/psp4.12692 -
The Journal of Headache and Pain Dec 2016Migraine is a neurological disorder resulting in large socioeconomic burden. This network meta-analysis (NMA) is designed to compare the relative efficacy and... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Migraine is a neurological disorder resulting in large socioeconomic burden. This network meta-analysis (NMA) is designed to compare the relative efficacy and tolerability of non-steroidal anti-inflammatory agents (NSAIDs) and triptans.
METHODS
We conducted systematic searches in database PubMed and Embase. Treatment effectiveness was compared by synthesizing direct and indirect evidences using NMA. The surface under curve ranking area (SUCRA) was created to rank those interventions.
RESULTS
Eletriptan and rizatriptan are superior to sumatriptan, zolmitriptan, almotriptan, ibuprofen and aspirin with respect to pain-relief. When analyzing 2 h-nausea-absence, rizatriptan has a better efficacy than sumatriptan, while other treatments indicate no distinctive difference compared with placebo. Furthermore, sumatriptan demonstrates a higher incidence of all-adverse-event compared with diclofenac-potassium, ibuprofen and almotriptan.
CONCLUSION
This study suggests that eletriptan may be the most suitable therapy for migraine from a comprehensive point of view. In the meantime ibuprofen may also be a good choice for its excellent tolerability. Multi-component medication also attracts attention and may be a promising avenue for the next generation of migraine treatment.
Topics: Anti-Inflammatory Agents, Non-Steroidal; Humans; Ibuprofen; Migraine Disorders; Oxazolidinones; Pyrrolidines; Randomized Controlled Trials as Topic; Sumatriptan; Treatment Outcome; Triazoles; Tryptamines
PubMed: 27957624
DOI: 10.1186/s10194-016-0703-0 -
Molecular Vision 2016Chronic oxidative stress and subacute inflammation have been implicated as causes of age-related macular degeneration (AMD). In this study, we tested whether an orally...
PURPOSE
Chronic oxidative stress and subacute inflammation have been implicated as causes of age-related macular degeneration (AMD). In this study, we tested whether an orally available 5-OH-tryptamine (5HT) 1a receptor agonist, xaliproden, could protect against retinal pigment epithelium (RPE) cell damage in culture and in a mouse model of geographic atrophy.
METHODS
Paraquat was used to create mitochondrial oxidative stress in ARPE-19 cells, and tumor necrosis factor-α (TNF-α) was used to stimulate the production of inflammatory cytokines in these cells. The production of antioxidant proteins, metallothionein, and inflammatory cytokines was assayed with quantitative real-time PCR. Cell survival was analyzed with microscopy and a cell titer assay. Integrity of the RPE monolayer was determined by measuring the transepithelial electrical resistance (TEER) and with immunocytochemistry with zona occludens protein 1 (ZO-1) antibody. RPE atrophy was studied in mice deleted for Sod2 (the gene for mitochondrial superoxide dismutase) specifically in the RPE. The mice were treated orally with daily doses of xaliproden at 0.5 and 3 mg/kg for 4 months. The retinal structure was analyzed with spectral domain optical coherence tomography (SD-OCT) and with light and electron microscopy. Retinal function was assessed with full-field electroretinography (ERG) and with optokinetic measurements.
RESULTS
Xaliproden led to a dose-dependent increase in cell survival following treatment with paraquat. Synthesis of the antioxidant response genes NqO1, GSTM1, CAT, HO-1, and Nrf2 was increased in response to the drug, as was the zinc chaperone metallothionein. Treatment of cells with TNF-α led to increased production of IL-1β, IL-6, chemokine (C-C motif) ligand 20 (CCL20), and vascular endothelial growth factor (VEGF) by ARPE-19 cells, and this response was attenuated by treatment with xaliproden. TNF-α also led to a decrease in the TEER that was prevented by treatment with the 5HT1a agonist. Daily gavage with xaliproden at either dose induced the production of protective enzymes in the mouse retina, and treatment of the Sod2-deleted mice with the drug showed improved thickness of the outer nuclear layer and improved visual acuity relative to the control-treated mice. There was no significant difference in full-field scotopic ERG among the treatment groups, however. Vacuolization of the RPE and disorganization of the photoreceptor outer segments were reduced at both dose levels of xaliproden.
CONCLUSIONS
Xaliproden protected RPE cells from oxidative and inflammatory insults and protected the mouse RPE and retina from RPE atrophy in the face of excess mitochondrial oxidative stress. These results suggest that this drug, which had a reasonable safety profile in clinical trials, may be used to prevent the progression of geographic atrophy in humans.
Topics: Administration, Oral; Animals; Cell Line; Cytokines; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Repositioning; Electric Impedance; Electroretinography; Enzyme-Linked Immunosorbent Assay; Geographic Atrophy; Humans; Metallothionein; Mice; Mice, Inbred C57BL; Mice, Transgenic; Naphthalenes; Pyridines; Real-Time Polymerase Chain Reaction; Retina; Retinal Pigment Epithelium; Serotonin 5-HT1 Receptor Agonists; Tomography, Optical Coherence; Zonula Occludens-1 Protein
PubMed: 27110092
DOI: No ID Found -
Basic & Clinical Pharmacology &... Jun 2021Clinical data on the transfer of triptans into human breast milk remain scarce. In a lactation study including 19 breastfeeding women with migraine, we examined the...
Clinical data on the transfer of triptans into human breast milk remain scarce. In a lactation study including 19 breastfeeding women with migraine, we examined the excretion of six different triptans into milk. Following intake of a single dose, each participant collected seven breast milk samples at predefined intervals up to 24 hours after dose. Triptan concentrations in milk were measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Infant drug exposure was estimated by calculating the relative infant dose (RID). Twenty-two breast milk sample sets were obtained for sumatriptan (n = 8), rizatriptan (n = 5), zolmitriptan (n = 4), eletriptan (n = 3), almotriptan (n = 1) and naratriptan (n = 1). Based on the average concentration in milk throughout the day, estimated mean RIDs (with range in parenthesis) were as follows: eletriptan 0.6% (0.3%-0.8%), sumatriptan 0.7% (0.2%-1.8%), rizatriptan 0.9% (0.3%-1.4%), almotriptan 1.8% (-), zolmitriptan 2.1% (0.7%-5.3%) and naratriptan 5.0% (-). Infant drug exposure through breastfeeding appears to be low and indicates that use of the triptans in this study is compatible with breastfeeding. Naratriptan may not be first choice in breastfeeding mothers initiating triptans during the neonatal period.
Topics: Adult; Breast Feeding; Female; Humans; Infant; Infant, Newborn; Migraine Disorders; Milk, Human; Oxazolidinones; Piperidines; Pyrrolidines; Triazoles; Tryptamines
PubMed: 33730376
DOI: 10.1111/bcpt.13579