Search

Pain strongly affects public health, both because of the patient suffering and the socioeconomic impact. The available drugs for pain treatment are not fully effective and have many adverse effects. Therefore, there is a need to obtain new analgesic compounds. This study evaluated the antinociceptive effect of N -(3-(phenylselanyl)prop-2-yn-1-yl)benzamide (SePB), an organoselenium compound containing the benzamide moiety, through time (15–120 min) and dose-response (1–50 mg/kg) curves in thermal and chemical mice models of nociception, as well as the involvement of the serotonergic system in this effect. The open-field test (OFT) was carried out to assess locomotor activity. SePB (10 mg/kg) induced an increase in the latency to nociception response in the tail immersion test from 30 min. In the dose-response curves, SePB at different doses reduced latency time to nociceptive response in the tail immersion and hot plate tests, and reduced the licking time in the glutamate test, demonstrating antinociceptive effect, without altering the locomotor activity of mice. WAY100635 (0.5 mg/kg, subcutaneously, a 5-HT 1A receptor antagonist), ketanserin (0.3 mg/kg, intraperitoneally, a 5-HT 2A/2C receptor antagonist), but not ondansetron (0.5 mg/kg, intraperitoneally, a 5-HT 3 receptor antagonist), administered 15 min before SePB, prevented the increased latency to nociceptive response induced by SePB in the tail immersion test, demonstrating that 5-HT 1A and 5-HT 2A/2C receptors are involved in the antinociceptive effect of SePB. Upon more studies evaluating SePB antinociceptive effects in chronic pain models and its toxicity, this compound could be indicated as an interesting molecule to treat pain. • New molecule containing selenium presents antinociceptive potential. • A selenopropargylic benzamide (SePB) showed antinociceptive effect in mice. • The serotonergic system is involved in the antinociceptive effect of SePB. [ABSTRACT FROM AUTHOR]

Earlier autoradiographic studies with the 5-HT receptor agonist [I](±)DOI in human brain showed unexpected biphasic competition curves for various 5-HT antagonists. We have performed similar studies in rat brain regions with selective 5-HT (M100907) and 5-HT (SB242084) antagonists together with ketanserin and mesulergine. The effect of GTP analogues on antagonist competition was also studied. Increasing concentrations of Gpp(NH)p or GTPγS resulted in a maximal inhibition of [I](±)DOI-specific binding of approximately 50 %. M100907 competed biphasically in all regions. In the presence of 100 μM Gpp(NH)p, M100907 still displaced biphasically the remaining [I](±)DOI binding. Ketanserin showed biphasic curves in some regions and monophasic curves in others. In the latter, Gpp(NH)p evidenced an additional high-affinity site. SB242084 competed biphasically in brainstem nuclei and monophasically in the other regions. In most areas, SB242084 affinities were not notably altered by Gpp(NH)p. Mesulergine competed monophasically in all regions without alteration by Gpp(NH)p. These results conform with the extended ternary complex model of receptor action: receptor exists as an equilibrium of multiple conformations, i.e. ground (R), partly activated (R*) and activated G-protein-coupled (R*G) conformation/s. Thus, [I](±)DOI would label multiple conformations of both 5-HT and 5-HT receptors in rat brain, and M100907 and ketanserin would recognise these conformations with different affinities. [ABSTRACT FROM AUTHOR]

We have investigated the ability of the 5 HT2-receptor antagonist ketanserin to affect the hyperthermia produced by methylenedioxymethamphetamine ( MDMA) in conscious mice and examined whether α1-adrenoceptor antagonist actions are involved., Mice were implanted with intra-abdominal temperature probes under anaesthesia and allowed 2 weeks recovery. MDMA (20 mg kg−1) was administered subcutaneously 30 min after vehicle or test antagonist and effects on body temperature monitored by telemetry., Following vehicle, MDMA produced a slowly developing hyperthermia, reaching a maximum increase of 1.24 °C at 150 min postinjection. Ketanserin (0.5 mg kg−1) revealed a significant and marked early hypothermia to MDMA, an effect that is mimicked by the α1-adrenoceptor antagonist prazosin (0.1 mg kg−1)., Functional studies revealed antagonist actions of ketanserin at α1-adrenoceptors in rat aorta and rat vas deferens in vitro indicative of α1-adrenoceptor antagonist actions at the concentration used in vivo., In conclusion, ketanserin (0.5 mg kg−1) modulates the hyperthermic actions of MDMA in mice. Although we cannot rule out additional actions at 5 HT2-receptors, the actions of ketanserin are consistent with α1-adrenoceptor antagonism. There is no clear evidence from this study that 5 HT2-receptors mediate the hyperthermic response to MDMA. [ABSTRACT FROM AUTHOR]

The article presents a study on the role of serotonin 2A receptor in processing of fear and anger. It mentions that the receptors were blocked with ketanserin by adjusting the time between ketanserin-infusion and onset of the functional magnetic resonance imaging (fMRI). The study concludes that the increase in the sensitivity of the orbitofrontal cortex (OFC) and strength regulation of negative feedback signal from the OFC to amygdala is done by the receptor mediated signaling.

Background/Aims: Functional activation of Gq coupled with 5-HT2 receptors was investigated in rat cerebral cortical membranes. Methods: Antibody-capture scintillation proximity assay (SPA)/[35S]GTPγS binding with anti-Gαq antibody was performed. Results: The specific [35S]GTPγS binding to Gαq was increased by 5-hydroxytryptamine (5-HT) in a concentration-dependent but unsaturable manner. The increase elicited by micromolar concentrations of 5-HT was inhibited completely by ketanserin, whereas it inhibited the response by submillimolar to millimolar concentrations of 5-HT only partially. Analysis of the concentration-dependent increases by 5-HT in the absence and presence of ketanserin, methiothepin, WAY100635, and pirenzepine clearly indicates that there are two distinct components of 5-HT-stimulated [35S]GTPγS binding, one of which is a pharmacologically relevant increase elicited by lower concentrations (-30 μmol/l) of 5-HT mediated through 5-HT2 receptors and the other is pharmacologically undefined stimulation by higher concentrations of 5-HT. When 5-HT and carbachol were added simultaneously, there was apparently lack of additivity. Conclusion: It is concluded that by means of antibody-capture SPA/[35S]GTPγS binding it is possible to detect two distinct components of 5-HT-elicited activation of Gq shared by M1 muscarinic receptors, one of which is mediated through 5-HT2 receptors and the other is derived from unknown origin in rat cerebral cortical membranes. Copyright © 2013 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Pharmacologic profiling of serotonin (5HT) receptors of bovine lateral saphenous vein has shown that cattle grazing endophyte-infected (Neotyphodium coenophialum) tall fescue (Lolium arimdinaceum) have altered responses to ergovaline, 5HT, 5HT-2A, and 5HT7 agonists. To detennine if 5HT receptor activity of tall fescue alkaloids is affected by grazing endophyte-free (EF), wild-type [Kentucky-31 (KY31)], novel endophyte AR542-infected (MAXQ), or novel endophyte AR584- infected (AR584) tall fescue, contractile responses of lateral saphenous veins biopsied from cattle grazing these different fescue-endophyte combinations were evaluated in presence or absence of antagonists for 5HT2A (ketanserin) or 5HT7 (SB-269970) receptors. Biopsies were conducted over 2 yr on 35 mixed-breed steers (361.5 ± 6.3 kg) grazing EF (n = 12), KY31 (n = 12), MAXQ (n = 6), or AR584 (n = 5) pasture treatments (3 ha) between 84 and 98 d (Yr 1) or 108 to 124 d (Yr 2). Segments (2 to 3 cm) of vein were surgically biopsied, sliced into 2- to 3-mm cross-sections, and suspended in a myograph chamber containing 5 mL of oxygenated Krebs-Henseleit buffer (95% O2/5% CO,; pH = 7.4; 37°C). Veins were exposed to increasing concentrations of 5HT, ergovaline, and ergovaline + 1 × 10-5 Mketanserin or + 1 × 10-6 M SB-269970 in Yr 1. In Yr 2, ergotamine and ergocornine were evaluated in presence or absence of 1 × 10-5 Mketanserin. Contractile response data were normalized to a reference addition of 1 × 10-4 Mnorepinephrine. In Yr 1, contractile response to 5HT and ergovaline were least (P < 0.05) in KY31 pastures and the presence of ketanserin greatly reduced (P < 0.05) the response to ergovaline in all pastures. However, presence of SB-269970 did not (P = 0.91) alter contractile response to ergovaline. In Yr 2, there was no difference in contractile response to ergotamine (P = 0.13) or ergocornine (P = 0.99) across pasture treatments, but ketanserin reduced (P < 0.05) the contractile response to both alkaloids. The 5HT2A receptor is involved in alkaloid-induced vascular contraction and alkaloid binding may be affected by exposure to different endophyte-fescue combinations. [ABSTRACT FROM AUTHOR]

Previous postmortem and neuroimaging studies have repeatedly suggested alterations in serotonin 5-HT2A receptor (5-HT2AR) binding associated with the pathophysiology of schizophrenia. These studies were performed with ligands, such as ketanserin, altanserin and LSD, that may bind with high-affinity to different structural or functional conformations of the 5-HT2AR. Interpretation of results may also be confounded by chronic antipsychotic treatment and suicidal behavior in the schizophrenia group. We quantified 5-HT2AR density by radioligand binding assays in postmortem prefrontal cortex of antipsychotic-free (n=29) and antipsychotic-treated (n=16) schizophrenics, suicide victims with other psychiatric diagnoses (n=13), and individually matched controls. [3H]Ketanserin binding, and its displacement by altanserin or the LSD-like agonist DOI, was assayed. Results indicate that the number of [3H]ketanserin binding sites to the 5-HT2AR was increased in antipsychotic-free (128±11%), but not in antipsychotic-treated (92±12%), schizophrenic subjects. In suicide victims, [3H]ketanserin binding did not differ as compared to controls. Aging correlated negatively with [3H]ketanserin binding in schizophrenia, suicide victims and controls. The fraction of high-affinity sites of DOI displacing [3H]ketanserin binding to the 5-HT2AR was increased in antipsychotic-free schizophrenic subjects. Functional uncoupling of heterotrimeric G proteins led to increased fraction of high-affinity sites of altanserin displacing [3H]ketanserin binding to the 5-HT2AR in schizophrenic subjects, but not in controls. Together, these results suggest that the active conformation of the 5-HT2AR is up-regulated in prefrontal cortex of antipsychotic-free schizophrenic subjects, and may provide a pharmacological explanation for discordant findings previously obtained. [ABSTRACT FROM AUTHOR]

Although past studies demonstrate that altered serotonin (5-HT) signaling is present in adults with idiopathic pulmonary arterial hypertension, whether serotonin contributes to the pathogenesis of persistent pulmonary hypertension of the newborn (PPHN) is unknown. Wehypothesized that 5-HT contributes to increased pulmonary vascular resistance (PVR) in a sheep model of PPHN and that selective 5-HT reuptake inhibitor (SSRI) treatment increasesPVR in this model. We studied the hemodynamic effects of 5-HT, ketanserin (5-HT2A receptor antagonist), and sertraline, an SSRI, on pulmonary hemodynamics of the late gestation fetal sheep with PPHN caused by prolonged constriction of the ductus arteriosis. Brief intrapulmonary infusions of 5-HT increased PVR from 1.0 ± 0.07 (baseline) to 1.4 ± 0.22 mmHg/ml per minute of treatment (P < 0.05). Ketanserin decreased PVR from 1.1 ± 0.15 (baseline) to 0.82 ± 0.09 mmHg/ml per minute of treatment (P < 0.05). Sertraline increased PVR from 1.1 ± 0.17 (baseline) to 1.4 ± 0.17 mmHg/ml per minute of treatment (P = 0.01). In addition, we studied 5-HT production and activity in vitro in experimental PPHN. Compared with controls, pulmonary artery endothelial cells from fetal sheep with PPHN exhibited increased expression of tryptophan hydroxylase 1 and 5-HT production by twofold and 56%, respectively. Compared with controls, 5-HT2A R expression was increased in lung homogenates and pulmonary artery smooth muscle cell lysates by 35% and 32%, respectively. We concluded that increased 5-HT contributes to high PVR in experimental PPHN through activation of the 5-HT2A receptor and that SSRI infusion further increases PVR in this model. [ABSTRACT FROM AUTHOR]

Opening of the oxirane ring in 1-oxiranylmethylindoles yielded new indole derivatives containing 1,2-amino alcohol residues at the nitrogen atom. Compounds were studied in vitro in relation to various types of pharmacological activity typical of this class of compounds, including receptor (5-HT, 5-HT, P2Y-ergic, κ-opioid), antiaggregant, hemorheological, antiarrhythmic, and antioxidant activities. [ABSTRACT FROM AUTHOR]

This study was designed to examine the effects of intracerebroventricular (ICV) injection of ketanserin (5-HT2a receptor antagonist) and SB242084 (5-HT2c receptor antagonist) on harmaline induced feeding and drinking response in 24-h food-deprived (FD24) broiler cockerels. At first, guide cannula was surgically implanted in the right lateral ventricle of chickens. In experiment 1, birds were injected intracerebroventriculary with 0, 25, 50 and 100 μg of harmaline. In experiment 2, chickens received 10 μg ketanserin prior to the injection of harmaline. In experiment 3, birds were administered with harmaline after 3 μg SB242084 and the cumulative food and water intake was determined at 3 h post injection. The results of this study showed that harmaline decreases food consumption and increases water intake in FD24 broiler cockerels (P⩽0.05). The effect of harmaline on food and water intake was significantly attenuated with ketanserin and SB242084 pretreatment (P⩽0.05). These results suggest that there is an interaction between harmaline and 5-HT (via 5-HT2a and 5-HT2c receptors) on eating response in chicken. [ABSTRACT FROM AUTHOR]

Abstract: Evidence from in vivo and in vitro experiments conclude that serotonin (5-HT) neurons are involved in and play an important role in central respiratory CO2/H+ chemosensitivity. This study was designed to assess the importance of 5-HT neurons and 5-HT receptor activation in the frequency and amplitude components of the hypercapnic response of the respiratory network in the unanesthetized perfused in situ juvenile rat brainstem preparation that exhibits patterns of phrenic nerve discharge similar to breathing in vivo. Exposure to a hypercapnic perfusate increased phrenic burst frequency and/or amplitude, the neural correlates of breathing frequency and tidal volume in vivo. Hypercapnic responses were also assessed during exposure to ketanserin (5-HT2 receptor antagonist), and 8-OH-DPAT (inhibiting 5-HT neurons via 5-HT1A autoreceptors). Neither of these drugs substantially altered baseline activity, however, both abolished hypercapnic responses of the respiratory network. These data illustrate that 5-HT neurons and 5-HT receptor activation are not required for respiratory rhythm generation per se, but are critical for CO2 responses in situ, supporting the hypothesis that 5-HT neurons play an important role in central ventilatory chemosensitivity in vivo. [Copyright &y& Elsevier]

Abstract: Aims: Olfactory bulbectomy (OBX) in rodents represents a valuable experimental model of depression. This study was designed to shed further light on the impact of putative serotonergic neuronal degeneration in OBX mice and to assess the effect of a widely used antidepressant on serotonergic related behavioral changes induced by OBX. Main methods: Adult male ddY mice were subject to bilateral OBX or sham surgery. The serotonin (5-HT)2A/2C receptor agonist 2,5-dimethoxy-4-iodoamphetamine (DOI) enhanced a head-twitch response (HTR) in OBX mice. Effects of 5-HT2A, 5-HT2C antagonists and fluvoxamine were observed in OBX mice following DOI administration. Key findings: The HTR elicited by the administration of DOI (0.5mg/kg and 1mg/kg, i.p.) was increased about twofold in OBX mice when compared with controls on the 14th day after the surgery. The injection of ketanserin (0.025mg/kg, i.p.), a 5-HT2A receptor antagonist, inhibited the enhancement of the DOI-induced HTR after OBX. Likewise, the administration of SB 242084 (1mg/kg, s.c.), a 5-HT2C receptor antagonist, also inhibited the DOI-induced HTR in OBX mice. Chronic but not acute treatment with the antidepressant fluvoxamine, a selective serotonin reuptake inhibitor (SSRI), suppressed the enhancement of DOI-induced HTR after OBX. Significance: These findings indicate that OBX, and the subsequent degeneration of neurons projecting from the olfactory bulb, caused a supersensitivity of 5-HT2A/2C receptors which may be involved in symptoms of depression. [Copyright &y& Elsevier]

Harmine is a β-carboline alkaloid and major component of ayahuasca, a traditional South American psychoactive tea with anecdotal efficacy for treatment of cocaine dependence. Harmine is an inhibitor of monoamine oxidase A (MAO-A) and interacts in vitro with several pharmacological targets which modulate dopamine (DA) neurotransmission. In vivo studies have demonstrated dopaminergic effects of harmine, attributed to monoamine oxidase inhibitor (MAOI) activity, however none have directly demonstrated a pharmacological mechanism. This study investigated the acute effects, and pharmacological mechanism(s), of harmine on electrically evoked DA efflux parameters in the nucleus accumbens both in the absence and presence of cocaine. Fast cyclic voltammetry in rat brain slices was used to measure electrically evoked DA efflux in accumbens core and shell. Harmine (300 nM) significantly augmented DA efflux (148±8% of baseline) in the accumbens shell. Cocaine augmented efflux in shell additive to harmine (260±35%). Harmine had no effect on efflux in the accumbens core or on reuptake in either sub-region. The effect of harmine in the shell was attenuated by the 5-HT2A/2C antagonist ketanserin. The MAOI moclobemide (10 µM) had no effect on DA efflux. These data suggest that harmine augments DA efflux via a novel, shell-specific, presynaptic 5-HT2A receptor-dependent mechanism, independent of MAOI activity. A DA-releasing ‘agonist therapy’ mechanism may thus contribute to the putative therapeutic efficacy of ayahuasca for cocaine dependence. [ABSTRACT FROM AUTHOR]

Opening of the five-member ring of indolylmethyleneoxazolones with aliphatic amines was used to synthesize a series of amides of 2-amino-3-indolylacrylic acid. These compounds were studied in vitro in relation to the various types of pharmacological activity typical of this class, including receptor (5-HT-, 5-HT-, and P2Y-ergic, K-opioid), antiaggregant, hemorheological, antiarrhythmic, and antioxidant activities. [ABSTRACT FROM AUTHOR]

Abstract: Based on early pharmacological work, the serotonin 2A (5-HT2A) receptor subtype is believed to be involved in the regulation of toadfish pulsatile urea excretion. The goal of the following study was to characterize the toadfish 5-HT2A receptor at a molecular level, to determine the tissues in which this receptor is predominantly expressed and to further investigate the pharmacological specificity of toadfish pulsatile urea excretion by examining the effect of ketanserin, a 5-HT2A receptor antagonist, on resting rates of pulsatile urea excretion. The full-length toadfish 5-HT2A receptor encodes a 496 amino acid sequence and shares 57–80% sequence identity to 5-HT2A receptors of other organisms, with 100% conservation among important ligand-binding residues. Toadfish 5-HT2A receptor mRNA expression was highest in the swim bladder and gonad, followed by the whole brain. All other tissues tested (esophagus, stomach, anterior intestine, posterior intestine, rectum, liver, kidney, heart, muscle and gill) had mRNA expression levels that were significantly less than whole brain. Toadfish 5-HT2A receptor mRNA expression within the brain was highest in the hindbrain, telencephalon and midbrain/diencephalon regions. Treatment with the 5-HT2A receptor antagonist, ketanserin, resulted in a significant decrease in the pulsatile component of spontaneous urea excretion due to a reduction in urea pulse size with no significant change in pulse frequency. These results lend further support for the 5-HT2A receptor in the regulation of pulsatile urea excretion in toadfish. [Copyright &y& Elsevier]

Abstract: Several findings have pointed to the role of the dorsal periaqueductal gray (dPAG) serotonin 5-HT1A and 5-HT2A–C receptor subtypes in the modulation of defensive behavior in animals exposed to the elevated plus-maze (EPM). Besides displaying anxiety-like behavior, rodents also exhibit antinociception in the EPM. This study investigated the effects of intra-dPAG injections of 5-HT1A and 5-HT2B/2C receptor ligands on EPM-induced antinociception in mice. Male Swiss mice received 0.1μl intra-dPAG injections of vehicle, 5.6 and 10nmol of 8-OHDPAT, a 5-HT1A receptor agonist (Experiment 1), or 0.01, 0.03 and 0.1nmol of mCPP, a 5-HT2B/2C receptor agonist (Experiment 2). Five minutes later, each mouse received an intraperitoneal injection of 0.6% acetic acid (0.1ml/10g body weight; nociceptive stimulus) and was individually confined in the open (OA) or enclosed (EA) arms of the EPM for 5min, during which the number of abdominal writhes induced by the acetic acid was recorded. While intra-dPAG injection of 8-OHDPAT did not change open-arm antinociception (OAA), mCPP (0.01nmol) enhanced it. Combined injections of ketanserin (10nmol/0.1μl), a 5-HT2A/2C receptor antagonist, and 0.01nmol of mCPP (Experiment 3), selectively and completely blocked the OAA enhancement induced by mCPP. Although intra-dPAG injection of mCPP (0.01nmol) also produced antinociception in EA-confined mice (Experiment 2), this effect was not confirmed in Experiment 3. Moreover, no other compound changed the nociceptive response in EA-confined animals. These results suggest that the 5-HT2C receptors located within the PAG play a role in this type of environmentally induced pain inhibition in mice. [Copyright &y& Elsevier]

Impulsivity is a heterogeneous construct according to clinical and preclinical behavioural measures and there is some preliminary evidence indicating distinct neurobiological substrates underlying the sub-components of impulsivity. Two preclinical assays, the five-choice serial reaction time task (5-CSRTT) and the delayed discounting task (DDT), are hypothesized to provide measures of impulsive action (premature responding) and impulsive choice (percent choice for delayed reward), respectively. In the present studies, we show that the norepinephrine reuptake inhibitor atomoxetine attenuated premature responding in the 5-CSRTT, but was ineffective in the DDT. The mixed dopamine/norepinephrine reuptake inhibitor methylphenidate exhibited an opposite profile of effects. In addition, blockade of 5-HT2A/C receptors via ketanserin decreased premature responding but had no effects on percent choice for delayed reward; blockade of 5-HT2C receptors via SB 242084 had opposite effects. Follow-up studies provided some limited evidence of additive effects of 5-HT2A/C receptor blockade on the effects of atomoxetine on impulsive action. These studies demonstrate dissociable profiles of stimulant vs. non-stimulant attention deficit hyperactivity disorder medications and 5-HT subtype-selective ligands, in the 5-CSRTT and DDT assays. Thus, the present findings support the sub-categorization of impulsivity and suggest that 5-HT receptor subtype-selective antagonists may provide therapeutic targets for disorders characterized by different forms of impulsivity. [ABSTRACT FROM PUBLISHER]

The influence of ageing on the passive and active tension and pharmacodynamic characteristics of intramural coronary arteries from 3-month-old and 2-year-old male Wistar rats was investigated using an isometric myograph. The passive vessel wall tension measured in Ca2+-free physiological salt solution at L0 was significantly greater in arteries from old rats (1.46 ± 0.10 Nm-1, n = 7) than in young rats (1.13 ± 0.13 Nm-1, n = 6). However, the maximal active tension at L0 was similar. The spontaneous myogenic tone was increased by age and the vasorelaxation induced by extracellular K+ was significantly higher in coronary arteries of old rats. The sensitivity (pD2) to 5-HT was significantly higher in arteries from old (6.43 ± 0.11, n = 22) than from young rats (6.16 ± 0.08, n = 29). Ketanserin induced a concentration-dependent rightward shift of the 5-HT concentration-response curve in arteries from both young and old rats. The slopes of the regression lines of the Schild plots were not significantly different from unity and the estimated pKB values for ketanserin were similar. In conclusion, ageing is associated with changes in passive mechanical characteristics as well as changes in pharmacological properties in rat coronary small arteries. Copyright © 2012 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Aljuffali, I. A., Brainard, B. M., Moore, J. N., Kwon, S., Allen, D., Robertson, T. P., Arnold, R. D. Pharmacokinetic assessment of ketanserin in the horse. J. vet. Pharmacol. Therap. 35, 472-477. The purpose of this study was to determine the pharmacokinetics (PK) of the 5-HT2A receptor antagonist ketanserin in healthy adult horses, and to develop a computational model that could be used to optimize dosing. Plasma concentrations of ketanserin were determined using liquid chromatography with mass spectrometry after single and multiple intravenous administration in the horse. A two-compartment linear pharmacokinetic model described the plasma concentration-time profile of ketanserin after single and multiple doses in healthy horses; the terminal half-life was 11.5 h; steady-state volume of distribution was 10.5 L/kg; AUC was 115 ng·h/mL; and clearance was 0.87 L/h/kg. Model simulations followed by the examination in three healthy horses suggest 0.3 mg/kg q.8 h exhibited linear PK and produced consistent systemic blood concentrations of ketanserin above 3 ng/mL. [ABSTRACT FROM AUTHOR]

Fragile X syndrome is a common inherited form of mental retardation caused by the lack of fragile X mental retardation protein (FMRP) because of Fmr1 gene silencing. Serotonin (5-HT) is significantly increased in the null mutants of Drosophila Fmr1, and elevated 5-HT brain levels result in cognitive and behavioral deficits in human patients. The serotonin type 2A receptor (5-HT2AR) is highly expressed in the cerebral cortex; it acts on pyramidal cells and GABAergic interneurons to modulate cortical functions. 5-HT2AR and FMRP both regulate synaptic plasticity. Therefore, the lack of FMRP may affect serotoninergic activity. In this study, we determined the involvement of FMRP in the 5-HT modulation of synaptic potentiation with the use of primary cortical neuron culture and brain slice recording. Pharmacological inhibition of 5- HT2AR by R-96544 or ketanserin facilitated long-term potentiation (LTP) in the anterior cingulate cortex (ACC) of WT mice. The prefrontal LTP induction was dependent on the activation of NMDARs and elevation of postsynaptic Ca2+ concentrations. By contrast, inhibition of 5-HT2AR could not restore the induction of LTP in the ACC of Fmr1 knock-out mice. Furthermore, 5-HT2AR inhibition induced AMPA receptor GluR1 subtype surface insertion in the cultured ACC neurons of Fmr1 WT mice, however, GluR1 surface insertion by inhibition of 5-HT2AR was impaired in the neurons of Fmr1KO mice. These findings suggested that FMRP was involved in serotonin receptor signaling and contributed in GluR1 surface expression induced by 5-HT2AR inactivation. [ABSTRACT FROM AUTHOR]

We compared the effects of an antagonist of 5-HT receptors, NAN-190 (0.1 mg/kg intraperitoneally), and an antagonist of 5-HT receptors, ketanserin (0.1 mg/kg intraperitoneally), which were chronically injected for 14 days, on the anxiety level in prenatally stressed female rats with an ovariectomyinduced experimental deficiency of estrogens. Chronic administration of ketanserin to ovariectomized prenatally stressed females had an anxiolytic effect and corrected disturbed levels of follitropin, lutropin, and estradiol. Administration of NAN-190 to ovariectomized prenatally stressed rats increased the anxiety level and decreased the ratio between the levels of tropic and peripheral sex hormones. [ABSTRACT FROM AUTHOR]

BACKGROUND AND PURPOSE Here, we have compared the neurochemical profile of three new cathinones, butylone, mephedrone and methylone, in terms of their potential to inhibit plasmalemmal and vesicular monoamine transporters. Their interaction with 5-HT and dopamine receptors and their psychostimulant effect was also studied. EXPERIMENTAL APPROACH Locomotor activity was recorded in mice following different doses of cathinones. Monoamine uptake assays were performed in purified rat synaptosomes. Radioligand-binding assays were carried out to assess the affinity of these compounds for monoamine transporters or receptors. KEY RESULTS Butylone, mephedrone and methylone (5-25 mg·kg−1) caused hyperlocomotion, which was prevented with ketanserin or haloperidol. Methylone was the most potent compound inhibiting both [3H]5-HT and [3H]dopamine uptake with IC50 values that correlate with its affinity for dopamine and 5-HT transporter. Mephedrone was found to be the cathinone derivative with highest affinity for vesicular monoamine transporter-2 causing the inhibition of dopamine uptake. The affinity of cathinones for 5-HT2A receptors was similar to that of MDMA. CONCLUSIONS AND IMPLICATIONS Butylone and methylone induced hyperlocomotion through activating 5-HT2A receptors and increasing extra-cellular dopamine. They inhibited 5-HT and dopamine uptake by competing with substrate. Methylone was the most potent 5-HT and dopamine uptake inhibitor and its effect partly persisted after withdrawal. Mephedrone-induced hyperlocomotion was dependent on endogenous 5-HT. Vesicular content played a key role in the effect of mephedrone, especially for 5-HT uptake inhibition. The potency of mephedrone in inhibiting noradrenaline uptake suggests a sympathetic effect of this cathinone. [ABSTRACT FROM AUTHOR]

Abstract: When stressed, toadfish become ureotelic and excrete almost all of their nitrogenous waste in 1–3 daily pulses of urea-N across the gills. Intravascular injections of 5-hydroxytyptamine (5-HT; serotonin) and analogues also elicit marked excretory pulses of urea-N from toadfish in vivo, suggesting that 5-HT release is the proximate trigger for spontaneous pulses. However it is unclear whether 5-HT is acting on the gills directly or elsewhere to cause the effect indirectly. A perfused whole gill preparation which maintained normal pressure relationships and stable vascular resistance was employed to address this question. Bolus injections into the ventral aortic perfusate of either 5-HT (1, 10μmolkg−1) or the specific 5-HT2 receptor agonist α-methyl 5-HT (1, 10μmolkg−1) elicited rapid urea-N pulses from perfused toadfish gills. The effective doses, the post-injection delays (5.5±1.3min, range=2–22), the percent occurrences (57–85%), and the magnitude of the induced urea-N pulses (615.4±131.3μmol-Nkg−1, range 66.0–2634.0), were all similar to those previously reported when these agents were injected in vivo. Bolus injections of 5-HT and α-methyl 5-HT also elicited a biphasic response in ventral aortic pressure, reflecting an initial rapid short-lived vasodilation and a subsequent longer-lasting vasoconstriction. These events were similar to those which have been recorded to occur at a greater frequency during spontaneous urea-N pulsing in vivo. Neither the urea-N pulsing nor the cardiovascular responses to 5-HT were inhibited by the 5-HT2A receptor subtype blocker, ketanserin (pre-injection with 10μmolkg−1 plus 33μmolL−1 in the perfusate). Overall, these results provide strong support for the idea that the proximate stimulus for natural urea pulsing in vivo is 5-HT mobilization, acting directly in the gills. [Copyright &y& Elsevier]

The influence of ageing on the passive and active tension and pharmacodynamic characteristics of intramural coronary arteries from 3-month-old and 2-year-old male Wistar rats was investigated using an isometric myograph. The passive vessel wall tension measured in Ca2+-free physiological salt solution at L0 was significantly greater in arteries from old rats (1.46 ± 0.10 Nn-1, η = 7) than in young rats (1.13 ± 0.13 Nm-1, n = 6). However, the maximal active tension at L0 was similar. The spontaneous myogenic tone was increased by age and the vasorelaxation induced by extracellular K+ was significantly higher in coronary arteries of old rats. The sensitivity (pD2) to 5-HT was significantly higher in arteries from old (6.43 ± 0.11, n = 22) than from young rats (6.16 ± 0.08, n = 29). Ketanserin induced a concentration-dependent rightward shift of the 5-HT concentration-response curve in arteries from both young and old rats. The slopes of the regression lines of the Schild plots were not significantly different from unity and the estimated pKB values for ketanserin were similar. In conclusion, ageing is associated with changes in passive mechanical characteristics as well as changes in pharmacological properties in rat coronary small arteries. [ABSTRACT FROM AUTHOR]

The influence of ageing on the passive and active tension and pharmacodynamic characteristics of intramural coronary arteries from 3-month-old and 2-year-old male Wistar rats was investigated using an isometric myograph. The passive vessel wall tension measured in Ca2+-free physiological salt solution at L0 was significantly greater in arteries from old rats (1.46 ± 0.10 Nn-1, η = 7) than in young rats (1.13 ± 0.13 Nm-1, n = 6). However, the maximal active tension at L0 was similar. The spontaneous myogenic tone was increased by age and the vasorelaxation induced by extracellular K+ was significantly higher in coronary arteries of old rats. The sensitivity (pD2) to 5-HT was significantly higher in arteries from old (6.43 ± 0.11, n = 22) than from young rats (6.16 ± 0.08, n = 29). Ketanserin induced a concentration-dependent rightward shift of the 5-HT concentration-response curve in arteries from both young and old rats. The slopes of the regression lines of the Schild plots were not significantly different from unity and the estimated pKB values for ketanserin were similar. In conclusion, ageing is associated with changes in passive mechanical characteristics as well as changes in pharmacological properties in rat coronary small arteries. [ABSTRACT FROM AUTHOR]

MDMA induces positive mood and increases impulse control during intoxication, but only a few studies on the neuropharmacological mechanisms underlying these processes have been conducted. It was hypothesized that pretreatment with 5-HT1 and 5-HT2 receptor blockers would prevent MDMA effects on mood and impulsivity. Subjects (N = 17) participated in a double-blind, placebo controlled, within-subject design involving 6 experimental conditions consisting of pretreatment (T1) and treatment (T2). T1 preceded T2 by 30 minutes. T1-T2 combinations were: placeboplacebo, 20 mg pindolol-placebo, 50 mg ketanserin-placebo, placebo-75 mg MDMA, 20 mg pindolol-75 mg MDMA and 50 mg ketanserin-75 g MDMA. Subjects completed a Profile of Mood States (POMS) questionnaire and several impulsivity tasks (Stop signal task, Matching familiar figures task, Cue dependent reversal learning task) at 1.5 hrs post-treatment. MDMA alone increased both positive (vigor, arousal, friendliness, elation, positive mood) and negative affect (anxiety, confusion) as assessed by the POMS questionnaire. MDMA also increased stop reaction time in the Stop signal task and reaction time in the Matching familiar figures task. Pretreatment with ketanserin blocked MDMA effects on positive affect, but not negative affect. Ketanserin did not influence the effects of MDMA on impulsivity. Pindolol did not interact with MDMA on any of the measures. In conclusion, 5-HT2 receptors mediate positive moods induced by MDMA but not negative moods or impulsivity. 5-HT1 receptors do not appear to be involved in MDMA effects on mood and impulse control. [ABSTRACT FROM AUTHOR]

BACKGROUND AND PURPOSE Dopamine released from the endings of descending dopaminergic nerve fibres in the spinal cord may be involved in modulating functions such as locomotion and nociception. Here, we examined the effects of dopamine on spinal synaptic transmissions in rats. EXPERIMENTAL APPROACH Spinal reflex potentials, monosynaptic reflex potential (MSR) and slow ventral root potential (sVRP), were measured in the isolated spinal cord of the neonatal rat. Dopamine release was measured by HPLC. KEY RESULTS Dopamine at lower concentrations (<1 µM) depressed sVRP, which is a C fibre-evoked polysynaptic response and believed to reflect nociceptive transmission. At higher concentrations (>1 µM), in addition to a potent sVRP depression, dopamine depolarized baseline potential and slightly depressed MSR. Depression of sVRP by dopamine was partially reversed by dopamine D1-like but not by D2-like receptor antagonists. SKF83959 and SKF81297, D1-like receptor agonists, and methamphetamine, an endogenous dopamine releaser, also caused the inhibition of sVRP. Methamphetamine also depressed MSR, which was inhibited by ketanserin, a 5-HT2A/2C receptor antagonist. Methamphetamine induced the release of dopamine and 5-HT from spinal cords, indicating that the release of endogenous dopamine and 5-HT depresses sVRP and MSR respectively. CONCLUSION AND IMPLICATIONS These results suggested that dopamine at lower concentrations preferentially inhibited sVRP, which is mediated via dopamine D1-like and other unidentified receptors. The dopamine-evoked depression is involved in modulating the spinal functions by the descending dopaminergic pathways. [ABSTRACT FROM AUTHOR]

Abstract: Our previous study has demonstrated that topical and systemic administration of the 5-HT2A receptor antagonist ketanserin attenuates neuropathic pain. To explore the mechanisms involved, we examined whether ketanserin reversed the plasticity changes associated with calcitonin gene-related peptides (CGRP) and neuropeptide Y (NPY) which may reflect distinct mechanisms: involvement and compensatory protection. Behavioral responses to thermal and tactile stimuli after spinal nerve ligation (SNL) at L5 demonstrated neuropathic pain and its attenuation in the vehicle- and ketanserin-treated groups, respectively. SNL surgery induced an increase in CGRP and NPY immunoreactivity (IR) in laminae I-II of the spinal cord. L5 SNL produced an expression of NPY-IR in large, medium and small diameter neurons in dorsal root ganglion (DRG) only at L5, but not adjacent L4 and L6. Daily injection of ketanserin (0.3mg/kg, s.c.) for two weeks suppressed the increase in CGRP-IR and NPY-IR in the spinal cord or DRG. The present study demonstrated that: (1) the expression of CGRP was enhanced in the spinal dorsal horn and NPY was expressed in the DRG containing injured neurons, but not in the adjacent DRG containing intact neurons, following L5 SNL; (2) the maladaptive changes in CGRP and NPY expression in the spinal cord and DRG mediated the bioactivity of 5-HT/5-HT2A receptors in neuropathic pain and (3) the blockade of 5-HT2A receptors by ketanserin reversed the evoked upregulation of both CGRP and NPY in the spinal cord and DRG contributing to the inhibition of neuropathic pain. [Copyright &y& Elsevier]

The aim of the present study was to clarify the responsiveness of the chicken basilar artery to 5-hydroxytryptamine (5-HT) and acetyicholine (ACh) and to characterize the related receptor subtypes in vitro. Basilar arteries were obtained from freshly slaughtered broiler chickens. The 5-HT induced concentration-dependent contraction of the arteries. The concentrationresponse curves for 5-HT were shifted 30-fold to the right by methiothepin (a 5-HT1 and 5-HT2 receptor antagonist) and 3-fold to the right by ketanserin (a 5-HT2 receptor antagonist). In the presence of ketanserin, the concentration-response curve for 5-HT was shifted 10-fold to the right by methiothepin. The pA2 value for methiothepin was 8.26. The ACh induced concentration-dependent relaxation under conditions of precontraction by 5-HT. The concentration-response curve for ACh was shifted to the right by atropine [a nonselective muscarinic (M) receptor antagonist] and hexahydro-sila-difenidol hydrochloride, a p-fluoroanalog (pFHHSiD, an M3 receptor antagonist), but not by pirenzepine (an M1 receptor antagonist) or methoctramine (an M2 receptor antagonist). The pA2 value for pFHHSiD was 7.55. Nω-Nitro-L-arginine (a nitric oxide synthase inhibitor) inhibited ACh-induced relaxation by approximately 50%. These results suggest that 5-HT induces contraction via activation of 5-HT1 and 5-HT2 receptors and that ACh induces relaxation via activation of the M3 receptor. The 5-HT1 receptor might play a dominant role in 5-HT-induced contraction. One of the factors involved in ACh-induced relaxation is probably nitric oxide released from endothelial cells. [ABSTRACT FROM AUTHOR]

Abstract: Objective: High ketanserin levels are found in the umbilical cord after maternal treatment. However, the effect on the circulation of the neonate has never been investigated. Study design: A prospective, observational study was performed at the neonate ward at the Medical Centre Leeuwarden, The Netherlands. All neonates exposed in utero to ketanserin administered to the mother, from May 2007 to December 2009 (n =58), were included. We studied the effect of ketanserin exposure on the circulation of the neonate, by monitoring heart rate and blood pressure during the first 24h of life. Non-parametric as well as parametric tests were used to analyze the effect of gestational age, birth weight, gender, various ketanserin factors (cumulative dosage, duration of therapy and last dosage rate), other maternal drug use and maternal diagnosis on the blood pressure of the neonate. Results: Eight neonates became hypotensive during the first 8h of life (13.8%). The last dosage rate as well as the mean dosage rate (cumulative dosage divided by duration of therapy in hours) were significantly higher in the group with hypotension (P =.005 and P =.002, respectively). All hypotensive neonates were exposed to a last dosage rate of at least 8mg/h. Maternal HELLP syndrome was diagnosed more often in hypotensive compared to normotensive neonates (P =.048). Conclusion: In utero exposure to ketanserin lowers the blood pressure of the neonate. The risk of hypotension is associated with the last dosage rate of maternal ketanserin treatment and the co-existence of maternal HELLP syndrome. [Copyright &y& Elsevier]

Studies in CBA mice and Wistar rats demonstrated the involvement of serotonin (5-HT) receptors in immunosuppression evoked using the selective δ2 opioid receptor (δ2-OR) agonist DSLET (100 μg/kg). This opioid effect was seen in conditions of selective activation of 5-HT autoreceptors with 8-OH-DPAT (0.1 mg/kg) and in conditions of prior blockade of postsynaptic 5-HT and 5-HT receptors with WAY-100635 and ketanserin (1 and 3 mg/kg). The question of the different contributions of these types of 5-HT receptor to δ-induced suppression of the immune response is discussed. [ABSTRACT FROM AUTHOR]

From computational simulations of a serotonin 2A receptor (5-HT2AR) model complexed with pharmacologically and structurally diverse ligands we identify different conformational states and dynamics adopted by the receptor bound to the full agonist 5-HT, the partial agonist LSD, and the inverse agonist Ketanserin. The results from the unbiased all-atom molecular dynamics (MD) simulations show that the three ligands affect differently the known GPCR activation elements including the toggle switch at W6.48, the changes in the ionic lock between E6.30 and R3.50 of the DRY motif in TM3, and the dynamics of the NPxxY motif in TM7. The computational results uncover a sequence of steps connecting these experimentally-identified elements of GPCR activation. The differences among the properties of the receptor molecule interacting with the ligands correlate with their distinct pharmacological properties. Combining these results with quantitative analysis of membrane deformation obtained with our new method (Mondal et al, Biophysical Journal 2011), we show that distinct conformational rearrangements produced by the three ligands also elicit different responses in the surrounding membrane. The differential reorganization of the receptor environment is reflected in (i)-the involvement of cholesterol in the activation of the 5-HT2AR, and (ii)-different extents and patterns of membrane deformations. These findings are discussed in the context of their likely functional consequences and a predicted mechanism of ligand-specific GPCR oligomerization. [ABSTRACT FROM AUTHOR]

Abstract: Although some studies have shown the essential role of descending serotonergic pathways and spinal 5-HT1A, 5-HT2A, or 5-HT3 receptors in the antinociceptive effects of paracetamol, other studies have presented conflicting results, and the particular subtype of spinal 5-HT receptors involved in paracetamol-induced analgesia remains to be clarified. Recent studies have demonstrated the importance of spinal 5-HT7 receptors in descending serotonergic pain inhibitory pathways. In this study, we investigated the role of descending serotonergic pathways and spinal 5-HT7 receptors compared with 5-HT3 and 5-HT2A receptors in the antinociceptive and antihyperalgesic effects of paracetamol. Tail-flick, hot plate and plantar incision tests were used to determine nociception in male BALB/c mice. Lesion of serotonergic bulbospinal pathways was performed by intrathecal (i.th.) injection of 5,7-dihydroxytryptamine (5,7-DHT), and spinal 5-HT levels were measured by HPLC. To evaluate the particular subtypes of the spinal 5-HT receptors, the selective 5-HT7, 5-HT3 and 5-HT2A receptor antagonists SB 269970, ondansetron and ketanserin, respectively, were given i.th. after oral administration of paracetamol. Oral paracetamol (200, 400 and 600mg/kg) elicits dose-dependent antinociceptive and antihyperalgesic effects. I.th. pretreatment with 5,7-DHT (50μg) sharply reduced 5-HT levels in the spinal cord. Depletion of spinal 5-HT totally abolished the antinociceptive and antihyperalgesic effects of paracetamol. I.th. injection of SB 2669970 (10μg) blocked the antinociceptive and antihyperalgesic effects of paracetamol, but ondansetron and ketanserin (10μg) did not. Our findings suggest that systemic administration of paracetamol may activate descending serotonergic pathways and spinal 5-HT7 receptors to produce a central antinociceptive and antihyperalgesic effects. [Copyright &y& Elsevier]

BACKGROUND AND PURPOSE 5-HT2A receptor antagonists improve antidepressant responses when added to 5-HT-selective reuptake inhibitors (SSRIs) or tricyclic antidepressants. Here, we have studied the involvement of neuroplasticity pathways and/or the 5-hydroxytryptaminergic system in the antidepressant-like effect of this combined treatment, given subchronically. EXPERIMENTAL APPROACH Expression of brain-derived neurotrophic factor (BDNF) and its receptor (TrkB), 5-bromo-2′-deoxyuridine (BrdU) incorporation, and β-catenin protein expression in different cellular fractions, as well as 5-HT1A receptor function were measured in the hippocampus of rats treated with fluoxetine, ketanserin and fluoxetine + ketanserin for 7 days, followed by a forced swimming test (FST) to analyse antidepressant efficacy. KEY RESULTS mRNA for BDNF was increased in the CA3 field and dentate gyrus of the hippocampus by combined treatment with fluoxetine + ketanserin. Expression of β-catenin was increased in total hippocampal homogenate and in the membrane fraction, but unchanged in the nuclear fraction after combined treatment with fluoxetine + ketanserin. These effects were paralleled by a decreased immobility time in the FST. There were no changes in BrdU incorporation, TrkB expression and 5-HT1A receptor function in any of the groups studied. CONCLUSIONS AND IMPLICATIONS The antidepressant-like effect induced by subchronic co-treatment with a SSRI and a 5-HT2A receptor antagonist may mainly be because of modifications in hippocampal neuroplasticity (BDNF and membrane-associated β-catenin), without a significant role for other mechanisms involved in chronic antidepressant response, such as hippocampal neuroproliferation or 5-HT1A receptor desensitization in the dorsal raphe nucleus. [ABSTRACT FROM AUTHOR]

Abstract: The peripheral serotonergic system has been implicated in the modulation of an array of pain states, from migraine to fibromyalgia; however, the mechanism by which serotonin (5HT) induces pain is unclear. Peripherally released 5HT induces thermal hyperalgesia, possibly via modulation of the transient receptor potential V1 (TRPV1) channel, which is gated by various noxious stimuli, including capsaicin. We previously reported in vitro that 5HT increases calcium accumulation in the capsaicin-sensitive population of sensory neurons with a corresponding increase in proinflammatory neuropeptide release, and both are antagonized by pretreatment with 5HT2A and 5HT3 antagonists, as well as the anti-migraine drug sumatriptan. In the current study, we extended these findings in vivo using the rat hind paw thermal assay to test the hypothesis that peripheral 5HT enhances TRPV1-evoked thermal hyperalgesia that can be attenuated with 5HT2A and 5HT3 receptor antagonists, as well as sumatriptan. Thermal hyperalgesia and edema were established by 5HT injection (0.1–10 nmol/100 μl) into the rat hind paw, and the latency to paw withdrawal (PWL) from noxious heat was determined. Rats were then pretreated with either 5HT before capsaicin (3 nmol/10 μl), the 5HT2A receptor antagonist ketanserin or the 5HT3 receptor antagonist granisetron (0.0001–0.1 nmol/100 μl) before 5HT and/or capsaicin, or the 5HT1B/1D receptor agonist sumatriptan (0.01–1 nmol/100 μl) before capsaicin, and PWL was determined. We report that 5HT pretreatment enhances TRPV1-evoked thermal hyperalgesia, which is attenuated with local pretreatment with ketanserin, granisetron, or sumatriptan. We also report that peripheral 5HT induced a similar magnitude of thermal hyperalgesia in male and female rats. Overall, our results provide in vivo evidence supporting an enhancing role of 5HT on TRPV1-evoked thermal hyperalgesia, which can be attenuated by peripheral serotonergic intervention. [Copyright &y& Elsevier]

Peripheral serotonin, synthesized by tryptophan hydroxylase-1 (TPH1), has been shown to play a key role in several physiological functions. Recently, controversy has emerged about whether peripheral serotonin has any effect on bone density and remodeling. We therefore decided to investigate in detail bone remodeling in growing and mature TPH1 knockout mice (TPH1-/-). Bone resorption in TPH1-/- mice, as assessed by biochemical markers and bone histomorphometry, was markedly decreased at both ages. Using bone marrow transplantation, we present evidence that the decrease in bone resorption in TPH1-/- mice is cell-autonomous. Cultures from TPH1-/- in the presence of macrophage colony-stimulating factor and receptor activator for NF-KB ligand (RANKL) displayed fewer osteoclasts, and the decreased differentiation could be rescued by adding serotonin. Our data also provide evidence that in the presence of RANKL, osteoclast precursors express TPH1 and synthesize serotonin. Furthermore, pharmacological inhibition of serotonin receptor 1B with SB224289, and of receptor 2A with ketanserin, also reduced the number of osteoclasts. Our findings reveal that serotonin has an important local action in bone, as it can amplify the effect of RANKL on osteoclastogenesis. [ABSTRACT FROM AUTHOR]

Cigarette smoking is a major risk factor in chronic obstructive pulmonary disease (COPD) with chronic airway inflammation as a key feature. Blockade of serotonin receptor 2A (5-HTR2A) with ketanserin has been found to improve lung function in COPD patients. Furthermore, ketanserin has been shown to possess anti-inflammatory properties in vivo. In this study, we investigated the antioxidative and anti-inflammatory properties of ketanserin and its underlying mechanism of action on cigarette smoke–induced interleukin (IL)-8 release in vitro. Primary normal human bronchial epithelial cells and human bronchial epithelial cell line (BEAS-2B) were treated with or without ketanserin prior to exposure to cigarette smoke medium (CSM). Exposure to CSM caused elevation of both mRNA and release of IL-8 with increased phosphorylation of p38 and extracellular signal-regulated kinases 1 and 2 (ERK1/2). Consistently, CSM-induced IL-8 release was blocked by SB203580, U0126, or MEK1 small interfering RNA (siRNA) but not SP600125. On the other hand, CSM caused a dose-dependent decrease in the ratio of reduced glutathione to oxidized glutathione (rGSH/GSSG) together with an increased translocation of Nrf2 to the nucleus demonstrated by Western blot analysis. Knock down of Nrf2 by siRNA completely blocked CSM-induced IL-8 release. Ketanserin suppressed CSM-induced IL-8 release by inhibiting p38, ERK1/2 MAPK, and Nrf2 signaling pathways and partially inhibited CSM-induced reduction of rGSH/GSSG ratio. Our data demonstrated the novel antioxidative and anti-inflammatory role of ketanserin via the Nrf2 signaling pathway in CSM-exposed human bronchial epithelial cells. This may open up new perspectives in the development of novel therapeutic targets in the treatment of cigarette smoke–related COPD. [ABSTRACT FROM PUBLISHER]