Chronotropic Responses to GLP-1 Receptor Agonists and Sitagliptin in Atria From Diabetic Rats.

ABSTRACT: Type 2 diabetes mellitus increases the risk of cardiovascular diseases. Therefore, elucidation of the cardiovascular effects of antidiabetics is crucial. Incretin-based therapies are increasingly used for type 2 diabetes mellitus treatment as monotherapy and in combination. We aimed to study the effects of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and sitagliptin on beating rates in isolated atria from diabetic rats. The chronotropic responses to GLP-1 RAs and sitagliptin as monotherapy and in combinations with metformin, pioglitazone, and glimepiride in isolated atria from control and diabetic rats were determined. GLP-1 (7-36), GLP-1 (9-36), and exendin-4 (1-39) produced increases in beating rates in both control and diabetic rat atria. However, sitagliptin increased the beating frequency only in the diabetic group. Exendin (9-39), nitro- l -arginine methyl ester hydrochloride, and indomethacin blocked responses to GLP-1 RAs but not the response to sitagliptin. Glibenclamide, 4-aminopyridine, apamin, charybdotoxin, superoxide dismutase, and catalase incubations did not change responses to GLP-1 RAs and sitagliptin. GLP-1 RAs increase beating rates in isolated rat atrium through GLP-1 receptor, nitric oxide, and cyclooxygenase pathways but not potassium channels and reactive oxygen radicals.

Frequency, risk factors, and impacts on quality of life of the restless legs syndrome and side effects among antidepressant users in a tertiary hospital: an observational cross-sectional study.

Restless leg syndrome (RLS) is a common but underestimated sensorimotor disorder that significantly affects the quality of life (QoL) which can be induced by antidepressants. This study aims to investigate the frequency and potential risk factors of RLS and side effects in selective serotonin reuptake inhibitors/serotonin and noradrenaline reuptake inhibitors (SSRI/SNRI) users. This cross-sectional study included 198 outpatients who received SSRI/SNRI for 4-8 weeks. Clinical evaluation was performed using the International Restless Leg Syndrome Study Group rating scale for RLS, Udvalg for Kliniske Undersøgelser side effects rating scale, and a short form 36 (SF-36) questionnaire for QoL. The frequency of RLS was 25%. RLS significantly increased with smoking and habituality. Also, habituality increased neurologic side effects reporting. The use of antipsychotics and calcium channel blockers decreased reporting of autonomic side effects. QoL decreased with RLS, psychiatric, neurologic, autonomic, and other side effects in different domains of SF-36. These findings suggested that SSRI/SNRI use could be associated with a higher risk of RLS, especially in smokers. QoL could be influenced negatively by RLS and all side effects. However, further prospective studies are needed to confirm these associations in large samples.

The Functional Effects of Visfatin on Human Left Internal Mammary Artery.

ABSTRACT: Visfatin may play a role in vascular dysfunction in metabolic disorders. Apart from its insulin-mimetic actions, it has divergent actions in the cardiovascular system with discordant results in the literature. Thus, we aimed to study the effects of visfatin on vascular responses of the human left internal mammary artery. Sections of redundant human left internal mammary artery were cut into 3-mm wide rings and hung in 20-mL organ baths containing physiologic salt solution and attached to an isometric force transducer connected to a computer-based data acquisition system. Removing endothelium caused an increase in pD2 values for visfatin-induced relaxation responses (10 -12 -10 -7 M) (9.06 ± 0.21 and 11.08 ± 0.92, respectively). Nicotinamide phosphoribosyltransferase inhibitor FK866 (10 µM) reversed the visfatin-induced relaxations (10 -12 -10 -7 M) ( P = 0.024). Incubations with nitric oxide synthase inhibitor nitro- l -arginine methylester and guanylate cyclase inhibitor 1H-[1,2,4] oxadiazolo [4,3-a] quinoxalin-1-one (ODQ) caused significant reductions in relaxation responses of visfatin ( P = 0.011 and 0.008, respectively). Visfatin incubations decreased relaxation responses to acetylcholine but not to sodium nitroprusside. Incubations with visfatin did not change contractile responses to angiotensin II, endothelin-1, noradrenalin, and phenylephrine. In this study, visfatin caused endothelium-dependent relaxations mediated by nitric oxide-cyclic guanosine monophosphate pathway and nicotinamide phosphoribosyltransferase activity. Furthermore, visfatin-induced decreases in relaxation responses were also related to endothelium-derived nitric oxide.

Vortioxetine ameliorates motor and cognitive impairments in the rotenone-induced Parkinson's disease via targeting TLR-2 mediated neuroinflammation.

Parkinson's disease (PD) is characterized by motor and non-motor symptoms associated with dopaminergic and non-dopaminergic injury. Vortioxetine is a multimodal serotonergic antidepressant with potential procognitive effects. This study aimed to explore the effects of vortioxetine on motor functions, spatial learning and memory, and depression-like behavior in the rotenone-induced rat model of PD. Male Sprague-Dawley rats were daily administered with the rotenone (2 mg kg-1, s.c.) and/or vortioxetine (10 mg kg-1, s.c.) for 28 days. Motor functions (rotarod, catalepsy, open-field), depression-like behaviors (sucrose preference test), anxiety (elevated plus maze), and spatial learning and memory abilities (novel object recognition and Morris water maze) were evaluated in behavioral tests. Then immunohistochemical, neurochemical, and biochemical analysis on specific brain areas were performed. Vortioxetine treatment markedly reduced rotenone-induced neurodegeneration, improved motor and cognitive dysfunction, decreased depression-like behaviors without affecting anxiety-like parameters. Vortioxetine also restored the impaired inflammatory response and affected neurotransmitter levels in brain tissues. Interestingly, vortioxetine was thought to trigger a sort of dysfunction in basal ganglia as evidenced by increased Toll-like receptor-2 (TLR-2) and decreased TH immunoreactivity only in substantia nigra tissue of PD rats compared to the control group. The present study indicates that vortioxetine has beneficial effects on motor dysfunction as well as cognitive impairment associated with neurodegeneration in the rotenone-induced PD model. Possible mechanisms underlying these beneficial effects cover TLR-2 inhibition and neurochemical restoration of vortioxetine.

Metformin protects rotenone-induced dopaminergic neurodegeneration by reducing lipid peroxidation.

BACKGROUND: Metformin, a widely prescribed antidiabetic drug, has been suggested to have a neuroprotective effect on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity in mice. In this study, we investigated the neuroprotective potential of metformin against rotenone-induced dopaminergic neuron damage and its underlying mechanisms. METHODS: C57BL/6 mice were given saline or rotenone (2.5 mg/kg/day, ip) injection for 10 days. Metformin treatment (300 mg/kg/day, ip) was started concurrently with rotenone administration and continued for 10 days. The neuroprotective effect of metformin on rotenone-induced dopaminergic toxicity was assessed by tyrosine hydroxylase (TH), cleaved caspase-3 and α-synuclein immunohistochemistry in substantia nigra (SN). SN tissues were extracted for biochemical analysis. Malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE) protein levels were measured by spectrophotometric assay. RESULTS: We found that metformin treatment attenuated the rotenone-induced loss of TH+ neurons in the SN. Additionally, metformin significantly decreased the rotenone-induced increase of cleaved caspase-3 and α-synuclein accumulation in the SN; however, there was no difference in motor behaviours between the experimental groups. Meanwhile, the levels of MDA and 4-HNE in SN were significantly reduced in the rotenone-metformin group compared to the rotenone group. CONCLUSIONS: Results showed that metformin treatment attenuated dopaminergic neuron loss in SN induced by rotenone by decreasing lipid peroxidation.

Serum N-Desmethylcitalopram Concentrations are Associated with the Clinical Response to Citalopram of Patients with Major Depression.

OBJECTIVE: Citalopram (CITA) is a widely used and well-tolerated selective serotonin reuptake inhibitor. The aim of the study was to evaluate the possible influences of serum concentrations of CITA and its major metabolite n-desmethylcitalopram (NDCITA) on the efficacy and tolerability of CITA in patients with major depressive disorder. METHODS: The study included 46 outpatients with major depressive disorder who received CITA. The efficacy and tolerability were assessed for 6 weeks. Serum CITA and NDCITA levels were measured at the 4th week. RESULTS: The HDRS17 total scores of the patients with high NDCITA and CITA & NDCITA concentrations showed a more significant reduction compared to the patients with expected and low serum NDCITA and CITA & NDCITA concentrations. However, we did not observe a correlation between the serum concentrations and the side effects of CITA, NDCITA, and CITA & NDCITA. CONCLUSION: Our results suggested the potential contribution of NDCITA to the antidepressant effect of CITA. Further studies involving larger clinical samples are required to confirm the impact of serum NDCITA concentrations on the efficacy of CITA.

The antidepressant-like activity of ellagic acid and its effect on hippocampal brain derived neurotrophic factor levels in mouse depression models.

The aim of present study was to evaluate the antidepressant-like activity of ellagic acid (EA) in mice-forced swim test (FST) and tail suspension test (TST) and the possible role of brain-derived neurotrophic factor (BDNF) in EA's antidepressant-like effect. We found that EA and sertraline did not affect the spontaneous locomotor activity of mice. EA produced statistically significant decrease in immobility time as compared to vehicle group in TST. EA at 1 and 5 mg/kg doses did not produce any significant effect in immobility time as compared to vehicle group in FST. But EA produced significantly reduced immobility time at 2.5 mg/kg dose. EA treatment increased hippocampal BDNF level. This study demonstrates that EA is able to produce antidepressant-like effect in both TST and FST in mice. Moreover, the antidepressant-like effects of EA seems to be mediated by increased BDNF level in mice hippocampus.

Influence of ABCB1 polymorphisms and serum concentrations on venlafaxine response in patients with major depressive disorder.

BACKGROUND: The pharmacokinetics and the pharmacodynamics of antidepressants show large inter-individual variations which result in unpredictable clinical responses. AIM: The aim of the study was to examine the effect of ABCB1 polymorphisms and the serum concentrations on the efficacy and tolerability of venlafaxine in patients with major depressive disorder (MDD). METHODS: Fifty-two outpatients who met the Diagnostic and Statistical Manual of Mental Disorders Fourth Edition (DSM-IV) criteria for MDD were recruited for the study. The severity of depression was assessed using the 17-item Hamilton Rating Scale for Depression scale (HDRS17) and tolerability was assessed based on a query regarding side-effects for 6 weeks. The ABCB1 C3435T/A and G2677T/A polymorphisms were genotyped by PCR/RFLP and steady-state serum venlafaxine concentrations were measured by high-performance liquid chromatography. RESULTS: Patients with the TT genotype for the C3435T and the TT/TA genotype for the G2677T/A polymorphism showed significantly higher frequencies in venlafaxine-induced akathisia. This relationship was not observed for efficacy. As regards serum venlafaxine concentrations, patient groups showed no significant differences in efficacy and tolerability. CONCLUSION: The results suggest that individuals with the TT-TT/TA genotypes for the C3435T-G2677T/A polymorphisms of ABCB1 may be pre-disposed to a risk of akathisia.

ABCB1 C3435T polymorphism is associated with susceptibility to major depression, but not with a clinical response to citalopram in a Turkish population.

BACKGROUND: The ATP-binding cassette sub-family B member 1 (ABCB1) gene, which encodes the p-glycoprotein at the blood-brain barrier, is investigated for patients' susceptibility to major depressive disorder (MDD) and their therapeutic response to antidepressants. However, there is an inconsistency between the studies of different ethnic groups. The current study aimed to determine the potential correlations of the ABCB1 gene C3435T polymorphism with the susceptibility to MDD and the therapeutic response to citalopram in a Turkish population. METHODS: Fifty-four patients with MDD who received citalopram and 70 controls from the Turkish population were genotyped for ABCB1 C3435T polymorphism. To assess the therapeutic response to citalopram, all patients were rated baseline, first, second, fourth and sixth weeks according to the 17-item Hamilton Rating Scale for Depression (HAMD-17). RESULTS: There was a significant correlation between the patient and control groups for ABCB1 C3435T polymorphism. Distribution of CC genotype and C allele frequency were higher in the patients than in the control group (p = 0.006, p = 0.020, respectively). However, no correlation between ABCB1 C3435T polymorphism and a therapeutic response to citalopram was observed. CONCLUSION: Our results suggested that C3435T polymorphism in the ABCB1 gene may be an indicator of the susceptibility to major depression, without a likely treatment response to citalopram in a Turkish population. These findings should be replicated in studies on larger patient groups with different ethnicities.

What may be happen after an organophosphate exposure: acute myocardial infarction?

The increase in accidental organophosphate poisoning as well as the rise in the number of cases of suicide attempts with organophosphate compounds is due to primarily to the widespread use of these compounds in agriculture. Organophosphates are anti-acetycholinesterase agents and their toxicity affects many organs, including the pancreas, liver and heart. Cardiac complications often accompany poisoning with these compounds and may be serious and often fatal. However, little is known about the myocardial infarction risk associated with exposure to pesticides. Herein, a rare case of acute myocardial infarction due to acute exposure to organophosphate compound is documented with electrocardiogram, enzyme and clinical characteristics in this report.

Influence of genetic polymorphisms, smoking, gender and age on CYP1A2 activity in a Turkish population.

AIMS: To study the variation in CYP1A2 activity in relation to smoking, gender, age and CYP1A2 polymorphisms. MATERIALS & METHODS: CYP1A2 activity was determined by plasma paraxanthine:caffeine ratio (17X:137X) 4 h after the intake of a standardized cup of coffee in 146 Turkish healthy volunteers. Seven CYP1A2 polymorphisms (-3860G>A, -3113G>A, -2467del/T, -739T>G, -729C>T, -163C>A and 5347T>C) were analyzed. RESULTS: The 17X:137X ratios were increased in smokers (p < 0.0001) and tended to be higher in men both among nonsmokers (p = 0.051) and smokers (p = 0.064). Age-related differences were observed only among nonsmoking women (p = 0.024). The -163C>A polymorphism correlated with 17X:137X ratios only in smokers (p = 0.006). Furthermore, increased 17X:137X ratios were observed in CYP1A2 haplotype H4 (-3860G, -3113G, -2467del, -739T, -729C, -163A and 5347T) carriers in the overall study population (p = 0.026). Multiple regression analyses including smoking, gender, -163C>A genotype and age revealed a significant influence of smoking (p < 0.0001) and gender (p = 0.002) in the overall study population. However, in nonsmokers only the influence of gender remained significant (p = 0.021), while in smokers the influence of the -163C>A genotype held the statistical significance (p = 0.019). The influence of haplotype H4 remained significant (p = 0.028) in the overall study population in similar analyses. CONCLUSION: Smoking has the strongest impact on CYP1A2 activity, while gender and haplotype H4 showed marginal effects. The influence of the -163C>A polymorphism on CYP1A2 activity in smokers suggests an effect on the inducibility of the enzyme.

Lack of a time-dependent effect of melatonin on radiation-induced apoptosis in cultured rat lymphocytes.

Ionizing radiation is widely used for the treatment of solid tumors and it is thought to act by directly targeting tumor clonogens, also known as stem cells. Apoptosis is a genetically programmed mechanism of cell death often characterized by internucleosomal DNA cleavage. Although it has been previously shown that lymphocytes readily undergo apoptosis in patients receiving anticancer drugs or treatment with ionizing radiation, this is the first study to investigate the influence of radiotherapy and melatonin on apoptosis in rat lymphocytes at two different times of the day. Melatonin, a free radical scavenger, is an endogenous neurohormone predominantly synthesized in and secreted by the pineal gland. It has been shown that melatonin inhibits apoptosis in normal cells but it increases the rate of apoptosis in various cancer cells. Therefore, in the present study, the effect of melatonin on apoptosis in cultured lymphocytes was studied after total body irradiation (TBI) was given to rats in the morning (1 HALO) or evening (13 HALO) with morphological and DNA fragmentation analysis. Two-way analysis of variance (ANOVA) revealed that radiation increased the rate of apoptosis in rat lymphocytes after TBI, and melatonin treatment did not reduce the rate of apoptosis after TBI at either time point. We conclude that the lack of an effect of melatonin on the apoptosis rate in rat lymphocytes might be due to the dose-dependent effect of melatonin, the time course of apoptosis investigated, or the cell type in which apoptosis was examined.