mdl-100907 and Chronic-Disease

Most of the available antidepressants, with different pharmacological profiles, such as inhibitors of serotonin reuptake (SSRIs) or norepinephrine reuptake (NRIs) or both (SNRIs), have limitations leading some patients to drop out of treatment. Another direction of research has therefore been undertaken, based initially on the fact that affective disorders are most often characterized by abnormal patterns of circadian rhythms. This consideration has led to the synthesis of agomelatine, a novel antidepressant combining melatonergic MT(1) and MT(2) agonism and serotonergic 5-HT(2C) antagonism. The antidepressant effects of agomelatine have been investigated in different animal models, including chronic mild stress, forced swimming, learned helplessness and psychosocial stress. All studies reported an antidepressant-like effect of agomelatine. A resynchronizing activity of agomelatine was seen in animal models for delayed sleep phase syndrome and in several original models of circadian disturbance, such as rodents infected by trypanosome or old hamsters. This activity of agomelatine on circadian rhythms was further confirmed in humans. Furthermore, several randomized, double-blind, placebo-controlled and comparator-controlled studies of agomelatine in the treatment of major depressive disorder indicate that agomelatine is effective and well tolerated.

Topics: Acetamides; Animals; Antidepressive Agents; Chronic Disease; Circadian Rhythm; Depressive Disorder, Major; Humans; Models, Animal; Receptor, Melatonin, MT1; Receptor, Melatonin, MT2; Recurrence; Serotonin 5-HT2 Receptor Antagonists; Serotonin Antagonists; Treatment Outcome

Major depressive disorder (MDD) is a prevalent condition with substantial heterogeneity in terms of clinical symptom profiles, overlapping syndromes and degree of severity. The challenge for any new antidepressant is to demonstrate efficacy across the spectrum of patient subpopulations with a diagnosis of MDD. The anxious depressed patient historically has a lower rate of response to traditional antidepressants and high pretreatment anxiety symptoms have also been shown to increase the risk of recurrence. In addition, severity based on standard antidepressant rating scale scores influences treatment outcomes. Some antidepressants display greater placebo separation at higher levels of severity while others fail to separate from placebo in more severe populations. Gender differences in antidepressant response have also been reported in several studies. In particular, women appear to experience a greater side-effect burden with current antidepressants. This is also important in treating late-life depression, where elderly patients are more prone to experiencing side effects and drug interactions. Despite the improved tolerability with SSRIs and other novel antidepressants, restoration of healthy sleep patterns has frequently been lacking. Finally, antidepressant efficacy must include demonstrated relapse prevention during placebo-controlled drug discontinuation trials. As a novel antidepressant with melatonin receptor agonist and 5HT(2C) antagonist properties, agomelatine has demonstrated efficacy in randomized placebo-controlled trials. Additional analyses support the benefits of agomelatine in anxious depression, increasing efficacy with greater baseline severity, including severe late-life depression. Agomelatine has also demonstrated favourable tolerability and efficacy in separate analyses of women and men and displays successful relapse prevention at doses 25 and 50 mg. Both subjective and polysomnographic measures of sleep support increased sleep efficiency and decreased awakenings during agomelatine treatment. Combining these efficacy data with favourable effects on sexual function, CNS and GI systems, there are grounds to endorse the view that agomelatine is a well-tolerated and efficacious antidepressant for a diverse range of depressed populations.

Topics: Acetamides; Age Factors; Antidepressive Agents; Anxiety; Chronic Disease; Circadian Rhythm; Depressive Disorder, Major; Female; Humans; Male; Patient Selection; Receptor, Melatonin, MT1; Receptor, Melatonin, MT2; Recurrence; Serotonin 5-HT2 Receptor Antagonists; Serotonin Antagonists; Severity of Illness Index; Sex Factors; Sleep; Time Factors; Treatment Outcome

Contrast-induced nephropathy (CIN) is a serious clinical problem associated with increased morbidity and mortality, particularly in patients with chronic renal insufficiency. Although some agents including hydration with saline are being prescribed to prevent renal deterioration in these high risk patients, their efficacy is not clearly defined and debatable. Therefore additional prophylactic pretreatments are needed.. The present study aims to investigate differences in occurrence of CIN after sarpogrelate premedication in patients with chronic kidney disease (CKD). 268 participants, aged 20-85 years with a clinical diagnosis of CKD will be recruited. They will be randomly allocated to one of two conditions: (i) routine treatment without sarpogrelate, and (ii) routine treatment with sarpogrelate (a fixed-flexible dose of 300 mg/day). The primary outcome is the occurrence of CIN during 4 weeks after receiving contrast agent.. As of May 2010, there were no registered trials evaluating the therapeutic potentials of sarpogrelate in preventing for CIN. If sarpogrelate decreases the worsening of renal function and occurrence of CIN, it will provide a safe, easy and inexpensive treatment option.. NCT01165567.

Topics: Adult; Aged; Aged, 80 and over; Chronic Disease; Clinical Protocols; Contrast Media; Humans; Kidney Diseases; Middle Aged; Prospective Studies; Research Design; Serotonin 5-HT2 Receptor Antagonists; Succinates; Young Adult

To investigate whether the voiding dysfunction caused by spinal cord injury (SCI) in rats can be improved by i.v. administration of the serotonin (5-HT). Female Sprague-Dawley rats were divided into two groups (SCI group vs normal control [NC] group). Under urethane anaesthesia, cystometry was performed to examine the variation in urodynamic variables before and after successive intrathecal (i.t.) administration of various doses of DOI into the lumbosacral cord. Changes in 5-HT. Compared with NC rats, the SCI rats had higher bladder capacity and post-void residual urine volume, and lower voiding efficiency. After SCI, DOI improved voiding efficiency, probably via external urethral sphincter (EUS) activity. Immunohistochemical staining and Western blot analysis showed that 5-HT. In rats with SCI, DOI can improve voiding efficiency; this may be attributable to 5-HT

Topics: Animals; Chronic Disease; Disease Models, Animal; Female; Injections, Intravenous; Injections, Spinal; Lumbosacral Region; Motor Neurons; Random Allocation; Rats; Rats, Sprague-Dawley; Receptor, Serotonin, 5-HT2A; Reference Values; Serotonin 5-HT2 Receptor Antagonists; Spinal Cord Injuries; Up-Regulation; Urination; Urodynamics

The fruit of Vaccinium bracteatum Thunb. (VBF) is commonly known as the oriental blueberry in Korea. The aim of this study was to evaluate the antidepressant-like effects of water VBF extract (VBFW) in a mouse model of chronic restraint stress (CRS) and to identify the underlying mechanisms of its action. The behavioral effects of VBFW were assessed in the forced swim test (FST) and open field test (OFT). The levels of serum corticosterone (CORT), brain monoamines, in addition to the extracellular signal-regulated kinases (ERKs)/protein kinase B (Akt) signaling pathway were evaluated. VBFW treatment significantly reduced the immobility time and increased swimming time in FST without altering the locomotor activity in unstressed mice. Furthermore, CRS mice treated with VBFW exhibited a significantly decreased immobility time in FST and serum CORT, increased locomotor activity in OFT, and enhanced brain monoamine neurotransmitters. Similarly, VBFW significantly upregulated the ERKs/Akt signaling pathway in the hippocampus and PFC. In addition, VBFW may reverse CORT-induced cell death by enhancing cyclic AMP-responsive element-binding protein expression through the up-regulation of ERKs/Akt signaling pathways. In addition, VBFW showed the strong antagonistic effect of the 5-HT[Formula: see text] receptor by inhibiting 5-HT-induced intracellular Ca[Formula: see text] and ERK1/2 phosphorylation. Our study provides evidence that antidepressant-like effects of VBFW might be mediated by the regulation of monoaminergic systems and glucocorticoids, which is possibly associated with neuroprotective effects and antagonism of 5-HT[Formula: see text] receptor.

Topics: Animals; Antidepressive Agents; Behavior, Animal; Biogenic Monoamines; Brain; Cells, Cultured; Chronic Disease; Corticosterone; Depression; Disease Models, Animal; Humans; Male; MAP Kinase Signaling System; Mice, Inbred ICR; Phytotherapy; Plant Extracts; Rats; Serotonin 5-HT2 Receptor Antagonists; Stress, Psychological; Vaccinium myrtillus

This study investigated whether sarpogrelate hydrochloride (SPG), a 5-HT2A receptor antagonist, alleviates chronic hypoxic pulmonary hypertension (CH-PH) in rats by stimulating apoptosis and inhibiting proliferation in pulmonary artery smooth muscle cells (PASMCs).. Forty male Sprague-Dawley rats were pretreated with SPG (50 mg/kg/day by oral gavage) or saline vehicle and then subjected to chronic hypoxia (CH) (hypobaric chamber set to 380 mmHg, 10% oxygen) or normoxia for 14 days. Mean pulmonary artery pressure (PAP) and right ventricular hypertrophy (RVH) were measured. Hypertensive pulmonary vascular remodeling was assayed by light microscopy. Terminal deoxynucletidyl transferase dUTP nick end ligase (TUNEL) assays, western blotting, and real-time polymerase chain reaction were used to assess apoptosis, proliferation and underlying signaling pathways in PASMCs from lung tissue and isolated pulmonary artery rings.. CH increased mean PAP and RVH. CH increased the percentage of muscularized arteries in the peripheral pulmonary vasculature and medial wall thickness in small muscular arteries. CH increased pulmonary protein and mRNA levels of the B-cell lymphoma protein 2 (Bcl-2), pyruvate dehydrogenase kinase (PDK), phosphorylation of extracellular signal-regulated kinases 1 and 2 (pERK1/2), cyclin D1, proliferating cell nuclear antigen (PCNA) and decreased protein and mRNA levels of Bcl-2-associated X protein (BAX), cleaved caspase-3. Pretreatment with SPG, which has been shown previously to inhibit ERK1/2 phosphorylation and PDK, countered all of these effects. Isolated pulmonary artery rings incubated with 5-HT increased pERK1/2, PDK, and Bcl-2 expression, and decreased Bax expression.. Administration of SPG ameliorated the development of CH-PH by stimulating apoptosis in and inhibiting proliferation of PASMCs.

Topics: Animals; Apoptosis; Cell Proliferation; Chronic Disease; Hypertension, Pulmonary; Hypoxia; Male; Myocytes, Smooth Muscle; Premedication; Pulmonary Artery; Rats; Rats, Sprague-Dawley; Serotonin 5-HT2 Receptor Antagonists; Succinates

Current antidepressants must be administered for several weeks to produce therapeutic effects. We show that selective serotonin 2C (5-HT2C) antagonists exert antidepressant actions with a faster-onset (5 days) than that of current antidepressants (14 days) in mice. Subchronic (5 days) treatment with 5-HT2C antagonists induced antidepressant behavioral effects in the chronic forced swim test (cFST), chronic mild stress (CMS) paradigm and olfactory bulbectomy paradigm. This treatment regimen also induced classical markers of antidepressant action: activation of cAMP response element-binding protein (CREB) and induction of brain-derived neurotrophic factor (BDNF) in the medial prefrontal cortex (mPFC). None of these effects were induced by subchronic treatment with citalopram, a prototypical selective serotonin reuptake inhibitor (SSRI). Local infusion of 5-HT2C antagonists into the ventral tegmental area was sufficient to induce BDNF in the mPFC, and dopamine D1 receptor antagonist treatment blocked the antidepressant behavioral effects of 5-HT2C antagonists. 5-HT2C antagonists also activated mammalian target of rapamycin (mTOR) and eukaryotic elongation factor 2 (eEF2) in the mPFC, effects recently linked to rapid antidepressant action. Furthermore, 5-HT2C antagonists reversed CMS-induced atrophy of mPFC pyramidal neurons. Subchronic SSRI treatment, which does not induce antidepressant behavioral effects, also activated mTOR and eEF2 and reversed CMS-induced neuronal atrophy, indicating that these effects are not sufficient for antidepressant onset. Our findings reveal that 5-HT2C antagonists are putative fast-onset antidepressants, which act through enhancement of mesocortical dopaminergic signaling.

Topics: Animals; Antidepressive Agents; Brain-Derived Neurotrophic Factor; Chronic Disease; Citalopram; Cyclic AMP Response Element-Binding Protein; Depressive Disorder; Disease Models, Animal; Elongation Factor 2 Kinase; Female; Mice, Inbred BALB C; Olfactory Bulb; Prefrontal Cortex; Pyramidal Cells; Receptor, Serotonin, 5-HT2C; Receptors, Dopamine D1; Selective Serotonin Reuptake Inhibitors; Serotonin 5-HT2 Receptor Antagonists; Stress, Psychological; Time Factors; TOR Serine-Threonine Kinases

Chronic stress is a risk factor for depression, and chronic stress can induce cognitive impairments associated with prefrontal cortical dysfunction, which are also major components of depression. We have previously shown that 5 wk chronic intermittent cold (CIC) stress induced a reversal-learning deficit in rats, associated with reduced serotonergic transmission in the orbitofrontal cortex (OFC) that was restored by chronic treatment with a selective serotonin reuptake inhibitor (SSRI). However, the mechanisms underlying the beneficial cognitive effects of chronic SSRI treatment are currently unknown. Thus, the purpose of this study was to investigate the potential modulatory influence specifically of 5-HT2A receptors (5-HT2ARs) in the OFC on reversal learning, and their potential contribution to the beneficial cognitive effects of chronic SSRI treatment. Bilateral microinjections of the selective 5-HT2AR antagonist, MDL 100,907 into OFC (0.02-2.0 nmol) had a dose-dependent detrimental effect on a reversal-learning task, suggesting a facilitatory influence of 5-HT2ARs in the OFC. In the next experiment, rats were exposed to 5 wk CIC stress, which compromised reversal learning, and treated chronically with the SSRI, citalopram (20 mg/kg.d) during the final 3 wk of chronic stress. Chronic citalopram treatment improved reversal learning in the CIC-stressed rats, and bilateral microinjection of MDL 100,907 (0.20 nmol, the optimal dose from the preceding experiment) into OFC once again had a detrimental effect on reversal learning, opposing the beneficial effect of citalopram. We conclude that 5-HT2ARs in the OFC facilitate reversal learning, and potentially contribute to the beneficial cognitive effects of chronic SSRI treatment.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; Animals; Attention; beta-Cyclodextrins; Chronic Disease; Citalopram; Cognition; Fluorobenzenes; Male; Microinjections; Pharmaceutical Vehicles; Piperidines; Prefrontal Cortex; Rats; Rats, Sprague-Dawley; Receptor, Serotonin, 5-HT2A; Reversal Learning; Selective Serotonin Reuptake Inhibitors; Serotonin Antagonists; Set, Psychology; Stress, Psychological

Tissue homeostasis requires an effective, limited wound-healing response to injury. In chronic disease, failure to regenerate parenchymal tissue leads to the replacement of lost cellular mass with a fibrotic matrix. The mechanisms that dictate the balance of cell regeneration and fibrogenesis are not well understood. Here we report that fibrogenic hepatic stellate cells (HSCs) in the liver are negative regulators of hepatocyte regeneration. This negative regulatory function requires stimulation of the 5-hydroxytryptamine 2B receptor (5-HT(2B)) on HSCs by serotonin, which activates expression of transforming growth factor β1 (TGF-β1), a powerful suppressor of hepatocyte proliferation, through signaling by mitogen-activated protein kinase 1 (ERK) and the transcription factor JunD. Selective antagonism of 5-HT(2B) enhanced hepatocyte growth in models of acute and chronic liver injury. We also observed similar effects in mice lacking 5-HT(2B) or JunD or upon selective depletion of HSCs in wild-type mice. Antagonism of 5-HT(2B) attenuated fibrogenesis and improved liver function in disease models in which fibrosis was pre-established and progressive. Pharmacological targeting of 5-HT(2B) is clinically safe in humans and may be therapeutic in chronic liver disease.

Topics: Animals; Cell Proliferation; Cells, Cultured; Chronic Disease; Electrophoresis, Polyacrylamide Gel; Hepatic Stellate Cells; Hepatocytes; Immunohistochemistry; Indoles; Liver Cirrhosis; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mitogen-Activated Protein Kinase 1; Proto-Oncogene Proteins c-jun; Rats; Rats, Sprague-Dawley; Receptor, Serotonin, 5-HT2B; Serotonin; Serotonin 5-HT2 Receptor Antagonists; Signal Transduction; Transforming Growth Factor beta1; Urea; Wound Healing

Topics: Acetamides; Animals; Antidepressive Agents; Chronic Disease; Circadian Rhythm; Depressive Disorder, Major; Humans; Receptor, Melatonin, MT1; Receptor, Melatonin, MT2; Recurrence; Serotonin 5-HT2 Receptor Antagonists; Serotonin Antagonists; Treatment Outcome

Individuals with chronic kidney disease (CKD) and/or diabetes mellitus (DM) are at increased risk of cardiovascular events and have elevated externalization of phosphatidylserine (PS; which propagates thrombus formation) in a small subpopulation of platelets. The purpose of this study was to examine the effect of 1) removing uremic toxins by hemodialysis on PS externalization in patients with either CKD or CKD and DM and 2) ultrafiltrate (UF) from these individuals on PS externalization in healthy platelets. PS externalization was quantified by a fluorescence-activated cell sorter using annexin V in platelet-rich plasma. PS externalization was elevated threefold in CKD patients and returned to basal values during 3-h hemodialysis. In contrast, it was elevated fivefold in individuals with CKD and DM and was still threefold above control after 3-h treatment. UF significantly increased PS externalization in a small subpopulation of platelets from healthy controls. The effect of UF from individuals with CKD and DM was significantly greater than that from patients with CKD alone, and the responses were partially inhibited by the protein kinase Cdelta (PKCdelta) inhibitor rottlerin and the 5-hydroxytryptamine (5-HT)(2A/2C) receptor antagonist ritanserin. The data suggest that uremic toxins present in UF mediate PS externalization in a small subpopulation of platelets, at least in part, via the 5-HT(2A/2C) receptor and PKCdelta and demonstrate that DM further enhances platelet PS externalization in CKD patients undergoing hemodialysis. This may explain, at least in part, the additional increase in vascular damage observed in CKD patients when DM is present.

Topics: Acetophenones; Adult; Aged; Aged, 80 and over; Benzopyrans; Blood Platelets; Case-Control Studies; Chronic Disease; Diabetes Mellitus, Type 2; Enzyme Inhibitors; Female; Hemodiafiltration; Humans; Kidney Diseases; Male; Middle Aged; Phosphatidylserines; Protein Kinase C-delta; Renal Dialysis; Ritanserin; Serotonin 5-HT2 Receptor Antagonists; Serotonin Antagonists

The effects of R-102444 ((2R, 4R)-4-lauroyloxy-2-[2-[2-[2-(3-methoxy)phenyl]ethyl]phenoxy]ethyl-1-methylpyrrolidine hydrochloride) and its active metabolite R-96544 ((2R, 4R)-2-[2-[2-[2-(3-methoxy)phenyl]ethyl]phenoxy]ethyl-4-hydroxy-1-methylpyrrolidine hydrochloride), potent and selective 5-hydroxytryptamine 2A (5-HT2A) receptor antagonists, on development of pancreatitis were investigated in experimental models of acute and chronic pancreatitis. Rat acute pancreatitis was induced by caerulein (20 microg/kg) intraperitoneal injection and by pancreatic duct ligation. In both the models, serum amylase and lipase activities were markedly increased. R-102444 dose-dependently reduced these enzyme activities at a dose range of 10 to 100 mg/kg (p.o.) for the caerulein model and 0.3 to 10 mg/kg (p.o.) for the ligation model. In a mouse model of acute pancreatitis induced by a choline-deficient, ethionine (0.5%)-supplemented diet, subcutaneous administration of R-96544 (10-100 mg/kg, bid) reduced serum amylase activity. Histological analysis showed that R-96544 dose-dependently attenuated pancreatic necrosis, inflammation and vacuolization. The effect of R-102444 was further examined in male Wistar Bonn/Kobori rats (4-9 months of age) which spontaneously show pancreatic fibrosis and parenchymal destruction compatible with human chronic pancreatitis. In Wistar Bonn/Kobori rats (from 3 to 9 months of age) fed a diet containing 0.017% and 0.17% of R-102444, pancreatic weight, pancreatic protein and amylase content were higher compared to those in non-treated pancreatitis control rats. Histological analysis showed that R-102444 suppressed parenchymal destruction and replacement with adipose tissue, indicating inhibition of pancreatic atrophy. These results clearly indicate that R-102444 and R-96544 inhibit the progression of acute and chronic pancreatitis and support the contention of possible involvement of 5-HT2A receptors in the progression of experimental pancreatitis.

Topics: Acute Disease; Amylases; Animals; Ceruletide; Choline; Chronic Disease; Dietary Supplements; Ethionine; Injections, Intraperitoneal; Ligation; Lipase; Male; Organ Size; Pancreas; Pancreatic Ducts; Pancreatitis; Pyrrolidines; Rats; Rats, Inbred Strains; Rats, Sprague-Dawley; Rats, Wistar; Receptor, Serotonin, 5-HT2A; Serotonin 5-HT2 Receptor Antagonists; Serotonin Antagonists; Time Factors