desvenlafaxine-succinate and Disease-Models--Animal

Oxidative stress is implicated in the neurobiology of depression. Here we investigated oxidative alterations in brain areas of animals submitted to the model of depression induced by corticosterone (CORT) and the effects of the antioxidant compound alpha-lipoic acid (ALA) alone or associated with the antidepressant desvenlafaxine (DVS) in these alterations. Female mice received vehicle or CORT (20 mg/kg) during 14 days. From the 15th to 21st days different animals received further administrations of: vehicle, DVS (10 or 20 mg/kg), ALA (100 or 200 mg/kg), or the combinations of DVS10+ALA100, DVS20+ALA100, DVS10+ALA200, or DVS20+ALA200. Twenty-four hours after the last drug administration prefrontal cortex (PFC), hippocampus (HC) and striatum (ST) were dissected for the determination of the activity of superoxide dismutase (SOD), reduced glutathione (GSH) and lipid peroxidation (LP) levels. CORT significantly increased SOD activity in the PFC and HC, decreased GSH levels in the HC and increased LP in all brain areas studied when compared to saline-treated animals. Decrements of SOD activity were observed in all groups and brain areas studied when compared to controls and CORT. The hippocampal decrease in GSH was reversed by ALA100, DVS10+ALA100, DVS20+ALA100 and DVS20+ALA200. The same DVS+ALA combination groups presented increased levels of GSH in the PFC and ST. The greater GSH levels were observed in the PFC, HC and ST of DVS20+ALA200 mice. LP was reversed in the groups ALA200 (PFC), DVS10+ALA100, DVS20+ALA100 (PFC, HC and ST), and DVS20+ALA200 (PFC, HC). Our findings contribute to the previous preclinical evidences implicating ALA as a promising agent for augmentation therapy in depression.

Topics: Animals; Antidepressive Agents; Antioxidants; Corpus Striatum; Corticosterone; Depressive Disorder; Desvenlafaxine Succinate; Disease Models, Animal; Drug Therapy, Combination; Female; Glutathione; Hippocampus; Lipid Peroxidation; Mice; Oxidative Stress; Prefrontal Cortex; Random Allocation; Superoxide Dismutase; Thioctic Acid

Triple reuptake inhibitors (TRIs) that inhibit the reuptake of serotonin (5-HT), norepinephrine (NE), and dopamine (DA) are being developed as a new class of antidepressants, which is hypothesized to produce more rapid onset and better efficacy than conventional antidepressants in part due to the addition of the DA component. 4-[2-(dimethylamino)-1-(1-hydroxycyclohexyl)-ethyl]-phenyl benzoate hydrochloride (PA01), a novel compound, potently bound to the human 5-HT, NE, and DA transporters (Ki=105, 644, and 813nM, respectively), and inhibited the reuptake of 5-HT, NE, and DA into recombinant cells (IC50=341, 427, and 753nM, respectively). In vivo, PA01 dose-dependently decreased immobility time in the forced swimming test (FST) in rats, and the tail suspension test (TST) in mice with higher efficacy than desvenlafaxine succinate (DVS), and showed no stimulatory effect on the spontaneous locomotor activity. The anti-immobility effect of PA01 in the TST was significantly prevented by the pretreatment of mice with DL-p-chlorophenylalanine (pCPA, 300mg/kg, an inhibitor of serotonin synthesis), SCH23390 (0.05mg/kg, s.c., dopamine D1 receptor antagonist), and sulpiride (50mg/kg, i.p., dopamine D2 receptor antagonist). PA01 significantly increased head-twitch response induced by 5-hydroxytryptophan (80mg/kg, i.p., a metabolic precursor to serotonin) in rats, potentiated yohimbine (25mg/kg, s.c., a α2-adrenoceptor antagonist) toxicity, and antagonized high dose apomorphine-induced hypothermia in mice. Taken together, these in vitro and in vivo results indicated that PA01 is a novel triple reuptake inhibitor, and exerts an excellent antidepressant activity in the behavioral despair animal models of depression, with more potent antidepressant activity than DVS at the same dose.

Topics: Animals; Antidepressive Agents; Binding, Competitive; CHO Cells; Cricetulus; Cyclohexanols; Depression; Desvenlafaxine Succinate; Disease Models, Animal; Dopamine; Dose-Response Relationship, Drug; Humans; Hypothermia; Male; Mice; Molecular Structure; Motor Activity; Neurotransmitter Uptake Inhibitors; Norepinephrine; Rats, Sprague-Dawley; Serotonin; Species Specificity

Serotonin/norepinephrine reuptake inhibitors antidepressants exert their effects by increasing serotonin and norepinephrine in the synaptic cleft. Studies show it takes 2-3 weeks for the mood-enhancing effects, which indicate other mechanisms may underlie their treatment effects. Here, we investigated the role of white matter in treatment and pathogenesis of depression using an unpredictable chronic mild stress (UCMS) mouse model. Desvenlafaxine (DVS) was orally administrated to UCMS mice at the dose of 10 mg/kg/day 1 week before they went through a 7-week stress procedure and lasted for over 8 weeks before the mice were killed. No significant changes were found for protein markers of neurons and astrocytes in UCMS mice. However, myelin and oligodendrocyte-related proteins were significantly reduced in UCMS mice. DVS prevented the stress-induced injury to white matter and the decrease of phosphorylated 5'-AMP-activated protein kinase and 3-hydroxy-3-methyl-glutaryl-CoA reductase protein expression. DVS increased open arm entries in an elevated plus-maze test, sucrose consumption in the sucrose preference test and decreased immobility in tail suspension and forced swimming tests. These findings suggest that stress induces depression-like behaviors and white matter deficits in UCMS mice. DVS may ameliorate the oligodendrocyte dysfunction by affecting cholesterol synthesis, alleviating the depression-like phenotypes in these mice. We examined the possible role of oligodendrocyte and myelin in the pathological changes of depression with an unpredictable chronic mild stress (UCMS) mouse model. Oligodendrocyte-related proteins in the mouse brain were specifically changed during the stress period. The depressive-like behaviors and oligodendrocyte deficits could be prevented by the administration of desvenlafaxine. Oligodendrocyte and myelin may be an essential target of desvenlafaxine for the treatment of depression.

Topics: Animals; Antidepressive Agents; Cholesterol; Cyclohexanols; Depression; Desvenlafaxine Succinate; Disease Models, Animal; Female; Mice; Mice, Inbred C57BL; Phosphorylation; Random Allocation; White Matter

This study was designed to determine if desvenlafaxine (DV), a serotonin-norepinephrine reuptake inhibitor, can attenuate apoptosis observed in the limbic system after myocardial infarction (MI). MI was induced in rats by occlusion of the left descending artery for 40 min followed by reperfusion. Another group of sham (control) rats was similarly manipulated, but without occlusion. Half of the full cohort received DV (3 mg/kg/day intraperitoneal), starting 5 min after the onset of reperfusion; the other half received the vehicle (0.5 ml of 0.9% saline). Rats were sacrificed after 3 days for biochemical analyses and MI size measurements. Infarct size was significantly smaller in DV- compared to vehicle-treated rats. At 3 days post-MI, caspase-3 and -8 activities and terminal deoxynucleotidyltransferase-mediated dUTP nick-end labeling-positive cells were decreased in the amygdala of DV-treated rats compared to MI-vehicle controls. No difference was observed between the sham groups. The data indicates that DV given immediately after an acute MI event can reduce MI size and apoptosis in amygdala when measured three days post-MI.

Topics: Amygdala; Analysis of Variance; Animals; Apoptosis; Caspase 3; Caspase 8; Cyclohexanols; Desvenlafaxine Succinate; Disease Models, Animal; In Situ Nick-End Labeling; Male; Myocardial Infarction; Neurotransmitter Uptake Inhibitors; Rats; Rats, Sprague-Dawley; Reperfusion; Statistics as Topic

Desvenlafaxine succinate (DVS) is a novel serotonin and norepinephrine reuptake inhibitor. The aim of this study was to investigate the effects of DVS on visceral hypersensitivity and solid gastric emptying in a rodent model of gastric hyperalgesia. Twenty-eight gastric hyperalgesia rats and 20 control rats were used. Visceral sensitivity during gastric distention (GD) was assessed by recording of electromyogram (EMG) at pressures of 20, 40, 60, and 80 mmHg. DVS with doses of 1, 10, and 30 mg/kg were administrated by gavage, 5-HT1A antagonist (WAY-100635, 0.3 mg/kg) was given subcutaneously, and 5-HT2A antagonist (ketanserin, 1 mg/kg) was given intraperitoneally. The level of norepinephrine in plasma was measured by enzyme-linked immunosorbent assay. We found that 1) visceral hypersensitivity induced by acetic acid was validated. 2) DVS dose-dependently reduced visceral hypersensitivity in the gastric hypersensitivity rats. The EMG (% of baseline value without GD) during GD at 60 and 80 mmHg with DVS at a dose of 30 mg/kg were 119.4 ± 2.3% (vs. saline 150.9 ± 2.7%, P < 0.001) and 128.2 ± 3.2% (vs. saline 171.1 ± 2.4%, P < 0.001). Similar findings were observed at a dose of 10 mg/kg. DVS at a dose of 1 mg/kg reduced visceral hypersensitivity only during GD at 60 mmHg. 3) Neither WAY-100635 nor ketanserin blocked the effect of DVS on visceral sensitivity. 4) DVS at 30 mg/kg significantly increased plasma NE level (P = 0.012 vs. saline). 5) DVS at 30 mg/kg significantly delayed solid gastric emptying (P < 0.05 vs. saline). We conclude that DVS reduces visceral sensitivity in a rodent model of visceral hypersensitivity and delays solid gastric emptying. Caution should be made when DVS is used for treating patients.

Topics: Acetic Acid; Administration, Oral; Adrenergic Uptake Inhibitors; Animals; Cyclohexanols; Desvenlafaxine Succinate; Disease Models, Animal; Dose-Response Relationship, Drug; Electromyography; Gastric Emptying; Gastroparesis; Hyperalgesia; Injections, Intraperitoneal; Injections, Subcutaneous; Male; Mechanotransduction, Cellular; Norepinephrine; Pain Measurement; Pain Threshold; Pressure; Rats; Rats, Sprague-Dawley; Selective Serotonin Reuptake Inhibitors; Serotonin 5-HT1 Receptor Antagonists; Serotonin 5-HT2 Receptor Antagonists; Stomach; Stomach Ulcer