ssr-125543a and Disease-Models--Animal

When Zika virus emerged as a public health emergency there were no drugs or vaccines approved for its prevention or treatment. We used a high-throughput screen for Zika virus protease inhibitors to identify several inhibitors of Zika virus infection. We expressed the NS2B-NS3 Zika virus protease and conducted a biochemical screen for small-molecule inhibitors. A quantitative structure-activity relationship model was employed to virtually screen ∼138,000 compounds, which increased the identification of active compounds, while decreasing screening time and resources. Candidate inhibitors were validated in several viral infection assays. Small molecules with favorable clinical profiles, especially the five-lipoxygenase-activating protein inhibitor, MK-591, inhibited the Zika virus protease and infection in neural stem cells. Members of the tetracycline family of antibiotics were more potent inhibitors of Zika virus infection than the protease, suggesting they may have multiple mechanisms of action. The most potent tetracycline, methacycline, reduced the amount of Zika virus present in the brain and the severity of Zika virus-induced motor deficits in an immunocompetent mouse model. As Food and Drug Administration-approved drugs, the tetracyclines could be quickly translated to the clinic. The compounds identified through our screening paradigm have the potential to be used as prophylactics for patients traveling to endemic regions or for the treatment of the neurological complications of Zika virus infection.

Topics: Animals; Antiviral Agents; Artificial Intelligence; Chlorocebus aethiops; Disease Models, Animal; Drug Evaluation, Preclinical; High-Throughput Screening Assays; Immunocompetence; Inhibitory Concentration 50; Methacycline; Mice, Inbred C57BL; Protease Inhibitors; Quantitative Structure-Activity Relationship; Small Molecule Libraries; Vero Cells; Zika Virus; Zika Virus Infection

The selective CRF₁ (corticotropin releasing factor type 1) receptor antagonist SSR125543 has been previously shown to attenuate the long-term behavioral and electrophysiological effects produced by traumatic stress exposure in mice. Sleep disturbances are one of the most commonly reported symptoms by people with post-traumatic stress disorder (PTSD). The present study aims at investigating whether SSR125543 (10 mg/kg/day/i.p. for 2 weeks) is able to attenuate sleep/wakefulness impairment induced by traumatic stress exposure in a model of PTSD in mice using electroencephalographic (EEG) analysis. Effects of SSR125543 were compared to those of the 5-HT reuptake inhibitor, paroxetine (10 mg/kg/day/i.p.), and the partial N-methyl-d-aspartate (NMDA) receptor agonist, d-cycloserine (10 mg/kg/day/i.p.), two compounds which have demonstrated clinical efficacy against PTSD. Baseline EEG recording was performed in the home cage for 6h prior to the application of two electric foot-shocks of 1.5 mA. Drugs were administered from day 1 post-stress to the day preceding the second EEG recording session, performed 14 days later. Results showed that at day 14 post-stress, shocked mice displayed sleep fragmentation as shown by an increase in the occurrence of both non-rapid eye movement (NREM) sleep and wakefulness bouts. The duration of wakefulness, NREM and REM sleep were not significantly affected. The stress-induced effects were prevented by repeated administration of SSR125543, paroxetine and D-cycloserine. These findings confirm further that the CRF₁ receptor antagonist SSR125543 is able to attenuate the deleterious effects of traumatic stress exposure.

Topics: Animals; Brain; Cycloserine; Disease Models, Animal; Electroencephalography; Electroshock; Hydrocarbons, Halogenated; Male; Mice; Paroxetine; Receptors, Corticotropin-Releasing Hormone; Receptors, N-Methyl-D-Aspartate; Selective Serotonin Reuptake Inhibitors; Sleep; Sleep Wake Disorders; Stress Disorders, Post-Traumatic; Stress, Psychological; Thiazines; Wakefulness

Recent research suggests an involvement of hippocampal neurogenesis in behavioral effects of antidepressants. However, the precise mechanisms through which newborn granule neurons might influence the antidepressant response remain elusive. Here, we demonstrate that unpredictable chronic mild stress in mice not only reduces hippocampal neurogenesis, but also dampens the relationship between hippocampus and the main stress hormone system, the hypothalamo-pituitary-adrenal (HPA) axis. Moreover, this relationship is restored by treatment with the antidepressant fluoxetine, in a neurogenesis-dependent manner. Specifically, chronic stress severely impairs HPA axis activity, the ability of hippocampus to modulate downstream brain areas involved in the stress response, the sensitivity of the hippocampal granule cell network to novelty/glucocorticoid effects and the hippocampus-dependent negative feedback of the HPA axis. Remarkably, we revealed that, although ablation of hippocampal neurogenesis alone does not impair HPA axis activity, the ability of fluoxetine to restore hippocampal regulation of the HPA axis under chronic stress conditions, occurs only in the presence of an intact neurogenic niche. These findings provide a mechanistic framework for understanding how adult-generated new neurons influence the response to antidepressants. We suggest that newly generated neurons may facilitate stress integration and that, during chronic stress or depression, enhancing neurogenesis enables a dysfunctional hippocampus to restore the central control on stress response systems, then allowing recovery.

Topics: Animals; Antidepressive Agents; Cell Count; Corticosterone; Depression; Dexamethasone; Disease Models, Animal; Fluoxetine; Hippocampus; Humans; Hydrocarbons, Halogenated; Hypothalamo-Hypophyseal System; Male; Mice; Mice, Inbred BALB C; Neurogenesis; Pituitary-Adrenal Function Tests; Pituitary-Adrenal System; Radiography; Stress, Psychological; Thiazines

Stress may elevate ethanol drinking and anxiety associated with ethanol drinking. Studies to identify relevant neurobiological substrates are needed.. To assess roles of brain regions in corticotrophin releasing factor (CRF) effects on stressor-enhanced, ethanol deprivation-induced drinking and anxiety-like behavior.. Ethanol-preferring rats (P rats) were exposed to three cycles of a two-bottle choice paradigm with two 2-day deprivation periods that included 1 h exposure to a restraint stressor. To assess the role of CRF and to identify relevant brain regions, a CRF-1 receptor antagonist (SSR125543; 10 ug) was injected into the nucleus accumbens (NAC), amygdala (Amyg), or dorsal raphe nucleus (DRN) prior to exposure to the restraint stressor. In a second study, CRF (0.5 ug) was injected into one of these regions, or the ventral tegmental area (VTA), or paraventricular nucleus of the hypothalamus (PVN).. Applying the restraint stressor during deprivation increased voluntary intake and sensitized anxiety-like behavior. Antagonist injection into the NAC prevented increased drinking without affecting anxiety-like behavior, whereas injection into the Amyg or DRN prevented the anxiety-like behavior without affecting drinking. To confirm CRF actions in the stressor effect, CRF was injected into selected brain regions. NAC injections (but not the VTA, Amyg, DRN, or PVN) facilitated drinking but did not change anxiety-like behavior. Injections into the DRN or Amyg (but not PVN or VTA) enhanced anxiety-like behavior.. Results emphasize that a restraint stressor elevates ethanol intake and sensitizes ethanol deprivation-induced anxiety-like behavior through CRF1 receptors in the NAC and Amyg/DRN, respectively.

Topics: Animals; Anxiety; Brain; Corticotropin-Releasing Hormone; Disease Models, Animal; Ethanol; Hydrocarbons, Halogenated; Male; Rats; Receptors, Corticotropin-Releasing Hormone; Stress, Psychological; Thiazines

Gene microarrays may enable the elucidation of neurobiological changes underlying the pathophysiology and treatment of major depression. However, previous studies of antidepressant treatments were performed in healthy normal rather than 'depressed' animals. Since antidepressants are devoid of mood-changing effects in normal individuals, the clinically relevant rodent transcriptional changes could remain undetected. We investigated antidepressant-related transcriptome changes in a corticolimbic network of mood regulation in the context of the unpredictable chronic mild stress (UCMS), a naturalistic model of depression based on socio-environmental stressors. Mice subjected to a 7-week UCMS displayed a progressive coat state deterioration, reduced weight gain, and increased agonistic and emotion-related behaviors. Chronic administration of an effective (fluoxetine) or putative antidepressant (corticotropin-releasing factor-1 (CRF1) antagonist, SSR125543) reversed all physical and behavioral effects. Changes in gene expression differed among cingulate cortex (CC), amygdala (AMY) and dentate gyrus (DG) and were extensively reversed by both drugs in CC and AMY, and to a lesser extent in DG. Fluoxetine and SSR125543 also induced additional and very similar molecular profiles in UCMS-treated mice, but the effects of the same drug differed considerably between control and UCMS states. These studies established on a large-scale that the molecular impacts of antidepressants are region-specific and state-dependent, revealed common transcriptional changes downstream from different antidepressant treatments and supported CRF1 targeting as an effective therapeutic strategy. Correlations between UCMS, drug treatments, and gene expression suggest distinct AMY neuronal and oligodendrocyte molecular phenotypes as candidate systems for mood regulation and therapeutic interventions.

Topics: Affect; Agonistic Behavior; Amygdala; Animals; Antidepressive Agents; Brain; Corticotropin-Releasing Hormone; Dentate Gyrus; Depressive Disorder; Disease Models, Animal; Emotions; Fluoxetine; Gene Expression; Gene Expression Profiling; Gyrus Cinguli; Hydrocarbons, Halogenated; Male; Mice; Mice, Inbred BALB C; Stress, Psychological; Thiazines; Weight Gain

Depression and anxiety disorders have been linked to dysfunction of the hypothalamo-pituitary-adrenal (HPA) axis and structural changes within the hippocampus. Unpredictable chronic mild stress (UCMS) can recapitulate these effects in a mouse model, and UCMS-induced changes, including downregulation of hippocampal neurogenesis, can be reversed by antidepressant (AD) treatment. We investigated causality between changes in hippocampal neurogenesis and the effects of both chronic stress and chronic ADs.. Mice were treated with either a sham procedure or focal hippocampal irradiation to disrupt cell proliferation before being confronted with 5 weeks of UCMS. From the third week onward, we administered monoaminergic ADs (imipramine, fluoxetine), the corticotropin-releasing factor 1 (CRF(1)) antagonist SSR125543, or the vasopressin 1b (V(1b)) antagonist SSR149415 daily. The effects of UCMS regimen, AD treatments, and irradiation were assessed by physical measures (coat state, weight), behavioral testing (Splash test, Novelty-Suppressed feeding test, locomotor activity), and hippocampal BrdU labeling.. Our results show that elimination of hippocampal neurogenesis has no effect on animals' sensitivity to UCMS in several behavioral assays, suggesting that reduced neurogenesis is not a cause of stress-related behavioral deficits. Second, we present evidence for both neurogenesis-dependent and -independent mechanisms for the reversal of stress-induced behaviors by AD drugs. Specifically, loss of neurogenesis completely blocked the effects of monoaminergic ADs (imipramine, fluoxetine) but did not prevent most effects of the CRF(1) and the V(1b) antagonists.. Hippocampal neurogenesis might thus be used by the monoaminergic ADs to counteract the effects of stress, whereas similar effects could be achieved by directly targeting the HPA axis and related neuropeptides.

Topics: Analysis of Variance; Animals; Antidepressive Agents; Behavior, Animal; Biogenic Monoamines; Bromodeoxyuridine; Cell Count; Cell Proliferation; Corticotropin-Releasing Hormone; Depression; Disease Models, Animal; Exploratory Behavior; Hemibody Irradiation; Hippocampus; Hydrocarbons, Halogenated; Indoles; Male; Mice; Mice, Inbred BALB C; Motor Activity; Neurons; Pyrrolidines; Reaction Time; Thiazines; Time Factors