pd-184161 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

Ischemic stroke is a leading cause of death. It has previously been shown that blocking activation of extracellular signal-regulated kinase (ERK) with the MEK inhibitor U0126 mitigates brain damage in rodent models of ischemic stroke. Here we show that the newer MEK inhibitor PD184161 reduces cell death and altered gene expression in cultured neurons and mice undergoing excitotoxicity, and has similar protective effects in a mouse model of stroke. This further supports ERK inhibition as a potential treatment for stroke.

Topics: Aniline Compounds; Animals; Benzamides; Brain; Cell Death; Cells, Cultured; Disease Models, Animal; Enzyme Inhibitors; Extracellular Signal-Regulated MAP Kinases; Gene Expression; Glutamic Acid; Infarction, Middle Cerebral Artery; Male; Mice, Inbred C57BL; Neurons; Stroke

Oxytocin (OT) levels in plasma increase during sexual response and are significantly lower in patients with depression. A drug for the treatment of sexual dysfunction, sildenafil, enhances the electrically evoked release of OT from the posterior pituitary. In this study, we showed that sildenafil had an antidepressant-like effect through activation of an OT signaling pathway. Application of sildenafil reduced depression-related behavior in male mice. The antidepressant-like effect was blocked by an OT receptor (OTR) antagonist and was absent in OTR knockout (KO) mice. Sildenafil increased the phosphorylation of cAMP response element-binding protein (CREB) in the hippocampus. The OTR antagonist inhibited sildenafil-induced CREB phosphorylation and sildenafil had no effect on CREB phosphorylation in OTR KO mice. These results suggest sildenafil to have an antidepressant-like effect through the activation of OT signaling and to be a promising drug for the treatment of depression.

Topics: Aniline Compounds; Animals; Antidepressive Agents; Benzamides; Cyclic AMP Response Element-Binding Protein; Depression; Disease Models, Animal; Dose-Response Relationship, Drug; Enzyme Inhibitors; Exploratory Behavior; Female; Gene Expression Regulation; Immobility Response, Tonic; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Oxytocin; Phosphorylation; Piperazines; Purines; Receptors, Oxytocin; Sex Factors; Sexual Behavior, Animal; Sildenafil Citrate; Sulfones; Swimming

Brain-derived neurotrophic factor (BDNF) is upregulated in the hippocampus by antidepressant treatments, and centrally administered BDNF can produce antidepressant-like effects in rodent behavioral models of depression. BDNF-regulated signaling pathways are thus potential targets for investigation of antidepressant mechanisms.. We examined the effects of inhibition of MAPK kinase (MEK) in mouse behavioral models for depression including interactions with effects of antidepressant drugs. We also assessed the behavioral consequences of a heterozygous gene deletion for BDNF combined with MEK inhibition or stress.. Acute administration of the MEK inhibitor PD184161 produced depressive-like behavior. PD184161 blocked the antidepressant-like effects of desipramine and sertraline in the forced swim test and blocked the effects of desipramine in the tail suspension test. Heterozygous deletion of BDNF alone did not influence behavior in the forced swim test but resulted in a depressive phenotype when combined with a low-dose MEK inhibitor or stress exposure.. We demonstrate that acute blockade of MAPK signaling produces a depressive-like phenotype and blocks behavioral actions of antidepressants. We also demonstrate in BDNF heterozygous knockout mice an example of a how a defined genetic alteration can confer vulnerability to a pharmacologic or environmental challenge resulting in a depressive behavioral phenotype.

Topics: Analysis of Variance; Aniline Compounds; Animals; Antidepressive Agents; Behavior, Animal; Benzamides; Brain-Derived Neurotrophic Factor; Depression; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Interactions; Enzyme Inhibitors; Helplessness, Learned; Hindlimb Suspension; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mitogen-Activated Protein Kinase Kinases; Motor Activity; Signal Transduction; Swimming