sb-399885 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

Topics: Animals; Behavior, Animal; Cell Proliferation; Conditioning, Psychological; Cytokines; Discrimination, Psychological; Disease Models, Animal; Freezing Reaction, Cataleptic; Hippocampus; Ki-67 Antigen; Motor Activity; Piperazines; Prepulse Inhibition; Rats; Receptors, Serotonin; Reflex, Acoustic; Reflex, Startle; Schizophrenia; Signal Transduction; Social Isolation; Sulfonamides

Post-traumatic stress disorder is an anxiety disorder for which current therapies are not effective. The 5-Hydroxytryptamine6 receptor antagonist SB399885 has been reported to have an anxiolytic effect. Hence, the current investigation was undertaken to evaluate its efficacy in post-traumatic stress disorder.. Rats were placed in the operant box and given 3 foot shocks at intervals of 1 min. The following day the duration of freezing was recorded. For the enhanced sustained prolonged stress (ESPS), the rats were subjected to various stressors such as restraint stress (2 h), forced swim (20 min), and anesthesia, followed by a foot shock for 4 s. The rats were then subjected to the elevated plus maze.. Treatment with SB399885 (1 and 3 mg/kg, I. p.) was found to significantly decrease the freezing time in the contextual fear conditioning model. Rats subjected to ESPS spent greater time in the open arm of the elevated plus maze when administered SB399885 at the above mentioned doses. The treatment had no effect on locomotor activity. SB399885 decreased the 5-hydroxytryptamine levels in the amygdala at doses that were effective in the above animal models.. 5-Hydroxytryptamine6 antagonists may hold potential in the treatment of post-traumatic stress.

Topics: Animals; Anti-Anxiety Agents; Anxiety Disorders; Disease Models, Animal; Fear; Male; Maze Learning; Motor Activity; Piperazines; Rats; Rats, Wistar; Serotonin; Serotonin Antagonists; Stress Disorders, Post-Traumatic; Sulfonamides

The combination of the selective serotonin reuptake inhibitors (SSRIs) and atypical antipsychotic drugs shows better therapeutic efficacy than SSRI monotherapy in the treatment of depression. However, the underlying mechanisms responsible for the augmenting effects of olanzapine are not fully understood. Here, we report that olanzapine enhances the SSRI-induced increase in extracellular serotonin (5-HT) levels and antidepressant-like effects by inhibiting GABAergic neurons through 5-HT6 receptor antagonism in the dorsal raphe nucleus (DRN). In organotypic raphe slice cultures, treatment with olanzapine (1-100 μM) enhanced the increase in extracellular 5-HT levels in the presence of fluoxetine (10 μM) or citalopram (1 μM). The enhancing effect of olanzapine was not further augmented by the GABAA receptor antagonist bicuculline. Electrophysiological analysis revealed that olanzapine (50 μM) decreased the firing frequency of GABAergic neurons in acute DRN slices. Among many serotonergic agents, the 5-HT6 receptor antagonist SB399885 (1-100 μM) mimicked the effects of olanzapine by enhancing the SSRI-induced increase in extracellular 5-HT levels, which was not further augmented by bicuculline or olanzapine. SB399885 (50 μM) also decreased the firing frequency of GABAergic neurons in the DRN. In addition, an intraperitoneal administration of SB399885 (10 mg/kg) to mice significantly enhanced the antidepressant-like effect of a subeffective dose of citalopram (3 mg/kg) in the tail-suspension test. These results suggest that olanzapine decreases local inhibitory GABAergic tone in the DRN through antagonism of 5-HT6 receptors, thereby increasing the activity of at least part of serotonergic neurons, which may contribute to the augmentation of the efficacy of SSRIs.

Topics: Animals; Antidepressive Agents; Benzodiazepines; Bicuculline; Citalopram; Depressive Disorder; Disease Models, Animal; Dorsal Raphe Nucleus; Female; Fluoxetine; GABA-A Receptor Antagonists; GABAergic Neurons; Male; Mice, Inbred C57BL; Neural Inhibition; Olanzapine; Piperazines; Rats, Wistar; Receptors, Serotonin; Selective Serotonin Reuptake Inhibitors; Serotonergic Neurons; Serotonin Antagonists; Sulfonamides; Tissue Culture Techniques

The central 5-hydroxytryptamine (5-HT; serotonin) system is well established as an important regulator of appetite and continues to remain a focus of obesity research. While much emphasis has focussed on the 5-HT(2C) receptor (5-HT(2C)R) in 5-HT's anorectic effect, pharmacological manipulation of the 5-HT₆ receptor (5-HT₆R) also reduces appetite and body weight and may be amenable to obesity treatment. However, the neurological circuits that underlie 5-HT₆R-induced hypophagia remain to be identified. Using c-fos immunoreactivity (FOS-IR) as a marker of neuronal activation, here we mapped the neuroanatomical targets activated by an anorectic dose of the 5-HT₆R antagonist SB-399885 throughout the brain. Furthermore, we quantified SB-399855 activated cells within brain appetitive nuclei, the hypothalamus, dorsal raphe nucleus (DRN) and nucleus of the solitary tract (NTS). Our results reveal that 5-HT₆R antagonist-induced hypophagia is associated with significantly increased neuronal activation in two nuclei with an established role in the central control of appetite, the paraventricular nucleus of the hypothalamus (PVH) and the NTS. In contrast, no changes in FOS-IR were observed between treatment groups within other hypothalamic nuclei or DRN. The data presented here provide a first insight into the neural circuitry underlying 5-HT₆R antagonist-induced appetite suppression and highlight the PVH and NTS in the coordination of 5-HT₆R hypophagia.

Topics: Animals; Appetite; Brain; Disease Models, Animal; Dose-Response Relationship, Drug; Eating; Feeding and Eating Disorders; Male; Piperazines; Proto-Oncogene Proteins c-fos; Rats; Rats, Sprague-Dawley; Receptors, Serotonin; Serotonin Antagonists; Sulfonamides

It is a well-known fact that 5HT6 ligands increase glutamate levels. In the current study we investigated whether a 5HT6 antagonist, SB399885 would show antidepressant like property at a dose which would significantly increase the glutamate levels. Further we studied if the combination of a 5HT6 antagonist and N-methyl-D-aspartate (NMDA) antagonist, memantine would restore the antidepressant property. As dementia and depression are co-morbid, we evaluated if this combination would have an effect on cognition.. The antidepressant like property of SB399885 alone and in combination with memantine was investigated using the forced swim test (FST). Object recognition task (ORT) was used to investigate the combination therapy on cognition. Additionally, glutamate levels in prefrontal cortex and corresponding brain concentration of SB399885 were determined.. Brain concentrations of SB399885 equal to or greater than 553 nM significantly increased brain glutamate levels and reduced immobility time in FST. When combined with memantine, glutamate levels and immobility time in FST was reduced. A dose dependent increase in the discriminative index was observed in ORT.. Loss of antidepressant like property seen at the highest tested dose of SB399885 could be due to increased glutamate levels which was reversed by memantine. Combining memantine and SB399885 offers the advantage of extending the therapeutic window of antidepressant like property of SB399885 as well as having procognitive effect. The combination therapy holds promise in treatment of dementia associated with depression.

Topics: Animals; Antidepressive Agents; Behavior, Animal; Depression; Disease Models, Animal; Glutamic Acid; Ligands; Male; Memantine; Motor Activity; N-Methylaspartate; Piperazines; Prefrontal Cortex; Rats; Rats, Wistar; Serotonin; Serotonin Antagonists; Sulfonamides; Swimming