su-1498 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

Selective inhibition of vascular endothelial growth factor receptor (VEGFR), particularly VEGFR-2, is an efficient method for the treatment of ocular neovascularization. SU1498 is a specific inhibitor of VEGFR-2. In this study, we investigated the role of SU1498 in ocular neovascularization. Administration of SU1498 did not show any cytotoxicity and tissue toxicity at the tested concentrations. Administration of SU1498 reduced the size and thickness of choroidal neovascularization and decreased the mean length and mean number of corneal neovascular vessels induced by alkali burn. Pretreatment of SU1498 significantly reduced the proliferation, migration, and tube formation ability of HUVECs. SU1498 played the anti-angiogenic role through the regulation of p38-MAPK signaling. Taken together, inhibition of VEGFR-2 by SU1498 provides a novel therapeutic approach for ocular neovascularization.

Topics: Angiogenesis Inhibitors; Animals; Cell Movement; Cell Proliferation; Cells, Cultured; Choroid; Choroidal Neovascularization; Cinnamates; Cornea; Corneal Neovascularization; Disease Models, Animal; Endothelial Cells; Human Umbilical Vein Endothelial Cells; Humans; Male; Mice, Inbred C57BL; Neovascularization, Physiologic; Signal Transduction; Vascular Endothelial Growth Factor Receptor-2

In animals, chronic stress leads to the development of depression-like behavior and decreases neurogenesis and blood vessel density in hippocampus, whereas antidepressants increase adult neurogenesis in hippocampus. Regular exercise training also has antidepressant action and increases hippocampal neurogenesis; however, whether exercise-induced antidepressant action is related to hippocampal microvasculature is unclear. To address this issue, we compared depression-like behavior, blood vessel density, and neurogenesis in hippocampal dentate gyrus between stressed and exercised mice with or without administration of inhibitor of vascular endothelial growth factor (VEGF) receptor. Chronic stress led to the development of depression-like behavior, decreased blood vessel density, and neurogenesis in hippocampus. Regular exercise training improved depression-like behavior, the decrease of hippocampal blood vessel density, and neurogenesis in the stress state, whereas the combination of regular exercise and administration of SU1498, VEGF receptor Flk-1 inhibitor, canceled the exercise-induced antidepressant effect. These findings suggested that the improvement of hippocampal blood vessel and adult neurogenesis via VEGF signaling pathway is necessary for exercise-induced antidepressant effect.

Topics: Animals; Chronic Disease; Cinnamates; Depressive Disorder; Disease Models, Animal; Exercise Therapy; Hippocampus; Male; Mice; Mice, Inbred ICR; Neurogenesis; Physical Conditioning, Animal; Signal Transduction; Stress, Psychological; Up-Regulation; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-2

Senescence-accelerated mouse prone/8 (SAMP8), a murine model of accelerated senescence, shows age-related deficits in learning and memory. We investigated the effect of oligomeric proanthocyanidins (oligomers) on memory impairment using the SAMP8 model involving the oral administration of oligomers for 5 weeks. To analyse memory improvement in SAMP8, we performed Morris water maze, object location and object recognition tests. The oral administration of oligomers improved spatial and object recognition impairment in SAMP8. Expressions of phosphorylated neurofilament-H (P-NF-H, axon marker), microtubule-associated proteins (MAP) 2a and 2b (MAP2; dendrite marker) and synaptophysin were increased in the brains of SAMP8-administered oligomers. In particular, the expression of P-NF-H was significantly elevated in the hippocampal CA1. This indicates that oligomers result in an increase in the densities of axons, dendrites and synapses. To investigate the protective mechanisms of oligomers against brain dysfunction with ageing, we carried out a receptor tyrosine kinase phosphorylation antibody array, and clarified that the administration of oligomers led to an increase in the phosphorylation of vascular endothelial growth factor receptor (VEGFR)-2, suggesting the neuroprotective role of oligomers. The phosphorylation of VEGFR-2 was more greatly increased in the hypothalamus and choroid plexus than in other brain regions of SAMP8. Memory in oligomer-treated mice was impaired by SU1498, a VEGFR-2-specific antagonist. Elucidating the relationship between memory impairment with ageing and VEGFR-2 signalling may provide new suggestions for protection against memory deficit in the ageing brain.

Topics: Aging; Animals; Brain; Cinnamates; Diospyros; Disease Models, Animal; Fruit; Male; Maze Learning; Memory Disorders; Mice; Mice, Inbred Strains; Microtubule-Associated Proteins; Neurofilament Proteins; Neurons; Neuroprotective Agents; Phosphorylation; Phytotherapy; Plant Extracts; Proanthocyanidins; Spatial Behavior; Synaptophysin; Vascular Endothelial Growth Factor Receptor-2

Vascular endothelial growth factor (VEGF) protects spinal motor neurons in models of familial amyotrophic lateral sclerosis. We previously demonstrated that VEGF also prevents motor neuron death and hindlimb paralysis in rats subjected to α-amino-3-hydroxy-5-isoxazolepropionate (AMPA)-induced chronic excitotoxic motor neuron degeneration. Here, we show that tyrosine kinase receptor-2 for VEGF (VEGFR2) is expressed in spinal motor neurons of the adult rat, and that its blockade impedes the VEGF-mediated protection against motor neuron death and paralysis. In addition, inhibition of phosphatidyl-inositol-3-kinase, which is activated by VEGFR2, completely prevented this protection, whereas blockade of mitogen-activated protein kinase kinases resulted only in a partial prevention. We show as well that AMPA induces an increased p38 mitogen-activated protein kinase (p38MAPK) phosphorylation and that VEGF blocks this effect. Furthermore, inhibition of p38MAPK prevents the paralysis induced by AMPA. These results shed light into the mechanisms of the protective effect of VEGF against excitotoxic motor neuron death in vivo and suggest that VEGFR2 and activation of phosphatidyl-inositol-3-kinase or inhibition of p38MAPK might be important therapeutic targets for amyotrophic lateral sclerosis.

Topics: alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Analysis of Variance; Animals; Choline O-Acetyltransferase; Chromones; Cinnamates; Disease Models, Animal; Drug Interactions; Enzyme Inhibitors; Excitatory Amino Acid Agonists; Glial Fibrillary Acidic Protein; Imidazoles; Infusion Pumps, Implantable; Male; Morpholines; Motor Activity; Motor Neurons; Nerve Degeneration; Neurotoxicity Syndromes; p38 Mitogen-Activated Protein Kinases; Phosphatidylinositol 3-Kinases; Pyridines; Rats; Rats, Wistar; Spinal Cord; Time Factors; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-2

We have successfully imaged the retinal tumor in a mouse model using an ultra-high resolution spectral-domain optical coherence tomography (SD-OCT) designed for small animal retinal imaging. For segmentation of the tumor boundaries and calculation of the tumor volume, we developed a novel segmentation algorithm. The algorithm is based on parametric deformable models (active contours) and is driven by machine learning-based region classification, namely a Conditional Random Field. With this algorithm we are able to obtain the tumor boundaries automatically, while the user can specify additional constraints (points on the boundary) to correct the segmentation result, if needed. The system and algorithm were successfully applied to studies on retinal tumor progression and monitoring treatment effects quantitatively in a mouse model of retinoblastoma.

Topics: Algorithms; Animals; Cinnamates; Disease Models, Animal; Image Processing, Computer-Assisted; Luteinizing Hormone, beta Subunit; Mice; Mice, Inbred BALB C; Mice, Transgenic; Retinal Neoplasms; Retinoblastoma; Tomography, Optical Coherence; Vascular Endothelial Growth Factor Receptor-2

Bronchial asthma is characterized by inflammation of the airways, which is usually accompanied by increased vascular permeability, resulting in plasma exudation. Vascular endothelial growth factor (VEGF) has been implicated in contributing to asthmatic tissue edema through its effect on vascular permeability. Many cellular responses of VEGF are regulated by the lipid products of phosphoinositide 3-kinase (PI3K). However, the effect of PI3K catalytic subunit p110delta on VEGF-mediated signaling is unknown. Recently, an isoform-specific small molecule inhibitor, IC87114, which is selective for p110delta catalytic activity, has been identified.. We have sought to investigate the role of PI3K-delta, more specifically in the increase of vascular permeability.. Female BALB/c mice were sensitized and challenged with ovalbumin. We have investigated the effect of IC87114 on airway inflammation, T(H)2 cytokines expression, airway hyperresponsiveness, plasma extravasation, hypoxia-inducible factor 1alpha expression, and VEGF expression in a murine model of asthma.. Our current study has revealed that IC87114 reduces antigen-induced airway infiltration of inflammatory cells, secretion of T(H)2 cytokines in lungs, airway hyperresponsiveness, and vascular permeability. Moreover, we have found that inhibition of p110delta reduces ovalbumin-induced upregulation of VEGF level.. These results suggest that PI3K-delta inhibitor attenuates antigen-induced airway inflammation and hyperresponsiveness by preventing vascular leakage in mice.. These findings provide a crucial molecular mechanism for the potential role of PI3K-delta in asthma and other airway inflammatory disorders.

Topics: Adenine; Animals; Asthma; Bronchial Hyperreactivity; Bronchoalveolar Lavage Fluid; Capillary Permeability; Cinnamates; Class I Phosphatidylinositol 3-Kinases; Cytokines; Disease Models, Animal; Enzyme Inhibitors; Female; Hypoxia-Inducible Factor 1, alpha Subunit; Indoles; Leukocyte Count; Lung; Mice; Mice, Inbred BALB C; Ovalbumin; Phosphoinositide-3 Kinase Inhibitors; Pneumonia; Quinazolines; Receptors, Vascular Endothelial Growth Factor; Vascular Endothelial Growth Factor A