cinnarizine 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

There is a major clinical need for new therapies for the treatment of chronic itch. Many of the molecular components involved in itch neurotransmission are known, including the neuropeptide NPPB, a transmitter required for normal itch responses to multiple pruritogens in mice. Here, we investigated the potential for a novel strategy for the treatment of itch that involves the inhibition of the NPPB receptor NPR1 (natriuretic peptide receptor 1). Because there are no available effective human NPR1 (hNPR1) antagonists, we performed a high-throughput cell-based screen and identified 15 small-molecule hNPR1 inhibitors. Using in vitro assays, we demonstrated that these compounds specifically inhibit hNPR1 and murine NPR1 (mNPR1). In vivo, NPR1 antagonism attenuated behavioral responses to both acute itch- and chronic itch-challenged mice. Together, our results suggest that inhibiting NPR1 might be an effective strategy for treating acute and chronic itch.

Topics: Animals; Behavior, Animal; Cell-Free System; Dermatitis, Contact; Disease Models, Animal; Ganglia, Spinal; Humans; Mice, Inbred C57BL; Mice, Knockout; Neurons; Pruritus; Receptors, Atrial Natriuretic Factor; Reproducibility of Results; Signal Transduction; Small Molecule Libraries

Topics: Adjuvants, Immunologic; Animals; Brain; Brain Ischemia; Calcium Channel Blockers; Chronic Disease; Cinnarizine; Disease Models, Animal; Hemodynamics; Interferon beta-1b; Interferon-beta; Proprioception; Rats; Vestibule, Labyrinth

We describe the production of an experimental model of parkinsonism induced by cinnarizine (CNZ) in three healthy sylvanna monkeys. The drug produced a severe but reversible parkinsonism in all animals. After discontinuation of CNZ, all animals recovered but the oldest one was akinetic for 6 weeks. CNZ produced a persistent reduction in HVA and 5-HIAA levels in the CSF. Our data suggest a predominant presynaptic effect on DA and 5-HT neurons; and could account for the longstanding parkinsonism induced by calcium antagonist in some patients as well as the depression observed in these subjects.

Topics: Animals; Biogenic Monoamines; Cinnarizine; Disease Models, Animal; Dopamine; Haplorhini; Homovanillic Acid; Hydroxyindoleacetic Acid; Male; Movement Disorders; Parkinson Disease, Secondary; Tremor

Topics: Animals; Brain; Cerebrovascular Circulation; Cinnarizine; Disease Models, Animal; Dogs; Flunarizine; Heart Arrest; Humans; Oxygen Consumption; Time Factors

Two new hypotheses suggest that the key pathology in migraine has a neuronal origin. A pivotal role is assigned to brain hypoxia (1) and spreading depression (SD) (neuronal depolarization spreading gradually over the cortex) (2). Flunarizine has been tested both against brain hypoxia and SD. Its potent antihypoxic properties in animal models led to its use as a prophylactic drug in migraine therapy. Earlier experiments suggested that flunarizine shortened recovery after neuronal depolarization. Recent experiments suggest that flunarizine may enhance the threshold for the elicitation of SD. Finally, it is often unclear whether the effects observed with flunarizine are due to a vascular or a direct neuronal effect. Therefore, a study was made to show whether flunarizine affected hypoxia-induced alterations in synaptic function in slices of hippocampus held in vitro. At physiological drug concentrations in brain, flunarizine improved post-hypoxic recovery of synaptic function. A direct neuronal protective effect was thus demonstrated.

Topics: Animals; Calcium Channel Blockers; Cells, Cultured; Cinnarizine; Cortical Spreading Depression; Disease Models, Animal; Flunarizine; Guinea Pigs; Hypoxia, Brain; Migraine Disorders; Neurons; Piperazines; Rats; Vasodilator Agents

Repeated weak electrical stimulations of rabbit carotid artery walls with implanted electrodes cause intimal proliferations of smooth muscle cells (SMC) and lead to fibromuscular plaques beneath the anode. If the animals receive a cholesterol-enriched diet the plaques become typical atheromas. The endothelial lining is maintained. The procedure for the production of an atheroma with 11 +/- 4 layers of SMC lasts 4 weeks. Addition of the calcium antagonist Flunarizine to the food during the stimulation periods inhibits the growth of the plaque. The inhibition is dose-dependent. Whether the drug inhibits atherogenesis by direct action on SMC or via an effect on permeation of macromolecules through the endothelium has been studied by measurement of (1) peroxidase (MW 40,000 dalton) permeability through the stimulated endothelium of the artery and (2) the inhibitory effects of Flunarizine on cultures of arterial SMC. Endothelial permeability increases for some hours after stimulation mainly beneath the anode. Flunarizine inhibits the permeation of peroxidase through the endothelial lining for the most part by its action on intercellular transport. The drug also inhibits the growth of SMC in mass cultures and clone cultures. The inhibition of proliferation is not specific for SMC. Skin fibroblasts obtained from the same animals as the artery smooth muscle cells are also inhibited in mass cultures and clone cultures. From the results it can be concluded that Flunarizine exerts its inhibitory action not only by its effect on the permeation through the endothelial lining but by a combined action on permeability and proliferation of cells in the artery wall.

Topics: Animals; Arteriosclerosis; Carotid Arteries; Cell Division; Cells, Cultured; Cinnarizine; Disease Models, Animal; Electric Stimulation; Endothelium; Fibroblasts; Flunarizine; Horseradish Peroxidase; Male; Muscle, Smooth, Vascular; Rabbits; Vasodilator Agents

Topics: Animals; Cinnarizine; Disease Models, Animal; Flunarizine; Heart Arrest; Hypoxia; Male; Piperazines; Rats; Rats, Inbred Strains; Vasodilator Agents