demeclocycline 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

Binding of vasopressin to its type 2 receptor in renal collecting ducts induces cAMP signaling, transcription and translocation of aquaporin (AQP)2 water channels to the plasma membrane, and water reabsorption from the prourine. Demeclocycline is currently used to treat hyponatremia in patients with the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Demeclocycline's mechanism of action, which is poorly understood, is studied here. In mouse cortical collecting duct (mpkCCD) cells, which exhibit deamino-8-D-arginine vasopressin (dDAVP)-dependent expression of endogenous AQP2, demeclocycline decreased AQP2 abundance and gene transcription but not its protein stability. Demeclocycline did not affect vasopressin type 2 receptor localization but decreased dDAVP-induced cAMP generation and the abundance of adenylate cyclase 3 and 5/6. The addition of exogenous cAMP partially corrected the demeclocycline effect. As in patients, demeclocycline increased urine volume, decreased urine osmolality, and reverted hyponatremia in an SIADH rat model. AQP2 and adenylate cyclase 5/6 abundances were reduced in the inner medulla but increased in the cortex and outer medulla, in the absence of any sign of toxicity. In conclusion, our in vitro and in vivo data indicate that demeclocycline mainly attenuates hyponatremia in SIADH by reducing adenylate cyclase 5/6 expression and, consequently, cAMP generation, AQP2 gene transcription, and AQP2 abundance in the renal inner medulla, coinciding with a reduced vasopressin escape response in other collecting duct segments.

Topics: Adenylyl Cyclases; Animals; Anti-Bacterial Agents; Aquaporin 2; Cells, Cultured; Cyclic AMP; Deamino Arginine Vasopressin; Demeclocycline; Disease Models, Animal; Hyponatremia; In Vitro Techniques; Inappropriate ADH Syndrome; Kidney Medulla; Male; Mice; Minocycline; Rats; Rats, Wistar; Vasopressins

The prognosis of replanted teeth depends on several factors, the most important being the length of extra-oral dry time. Studies show that after 60 min dry time, root resorption is predicted. Immediate intracanal placement of Ledermix, a paste containing triamcinolone (corticosteroid) and demeclocycline (tetracycline) has been shown to inhibit root resorption after extended dry time. However, discoloration is possible from the tetracycline in Ledermix. To evaluate the individual influence of corticosteroid and tetracycline on external root resorption after extended extra-oral dry time. Sixty-nine premolar roots of four beagle dogs were extracted and instrumented with NiTi files. Group 1 (negative control) was immediately replanted after root filling with GP and sealer; Group 2 (positive control) was root filled with GP and sealer and replanted after 60 min dry time; In groups 3-5, the canals were filled with Ledermix, Triamcinolone, and Demeclocycline, respectively, and replanted after 60 min dry time. After 4 months, the dogs were sacrificed and the roots were examined histologically for type of healing (favorable or unfavorable) and remaining root diameter. The groups treated with Ledermix, Triamcinolone and Demeclocycline had statistically significantly more favorable healing (75.8%; 69.8%; 52.4%) and more remaining root structure (5.59; 5.48; 5.09) than the group filled with GP and sealer (positive control) (0; 1.15). Corticosteroids were as effective as Ledermix at inhibiting external root resorption.

Topics: Animals; Anti-Inflammatory Agents; Demeclocycline; Dental Alloys; Desiccation; Disease Models, Animal; Dogs; Drug Combinations; Edetic Acid; Epoxy Resins; Glucocorticoids; Gutta-Percha; Nickel; Root Canal Filling Materials; Root Canal Irrigants; Root Canal Preparation; Root Resorption; Sodium Hypochlorite; Time Factors; Titanium; Tooth Avulsion; Tooth Replantation; Triamcinolone Acetonide; Wound Healing

Topics: 4-Aminobenzoic Acid; Aminobenzoates; Animals; Chlorpromazine; Demeclocycline; Disease Models, Animal; Guinea Pigs; Male; Methoxsalen; Mice; Mice, Nude; Photosensitivity Disorders; Spectrophotometry, Ultraviolet; Sunscreening Agents

A technique for inducing pneumococcal meningitis in mice and a description of the histopathologic changes that accompany this experimentally produced disease are provided in the present report. This infection of mice was investigated to determine whether it could serve as a suitable model for detecting agents that have potential therapeutic utility in bacterial meningitis in man. 21 antibiotics, belonging to six major classes were evaluated for efficacy in the experimental infection. The three most active agents proved to be amoxicillin, cephaloridine, and chlortetracycline. Up to this time, amoxicillin has not been commercially available as an injectable dosage form. However, in view of the compound's outstanding efficacy in the present experiments, it would be desirable to investigate its effectiveness in the naturally occurring disease in man.

Topics: Animals; Anti-Bacterial Agents; Cephalosporins; Cerebellum; Cerebral Cortex; Chloramphenicol; Chlortetracycline; Demeclocycline; Disease Models, Animal; Erythromycin; Lincomycin; Male; Meningitis, Pneumococcal; Mice; Penicillins; Rolitetracycline; Streptococcus pneumoniae; Tetracycline; Virulence

Topics: Animals; Candida albicans; Candidiasis, Oral; Demeclocycline; Disease Models, Animal; Female; Haplorhini; Hypersensitivity, Delayed; Male; Mouth Diseases; Stomatitis, Denture

Topics: Ammonia; Animals; Anti-Bacterial Agents; Ascorbic Acid; Bacitracin; Chloramphenicol; Chlortetracycline; Demeclocycline; Depression, Chemical; Disease Models, Animal; Enzyme Repression; Erythromycin; Female; Hydroxamic Acids; In Vitro Techniques; Intestines; Kanamycin; Male; Neomycin; Niacinamide; Oxytetracycline; Penicillin G; Rats; Streptomycin; Sulfamethoxypyridazine; Sulfisoxazole; Sulfonamides; Tetracycline; Urease