Regulation of Adrenergic, Serotonin, and Dopamine Receptors to Inhibit Diabetic Retinopathy: Monotherapies versus Combination Therapies
| Autor: | Yunpeng Du, Krzysztof Palczewski, Alyssa Dreffs, David A Antonetti, Chieh Allen Lee, Jie Tang, Timothy S. Kern, Haitao Liu, Henri Leinonen |
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| Rok vydání: | 2021 |
| Předmět: |
Male
Dopamine Vascular permeability Pharmacology Inbred C57BL Eye Receptors Dopamine Mice chemistry.chemical_compound Receptors Pharmacology & Pharmacy Receptor Diabetes Pharmacology and Pharmaceutical Sciences Articles Diabetic retinopathy Receptors Adrenergic Adrenergic Dopamine receptor Combination Molecular Medicine Drug Therapy Combination Drug medicine.drug Serotonin Diabetes Mellitus Experimental Dose-Response Relationship Experimental Drug Therapy Diabetes Mellitus medicine Doxazosin Animals Hypoglycemic Agents Eye Disease and Disorders of Vision Metabolic and endocrine 5-HT receptor Diabetic Retinopathy Dose-Response Relationship Drug business.industry Neurosciences Retinal Vessels Retinal medicine.disease Bromocriptine Mice Inbred C57BL chemistry Receptors Serotonin Biochemistry and Cell Biology business |
| Zdroj: | Mol Pharmacol Molecular pharmacology, vol 100, iss 5 |
| ISSN: | 1521-0111 0026-895X |
| Popis: | We compared monotherapies and combinations of therapies that regulate G-protein coupled receptors (GPCR) with respect to their abilities to inhibit early stages of diabetic retinopathy (DR) in streptozotocin-diabetic mice. Metoprolol (MTP; 0.04-1.0 mg/kgbw/day), bromocriptine (BRM; 0.01-0.1 mg/kgbw/day), doxazosin (DOX; 0.01-1.0 mg/kgbw/day) or tamsulosin (TAM; 0.05-0.25 mg/kgbw/day) were injected individually daily for 2 months in dose-response studies to assess their effects on the diabetes-induced increases in retinal superoxide and leukocyte-mediated cytotoxicity against vascular endothelial cells (ECs), both of which abnormalities have been implicated in the development of DR. Each of the individual drugs inhibited the diabetes-induced increase in retinal superoxide at the higher concentrations tested, but the inhibition was lost at lower doses. To determine if combination therapies had superior effects over individual drugs, we intentionally selected for each drug a low dose that had little or no effect on the diabetes-induced retinal superoxide for use separately or in combinations in 8-month studies of retinal function, vascular permeability and capillary degeneration in diabetes. At the low doses used, combinations of the drugs generally were more effective than individual drugs, but the low dose MTP alone totally inhibited diabetes-induced reduction in a vision task, BRM or DOX alone totally inhibited the vascular permeability defect, and DOX alone totally inhibited diabetes-induced degeneration of retinal capillaries. Although low-dose MTP, BRM, DOX or TAM individually had beneficial effects on some endpoints, combination of the therapies better inhibited the spectrum of DR lesions evaluated. Significance Statement The pathogenesis of early stages of diabetic retinopathy remain incompletely understood, but multiple different cell-types are known to be involved in the pathogenic process. We have compared the effects of monotherapies to those of combinations of drugs that regulate G-protein coupled receptors (GPCR) signaling pathways with respect to their relative abilities to inhibit the development of early diabetic retinopathy. |
| Databáze: | OpenAIRE |
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