Our goal is to evaluate the efficacy of the FDA-approved drug Carbidopa for the treatment of gouty arthritis in mouse models. Carbidopa is used to treat Parkinson?s disease, but always in combination of L-DOPA, never alone by itself. Gouty arthritis is caused by deposition of monosodium urate (MSU) crystals in joints, initiating inflammation and arthritis. Interestingly, gout is not always directly related to increased levels of uric acid; there are individuals with elevated uric acid but don?t have gout, implicating other factors in the promotion of MSU-dependent inflammation and arthritis. MSU complexes with iron; the resultant complex enhances oxidative damage and inflammation following phagocytosis in monocytes/neutrophils. As such, uric acid and iron play the ?partners in crime? in the etiology of gouty arthritis. What would be the ideal features of a drug to treat this disease most effectively? A drug which prevents the complexation of iron with MSU and also which promotes excretion of uric acid and decrease its levels in blood and tissues! Carbidopa has both of these features. it is an agonist for the aryl hydrocarbon receptor (AhR) and also is an iron chelator. AhR is a known inducer of ABCG2, the primary transporter for uric acid elimination in kidney and intestine. Carbidopa, as an iron chelator, would prevent the complexation of iron with MSU; as an AhR agonist, it would also promote uric acid excretion in kidney and intestine via AhR-induced induction of ABCG2. For the proof of concept, we will: (1) Determine if iron facilitates the detrimental consequences of the phagocytic uptake of monosodium urate (MSU) crystals in monocytes and neutrophils and if Carbidopa effectively blocks this effect. This will test the hypotheses that (a) Complexation MSU with iron induces oxidative damage in monocytes/neutrophils following phagocytic uptake of MSU-iron; (b) Carbidopa blocks this effect by chelating iron; (2A) Determine if Carbidopa induces ABCG2 in renal and intestinal epithelial cells at therapeutically relevant doses and investigate if AhR is involved in the process. This will test the hypotheses that (a) Carbidopa increases ABCG2 expression in kidney and intestine transcriptionally, thus increasing the transporter mRNA and protein, demonstrable at the functional level; (b) Carbidopa activates AhR and increases its transcriptional activity at the ABCG2 promoter, demonstrable in ChIP assay. (2B) Evaluate the efficacy of Carbidopa to reduce serum and tissue levels of uric acid in hemochromatosis mice (Hfe-/-), Abcg2 Q140K mutant knock-in mice (Abcg2Q140K) and Hfe-/-/Abcg2Q140K mice. This will test the hypotheses that (a) Uric acid is elevated in both Hfe-/- mice and Abcg2Q140K knock-in mice, and the two genotypes work synergistically to increase uric acid levels even further in Hfe-/- /Abcg2Q140K mice; (b) Carbidopa significantly decreases the serum/tissue levels of uric acid and increases uric acid excretion in urine and feces in all three mouse lines. If successful, these studies would highlight the potential of Carbidopa in treatment of gouty arthritis, a common debilitating disease affecting millions of people.
Using preclinical mouse models, we will evaluate the efficacy of the FDA-approved drug Carbidopa for the treatment of gouty arthritis, a common debilitating disease affecting millions of people. Uric acid and iron play the ?partners in crime? in the etiology of gouty inflammation and arthritis. We predict that Carbidopa would chelate iron and prevent the complexation of iron with monosodium urate crystals, thus reducing oxidative damage and cellular pathology, and that it would also increase renal and intestinal excretion of uric acid by inducing the urate exporter ABCG2 via activation of aryl hydrocarbon receptor.
