Carbidopa, an iron chelator and an ABCG2 inducer, for treatment of gouty arthritis

Our goal is to evaluate the efficacy of the FDA approved drug Carbidopa for the treatment of gouty arthritis in mouse modelsCarbidopa is used to treat Parkinson s diseasebut always in combination of L DOPAnever alone by itselfGouty arthritis is caused by deposition of monosodium urateMSUcrystals in jointsinitiating inflammation and arthritisInterestinglygout is not always directly related to increased levels of uric acidthere are individuals with elevated uric acid but don t have goutimplicating other factors in the promotion of MSU dependent inflammation and arthritisMSU complexes with ironthe resultant complex enhances oxidative damage and inflammation following phagocytosis in monocytes neutrophilsAs suchuric acid and iron play thepartners in crimein the etiology of gouty arthritisWhat would be the ideal features of a drug to treat this disease most effectivelyA 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 featuresit is an agonist for the aryl hydrocarbon receptorAhRand also is an iron chelatorAhR is a known inducer of ABCGthe primary transporter for uric acid elimination in kidney and intestineCarbidopaas an iron chelatorwould prevent the complexation of iron with MSUas an AhR agonistit would also promote uric acid excretion in kidney and intestine via AhR induced induction of ABCGFor the proof of conceptwe willDetermine if iron facilitates the detrimental consequences of the phagocytic uptake of monosodium urateMSUcrystals in monocytes and neutrophils and if Carbidopa effectively blocks this effectThis will test the hypotheses thataComplexation MSU with iron induces oxidative damage in monocytes neutrophils following phagocytic uptake of MSU ironbCarbidopa blocks this effect by chelating ironADetermine if Carbidopa induces ABCGin renal and intestinal epithelial cells at therapeutically relevant doses and investigate if AhR is involved in the processThis will test the hypotheses thataCarbidopa increases ABCGexpression in kidney and intestine transcriptionallythus increasing the transporter mRNA and proteindemonstrable at the functional levelbCarbidopa activates AhR and increases its transcriptional activity at the ABCGpromoterdemonstrable in ChIP assayBEvaluate the efficacy of Carbidopa to reduce serum and tissue levels of uric acid in hemochromatosis miceHfeAbcgQK mutant knock in miceAbcg QKand HfeAbcg QK miceThis will test the hypotheses thataUric acid is elevated in both Hfemice and Abcg QK knock in miceand the two genotypes work synergistically to increase uric acid levels even further in HfeAbcg QK micebCarbidopa significantly decreases the serum tissue levels of uric acid and increases uric acid excretion in urine and feces in all three mouse linesIf successfulthese studies would highlight the potential of Carbidopa in treatment of gouty arthritisa common debilitating disease affecting millions of people Using preclinical mouse modelswe will evaluate the efficacy of the FDA approved drug Carbidopa for the treatment of gouty arthritisa common debilitating disease affecting millions of peopleUric acid and iron play thepartners in crimein the etiology of gouty inflammation and arthritisWe predict that Carbidopa would chelate iron and prevent the complexation of iron with monosodium urate crystalsthus reducing oxidative damage and cellular pathologyand that it would also increase renal and intestinal excretion of uric acid by inducing the urate exporter ABCGvia activation of aryl hydrocarbon receptor