Modifications of expression of genes and proteins involved in DNA repair and nitric oxide metabolism by carbatonides [disodium-2,6-dimethyl-1,4-dihydropyridine-3,5-bis(carbonyloxyacetate) derivatives] in intact and diabetic rats
Kristīne Ošiņa
Institute of Biology of the University of Latvia, Salaspils, Latvia; Latvian Institute of Organic Synthesis, Riga, Latvia
Elina Leonova
Sergejs Isajevs
Larisa Baumane
Evita Rostoka
Tatjana Sjakste
Egils Bisenieks
Gunars Duburs
Brigita Vigante
Nikolajs Sjakste
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Keywords

1,4-dihydropyridine derivatives
1
diabetes mellitus
4-dihydropyridine derivatives
DNA damage
streptozotocin
free radical scavengers
nitric oxide synthases
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Abstract

Studies on the pathogenesis of diabetes mellitus complications indicate that the compounds reducing free radicals and enhancing DNA repair could be prospective as possible remedies. Carbatonides, the disodium-2,6-dimethyl-1,4-dihydropyridine-3,5-bis(carbonyloxyacetate) derivatives, were tested for these properties. EPR spectroscopy showed that metcarbatone was an effective scavenger of hydroxyl radicals produced in the Fenton reaction, etcarbatone, and propcarbatone were less effective, styrylcarbatone was ineffective. UV/VIS spectroscopy revealed that styrylcarbatone manifested a hyperchromic effect when interacting with DNA, while all other carbatonides showeda hypochromic effect. Rats with streptozotocin induced type 1 DM were treated with metcarbatone, etcarbatone or styrylcarbatone (all compounds at doses 0.05 mg kg-1 or 0.5 mg kg-1) nine days after the DM approval. Gene expression levels in kidneys and blood were evaluated by quantitative RT-PCR; protein expression - immunohistochemically in kidneys, heart, sciatic nerve, and eyes; DNA breakage - by comet assay in nucleated blood cells. Induction of DM induced DNA breaks; metcarbatone and styrylcarbatone (low dose) alleviated this effect. Metcarbatone and etcarbatone up-regulated mRNA and protein of eNOS in kidneys of diabetic animals; etcarbatone also in myocardium. Etcarbatone reduced the expression of increased iNOS protein in myocardium, nerve, and kidneys. iNos gene expression was up-regulated in kidneys by etcarbatone and metcarbatone in diabetic animals. In blood, development of DM increased iNos gene expression; etcarbatone and metcarbatone normalised it. Etcarbatone up-regulated the expression of H2AX in kidneys of diabetic animals but decreased the production of c-PARP1. Taken together, our data indicate that carbatonides might have a potential as drugs intended to treat DM complications.

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