Effects of an Antimutagenic 1,4‐Dihydropyridine AV‐153 on Expression of Nitric Oxide Synthases and DNA Repair‐related Enzymes and Genes in Kidneys of Rats with a Streptozotocin Model of Diabetes Mellitus

Abstract

Development of complications of diabetes mellitus (DM), including diabetic nephropathy, is a complex multi-stage process, dependent on many factors including the modification of nitric oxide (NO) production and an impaired DNA repair. The goal of this work was to study in vivo effects of 1,4-dihydropyridine AV-153, known as antimutagen and DNA binder, on the expression of several genes and proteins involved in NO metabolism and DNA repair in the kidneys of rats with a streptozotocin (STZ)-induced model of DM. Transcription intensity was monitored by means of real-time RT-PCR and the expression of proteins by immunohistochemistry. Development of DM significantly induced PARP1 protein expression, while AV-153 (0.5 mg/kg) administration decreased it. AV-153 increased the expression of Parp1 gene in the kidneys of both intact and diabetic animals. Expression of H2afx mRNA and γH2AX histone protein, a marker of DNA breakage, was not changed in diabetic animals, but AV-153 up-regulated the expression of the gene without any impact on the protein expression. Development of DM was followed by a significant increase in iNOS enzyme expression, while AV-153 down-regulated the enzyme expression up to normal levels. iNos gene expression was also found to be increased in diabetic animals, but unlike the protein, the expression of mRNA was found to be enhanced by AV-153 administration. Expression of both eNOS protein and eNos gene in the kidneys was down-regulated, and the administration of AV-153 normalized the expression level. The effects of the compound in the kidneys of diabetic animals appear to be beneficial, as a trend for the normalization of expression of NO synthases is observed.

Genome protecting and genotoxic effects produced by derivatives of 1,4-dihydropyridine

“…In most cases 1,4-DHP increased the expression of the genes, which could indicate some impact on general pathways of the regulation of transcription. Down-regulation of the inducible NO synthase protein (iNOS) in diabetes mellitus by carbatonides [13], AV-153 [28] and both iNOS expression and NO production by etaftorone, fenoftorone and cerebrocrast [13] seem to be a promising result.…”

Highly Efficient Electrocarboxylation Method to Synthesize Novel Acid Derivatives of 1,4-Dihydropyridines and to Study Their Antimicrobial Activity

“…Extensive pharmaceutical research furnished an extended catalog of medicines containing 1,4-DHP as the nucleus, and it is evident by the existence in many commercially available drugs such as amlodipine 1 (hypertension), nifedipine 2 (treats high blood pressure), isradipine 3 (calcium channel blocker), nimodipine 4 (decreases brain damage), among other drugs. Pharmaceutical potencies of 1,4-dihydropyridines have also been studied in other significant areas like anticancer, 5 antimutagenic, 6 neuroprotective, 7 growth stimulants, 8 antioxidant, 9 and radioprotective agents. 10 …”

Hantzsch Reaction Starting Directly from Alcohols through a Tandem Oxidation Process

“…1,4-Dihydropyridines and their derivatives are an important class of heterocycles in biologically active and naturally occurring molecules [1][2][3]. Many methods for the preparation of 1,4-dihydropyridines have been reported and most of them are mainly confined to the modification and optimization of the Hantzsch multicomponent synthesis between an aldehyde, a 1,3-dicarbonyl compound, and a source of ammonia [4][5][6].…”