INFLUENCE OF DIPHENYL DISELENIDE ON REDOX INDICES AND THE EXPRESSION OF GENES ASSOCIATED WITH DIABETIC PROGRESSION IN RATS

Abstract

Diphenyl diselenide (DPDSe) has demonstrated promising pharmacological properties against pathologies that are intrinsically linked to radical-mediated oxidative stress such as diabetes. However, the possible influence of DPDSe to mitigate the diverse metabolic assaults associated with diabetes progression at biochemical and molecular levels have not been fully explored. Herein, the effect of single oral dose administration of DPDSe (10 mg/kg bw) in simulated postprandial and fasting hyperglycemia was tested in naïve and diabetic male Wistar rat. Besides, alterations in some redox indices, toxicological markers, biochemical and molecular parameters associated with diabetes progression were evaluated. Moreover, the influence of DPDSe on the expression of mRNA associated with pathways that are linked to glucose metabolism, redox system, and inflammatory process, cardiac, renal and testicular functions were also determined. The effect of DPDSe treatment on the possible histopathological changes associated with prolonged STZ induction was assessed in the brain, heart, liver, pancreas, kidney and testes. The results revealed that single oral dose of DPDSe attenuated high glucose level in both postprandial and fasting hyperglycemia. This hypo- and anti-hyperglycemic effects were accompanied with improved redox indices. Also, derangement in the expression of mRNAs that characterize glucose metabolism (glucagon like protein-1, Insulin, peroxisome proliferative activated receptor-γ, Glut- 2, Glut-4), inflammatory processes (interlukin-1β, interleukin -6, tumor necrotic factor-α, adiponectin, adipsin, leptin), redox system (nuclear factor erythroid 2-related factor 2, kelch-like protein-1, heamoxygenase-1), lipid metabolism (Sterol element binding proptein-2), renal (renalase, kidney induced molecule, neutrophil gelatinase activated lipocalin, proprotein convertase subtilisin 9), cardiac (rhokinase-1, rhokinase-2, troponin-c) and testicular functions (17-beta hydroxysteroid dehydrogenase, 3-beta hydroxysteroid dehydrogenase) were observed on day 3 of the diabetes progression. Similarly, the activities of purine-dependent enzymes (E- NTPDase, 5′-nucleotidase) signaling cascades were markedly increased on the third day of diabetic progression. Conversely, diabetic progression evoked a profound alteration in redox, hematological and toxicological indices as well as activities of redox sensitive sulfhydryl (Na + /K + ATPase and δ-ALA D) enzymes on day 7 of untreated STZ-induced persistent hyperglycemia in the rats. Interestingly, DPDSe reversed diabetes-induced alteration in the expression of mRNAs that are linked with glucose metabolism, adipokines, pro-inflammatory responses as well as markers of renal, cardiac and testicular functions. In addition, DPDSe restored altered cellular architectural integrity of brain, liver, heart and pancreas, occasioned by diabetes progression. These results suggest that molecular markers that characterize diabetic progression may be a reliable diagnostic tool in monitoring the disease progression. In conclusion, aside its known anti- hyperglycemic properties coupled with its ability to reverse altered biochemical processes in diabetic condition, DPDSe may also be exerting diverse pharmacological potentials in ameliorating the deranged molecular events that are linked with the disease progression.