Multiple low-dose and single high-dose treatments with streptozotocin do not generate nitric oxide

Abstract

Streptozotocin (STZ) is a widely used diabetogenic agent that damages pancreatic islet beta cells by activating immune mechanisms, when given in multiple low doses, and by alkylating DNA, when given at a single high dose. Actually, STZ contains a nitroso moiety. Incubation of rat islets with this compound has been found to generate nitrite; moreover, photoinduced NO production from STZ has been demonstrated. These reports have suggested that direct NO generation may be a mechanism for STZ toxicity in diabetogenesis. Several other studies have denied such a mechanism of action. This study has shown that (1) the multiple low-dose (MLDS) treatment does not stimulate NO production at the islet level; in fact, nitrite + nitrate levels and aconitase activity (also in the presence of an NO-synthase inhibitor, namely NAME) remain unmodified; RT-PCR analysis demonstrates that this treatment does not stimulate iNOS activity; (2) the high-dose (HDS) treatment does not stimulate NO production; in fact nitrite + nitrate levels remain unmodified and iNOS mRNA levels are not altered, although aconitase activity is significantly decreased. Moreover, we have confirmed that the MLDS treatment is able to decrease SOD activity by day 11 and that STZ, given in a single high dose, transiently increases superoxide dismutase (SOD) values (24 h from the administration), then dramatically lowers SOD levels. On the basis of our results, we conclude that STZ, "in vivo" is unable to generate NO, both as a MLDS or HDS treatment, thus excluding that NO exerts a role in streptozotocin-dependent diabetes mellitus.

Renal oxidative stress and nitric oxide production in streptozotocin‐induced diabetic nephropathy in rats: the possible modulatory effects of garlic (Allium sativum L.)

“…Results of the present study revealed a significant increase in TBARS generation, accompanied by a significant decrease in the level of GSH (Figure 1) which indicate the ability of STZ‐induced diabetic nephropathy to modulate kidney oxidative status, and support the notion that STZ diabetic nephrotoxicity is associated with increased oxidative stress [40–42]. The contribution of FGH in prevention of renal oxidative stress induced by STZ is obvious in the present study (Figure 1).…”

The effect of pomegranate fresh juice versus pomegranate seed powder on metabolic indices, lipid profile, inflammatory biomarkers, and the histopathology of pancreatic islets of Langerhans in streptozotocin-nicotinamide induced type 2 diabetic Sprague–Dawley rats

“…Streptozotocin is selectively cytotoxic to pancreatic β-cells which damage beta-cells through the production of free radicals and involving with the cellular metabolic oxidative mechanisms [28]. Antioxidants can mitigate oxidative stress produced by STZ induced free radicals by neutralizing the available free radicals.…”

Biochanin-A attenuates neuropathic pain in diabetic rats

“…Streptozotocin is well reported for its selective pancreatic islet β-cell cytotoxicity [12] and has been widely used to induce diabetes mellitus in animals. Our results reveal that STZ injected rats exhibited significantly increased blood glucose levels as compared with control rats.…”