Pharmacological and Toxicological Threshold of Bisammonium Tetrakis 4-(N,N-Dimethylamino)pyridinium Decavanadate in a Rat Model of Metabolic Syndrome and Insulin Resistance

Abstract

Vanadium(IV/V) compounds have been studied as possible metallopharmaceutical drugs against diabetes mellitus. However, mechanisms of action and toxicological threshold have been tackled poorly so far. In this paper, our purposes were to evaluate the metabolic activity on dyslipidemia and dysglycemia, insulin signaling in liver and adipose tissue, and toxicology of the title compound. To do so, the previously reported bisammonium tetrakis 4-(N,N-dimethylamino)pyridinium decavanadate, the formula of which is [DMAPH]4(NH4)2[V10O28]·8H2O (where DMAPH is 4-dimethylaminopyridinium ion), was synthesized, and its dose-response curve on hyperglycemic rats was evaluated. A Long–Evans rat model showing dyslipidemia and dysglycemia with parameters that reproduce metabolic syndrome and severe insulin resistance was generated. Two different dosages, 5 µmol and 10 µmol twice a week of the title compound (equivalent to 2.43 mg·V/kg/day and 4.86 mg·V/kg/day, resp.), were administered intraperitoneal (i.p.) for two months. Then, an improvement on each of the following parameters was observed at a 5 µmol dose: weight reduction, abdominal perimeter, fatty index, body mass index, oral glucose tolerance test, lipid profile, and adipokine and insulin resistance indexes. Nevertheless, when the toxicological profile was evaluated at a 10 µmol dose, it did not show complete improvement, tested by the liver and adipose histology, as well as by insulin receptor phosphorylation and GLUT-4 expression. In conclusion, the title compound administration produces regulation on lipids and carbohydrates, regardless of dose, but the pharmacological and toxicological threshold for cell regulation are suggested to be up to 5 µmol (2.43 mg·V/kg/day) dose twice per week.

Decavanadate Salts of Cytosine and Metformin: A Combined Experimental-Theoretical Study of Potential Metallodrugs Against Diabetes and Cancer

“…As for the Metforminium decavanadate 3:1, promising results have been obtained in type 1 and 2 murine models of D. mellitus . (Treviño et al, 2015 , 2016 , 2018 ). The combination of two therapeutic agents opens up a window toward the generation of potential metalopharmaceuticals with new and exciting pharmacological properties.…”

“…Special emphasis was placed in the compounds' physical and chemical characterization and strengthened with the theoretical analysis. We thus think that the structural study here presented to justify an in-depth biological study to understand, for example, the outcome on the bioactivity of some decavanadate compounds with specific counterions (Yraola et al, 2007 ; Zorzano et al, 2009 ; Treviño et al, 2015 , 2016 , 2018 ).…”

“…With respect to the biological activity of decameric species, it has been shown that decavanadate induce several changes in biological processes through the interaction with biological systems, such as myosin, actin, and ion pumps, which are major proteins implicated in muscle contraction and its regulation (Aureliano, 2011 , 2016 , 2017 ; Winkler et al, 2017 ). Furthermore, it has been reported that decavanadate has an insulin-enhancing activity in streptozotocin-induced diabetic rats (Pereira et al, 2009 ) and in murine diabetic models induced by hypercaloric diets or alloxan (Treviño et al, 2015 , 2016 , 2018 ). Recently it has been suggested that it's in vitro anticancer activity may be related to the inhibitory effects on specific enzymes involved in tumor proliferation (Aureliano, 2017 ; Bijelic et al, 2018 ).…”

Tris(2-Pyridylmethylamine)V(O)2 Complexes as Counter Ions of Diprotonated Decavanadate Anion: Potential Antineoplastic Activity

“…Decavanadate’s high negative charge allows it to interact with a wide range of molecules, including proteins, counterions, and lipid structures, influencing a variety of biological processes such as muscle contraction, calcium homeostasis, necrosis, actin polymerization, oxidative stress markers, and glucose uptake ( Aureliano, 2009 ). As a result, numerous compounds based on decavanadate and cationic organic ligands have been published in recent years, which have been shown to lower blood sugar levels ( Garcia-Vicente et al, 2007 ; Treviño et al, 2015 ; Treviño et al, 2018 ; Treviño and González-Vergara, 2019 ), induce neuronal and cognitive restoration mechanisms while treating metabolic syndrome ( Diaz et al, 2021 ), and inhibit the growth of protozoan parasites ( Li et al, 2010 ; Silva-Nolasco et al, 2020 ). The cytotoxic or differentiating activity of oxidovanadium complexes with organic ligands against various cancer cell types is well known ( Kioseoglou et al, 2015 ; Crans et al, 2018 ; Crans et al, 2019 ; Redher, 2020 ; Samart et al, 2020 ; Macedo Alves de Lima et al, 2021 ; Pessoa et al, 2021 ).…”