Neuromodulatory effect of the combination of metformin and vitamin D3 triggered by purinergic signaling in type 1 diabetes induced-rats

• DOI: 10.1016/j.mce.2023.111852
• Publication Date: 2023-01-16T16:19:36Z
• Authors: Aline da Silva Pe...; Vanessa Valéria M...; Milagros Fanny Ve...; Nathieli Bianchin...; Charles Elias Ass...; Jelson Norberto N...; Bianca Fagan Biss...; Vitor Bastianello...; Naiara Stefanello; Jucimara Baldissa...; Taís Vidal Palma; Vera Maria Melchi...; Maria Rosa Chitol...
• Keywords: 0301 basic medicine; 03 medical and health sciences; Diabetes Mellitus, Type 1; Adenosine; Animals; 5'-Nucleotidase; Metformin; Rats; Cholecalciferol

Several studies have indicated the vitamin D deficiency in the development of macro- and microvascular complications of diabetes mellitus (DM) including DM-related cognitive dysfunction. The purinergic system plays an important role in the modulation of a variety of mechanisms, including neuroinflammation, plasticity, and cell-cell communication. In addition, purines, their receptors, and enzymes can regulate the purinergic axis at different levels in type 1 DM (T1DM). This study evaluated the effects of vitamin D3 alone or in combination with metformin in the behavioral performance of streptozotocin-induced T1DM rats. The effects of this combination on the metabolism of ATP and ADP were also studied by NTPDase (CD39), AMP by 5'-nucleotidase (CD73), and adenosine by adenosine deaminase (E-ADA) in the brain and peripheral lymphocytes of type 1 diabetic STZ-induced rats. The results showed that anxiety and memory loss from the DM condition reverted after 30 days of vitamin D3 treatment. Furthermore, the DM state affected systemic enzymes, with no effect on the central enzymes hydrolyzing extracellular nucleotides and nucleosides. Vitamin D3 treatment positively regulated ectonucleotidase (NTPDase and 5'-nucleotidase) activity, E-ADA, and the purinergic receptors as a mechanism to prevent oxidative damage in the cerebral cortex of T1DM rats. A neuroprotector effect of vitamin D3 through adenosine signaling was also observed, by regulating A1 and A2A receptors proteins levels. The present findings suggest that purinergic signaling through vitamin D3 modulation may be a novel alternative strategy for T1DM treatment, and may compensate for the negative changes in the central nervous system.