Insulin treatment reverses hippocampus hypermethylation and cognitive deficits in chronic hyperglycemia

RODRIGO AUGUSTO DA SILV; FILIPE JOSÉ DE MATOS; ALINE PERTILE REMOR; VIVIANE GLASER; PRISCILA MAXIMILIANA DE PAULA FERREIRA; ALEX RAFACHO; PAULO ALEXANDRE DE OLIVEIRA; RUI DANIEL SCHRÖDER PREDIGER; SUSANA GENTI-RAIMONDI; ANA LUCIA DE PAUL; ADERBAL AGUIAR JR; CARLA INÊS TASCA; ALEXANDRA LATINI

Foz de Iguazu

Congreso; XLIII Meeting Anual de la Sociedad Brasilera de Bioquímica y Biología Molecular SBBq; 2014

Sociedad Brasilera de Bioquímica y Biología Molecular SBBq

  Diabetes mellitus (DM) is associated with cognitive deficits and an increased risk of dementia, particularly in the elderly. These deficits are normally accompanied by neurophysiological, biochemical, molecular and structural changes in the brain. Several lines of evidence have shown that long-term complications of DM occur as a result of systemic persistent hyperglycemic state. Numerous metabolic and physiological changes promoted by chronic hyperglycemia are already well characterized. However, epigenetic changes in the CSN are virtually unknown. Here, it was investigated the impact of chronic hyperglycemia on cognitive performance, and biochemical parameters in the brain of streptozotocin (STZ)-induced hyperglycemic Wistar rats. The activity chamber, step-down inhibitory avoidance and Water maze tasks were performed. In parallel, the markers of oxidative stress state, thiobarbituric acid-reactive substances (TBARS) and non-protein thiol groups (NPSH), the gene expression of IL-10, L-6, BDNF, CK, NDUFA6 and COXI, the content of IRS-1, p-IRS-1, AKT and p-AKT, and the DNA methylation profiles were evaluated in cerebellum, hippocampus and striatum of hyperglycemic (60 days) and hyperglycemic-insulin (INS; 1.5 IU; human insulin NPH; Novolin®N twice per day)-treated rats. It was shown that chronic hyperglycemia compromised short- and long-term spatial memory, effect that was accompanied by significant reduction of plasma antioxidant capacity (NPSH) and increase of lipid peroxidation (TBARS). Furthermore, it was observed reduced gene expression of hippocampal insulin and interleukin-10 (IL-10); correct phosphorylation of target proteins of the insulin receptors, including insulin receptor substrate-1 (IRS-1) and Akt in the cerebral cortex; and increased DNA methylation in hippocampus. The alterations linked to reduced IL-10 expression, TBA-RS levels and DNA methylation were significantly prevented and/or reverted by the exogenous insulin. The hormone administration also prevented the long-term cognitive deficits observed. Therefore, the data strongly indicate that the compromised cognitive performance might be associated to increased brain inflammation and DNA hypermetilation triggered by persistent hyperglycemia.