Gestational Diabetes Triggers Oxidative Stress in Hippocampus and Cerebral Cortex and Cognitive Behavior Modifications in Rat Offspring: Age- and Sex-Dependent Effects

Abstract

Gestational diabetes (GD) has been linked with an increased risk of developing metabolic disorders and behavioral abnormalities in the offspring. Oxidative stress is strongly associated with neurodegeneration and cognitive disruption. In the offspring brains in a GD experimental rat model, increased oxidative stress in the prenatal and postnatal stages was reported. However, long-term alterations to offspring behavior and oxidative stress, caused by changes in the cerebral cortex and hippocampus, remain unclear. In this study, we evaluated the effect of GD on young and adult male and female rat offspring in metabolic parameters, cognitive behavior, and oxidative stress. GD was induced using streptozotocin in dams. Next, the offspring were evaluated at two and six months of age. Anxiety-like behavior was evaluated using the elevated plus maze and open field maze; spatial learning and short-term memory were evaluated using the Morris water maze and radial maze, respectively. We determined oxidative stress biomarkers (reactive oxygen species (ROS), lipid peroxidation and glutathione status) and antioxidant enzymes (superoxide dismutase and catalase) in the brain of offspring. We observed that male GD offspring showed a reduced level of anxiety at both ages as they spent less time in the closed arms of the elevated plus maze at adult age ((P = 0.019, d = 1.083 ( size effect)) and spent more time in the open area of an open field (P = 0.0412, d = 0.743) when young and adult age (P = 0.018, d = 0.65). Adult female GD offspring showed a reduced level of anxiety (P = 0.036; d = 0.966), and young female GD offspring showed a deficiency in spatial learning (P = 0.0291 vs. control, d = 3.207). Adult male GD offspring showed a deficiency in short-term memory (P = 0.017, d = 1.795). We found an increase in ROS and lipid peroxidation, a disruption in the glutathione status, and decreased activity of catalase and superoxide dismutase (P < 0.05 vs. control, d > 1.0), in the cerebral cortex and hippocampus of male and female GD offspring. GD altered metabolism; male offspring of both ages and adult females showed a high level of triglycerides and a lower level of high-density lipoprotein-cholesterol (P < 0.05 vs. control, d > 1.0). Young and adult female offspring displayed higher insulin levels (P < 0.05, d > 1.0). These results suggest that gestational diabetes modifies oxidative stress and cognitive behavior in an age- and sex-dependent manner.

Effects of Gestational Diabetes in Cognitive Behavior, Oxidative Stress and Metabolism on the Second-Generation Off-Spring of Rats

“…GD were each induced by a single dose of STZ. The model of GD and obtaining first-generation offspring (F1) has already been previously reported [ 24 ].…”

“…Ours laboratories recently reported the impact of GD on metabolism, cognitive ability and oxidative stress in areas of the brain associated with cognition in the first-generation offspring (F1). We observed alterations in glucose and lipid metabolism, deficiencies in spatial learning and short-term memory, modifications in anxiety-like behavior and a rise in oxidative stress resulting in oxidative injury as lipid-peroxidation; these effects are dependent on age and sex [ 24 ]. However, there is limited information about the effect of GD on F2 offspring cognitive ability.…”

Gestational Diabetes and Cold Stress Trigger Protein Oxidation in Discrete Brain Regions

“…To assess if there is an increase in oxidants that cause oxidative damage in lipids, we evaluated lipid peroxidation and observed a consistent increase in MDA levels in all experimental rats, confirming oxidative stress in brain functional tissues. Using MDA as a marker, Huerta-Cervantes et al, [16] reported gestational diabetes triggered oxidative stress in the hippocampus and cerebral cortex and cognitive behavior modifications in rat offspring. Their results suggest that intrauterine milieu with chronic hyperglycemia causes oxidative stress and alter cognitive behavior in an age-and sex-dependent manner and any reduction in ROS burden contributes to decreasing oxidative damage in developing embryos of rats with gestational diabetes [16].…”

“…Using MDA as a marker, Huerta-Cervantes et al, [16] reported gestational diabetes triggered oxidative stress in the hippocampus and cerebral cortex and cognitive behavior modifications in rat offspring. Their results suggest that intrauterine milieu with chronic hyperglycemia causes oxidative stress and alter cognitive behavior in an age-and sex-dependent manner and any reduction in ROS burden contributes to decreasing oxidative damage in developing embryos of rats with gestational diabetes [16]. In this study, the MDA levels increased significantly in discrete brain regions in both diabetic and cold-stressed offspring, thereby the results of this study corroborate with the findings of recent studies of Huerta-Cervantes et al [16].…”

“…Their results suggest that intrauterine milieu with chronic hyperglycemia causes oxidative stress and alter cognitive behavior in an age-and sex-dependent manner and any reduction in ROS burden contributes to decreasing oxidative damage in developing embryos of rats with gestational diabetes [16]. In this study, the MDA levels increased significantly in discrete brain regions in both diabetic and cold-stressed offspring, thereby the results of this study corroborate with the findings of recent studies of Huerta-Cervantes et al [16]. Further, exacerbated effects witnessed as a function of cold stress in diabetic rats, infer synergetic actions due to bioaccumulation of LPO metabolites and their interference with the developing neuronal tissues because of poor antioxidant defense; resultantly cold stress intensifies the oxidative burden in diabetic rats causing severity of effects in developing brain because optimal brain function is dependent on cellular redox homeostasis and these changes initiate tissue damage.…”