Regulation of the Nrf2 Pathway by Glycogen Synthase Kinase-3ß in MPP⁺-Induced Cell Damage.

Recently, nuclear translocation and stability of nuclear factor erythroid 2 (NF-E2)-related factor 2 (Nrf2) have gained increasing attention in the prevention of oxidative stress. The present study was aimed to evaluate the regulatory role of glycogen synthase kinase-3ß (GSK-3ß) inhibition by tideglusib through the Nrf2 pathway in a cellular damage model. Gene silencing (siRNA-mediated) was performed to examine the responses of Nrf2-target genes (i.e., heme oxygenase-1, NAD(P)H:quinone oxidoreductase1) to siRNA depletion of Nrf2 in MPP⁺-induced dopaminergic cell death. Nrf2 and its downstream regulated genes/proteins were analyzed using Real-time PCR and Western Blotting techniques, respectively. Moreover, free radical production, the changes in mitochondrial membrane potential, total glutathione, and glutathione-S-transferase were examined. The possible contribution of peroxisome proliferator-activated receptor gamma (PPARγ) to tideglusib-mediated neuroprotection was evaluated. The number of viable cells and mitochondrial membrane potential were increased following GSK-3ß enzyme inhibition against MPP⁺. HO-1, NQO1 mRNA/protein expressions and Nrf2 nuclear translocation significantly triggered by tideglusib. Moreover, the neuroprotection by tideglusib was not observed in the presence of siRNA Nrf2. Our study supports the idea that GSK-3ß enzyme inhibition may modulate the Nrf2/ARE pathway in cellular damage and the inhibitory role of tideglusib on GSK-3ß along with PPARγ activation may be responsible for neuroprotection.

Neurobehavioral effects of long-term maternal fructose intake in rat offspring.

BACKGROUND: Previous studies have indicated an association between maternal metabolic conditions and general developmental disturbances of the offspring. OBJECTIVE: We aimed to investigate the influence of long-term maternal fructose intake during gestation and lactation on neurobehavioral development of rat offspring. METHODS: Twelve female Sprague Dawley rats were received either 30% fructose enriched water (n = 6) or regular tap water (control, n = 6) for 12 weeks. Then, control and fructose-received females were caged with a fertile male, and received 30% fructose and regular chow throughout pregnancy, delivery and until offspring's weaning. On P21, forty littermates (10 male control, 10 female control, 10 male fructose and 10 female fructose) were separated and housed with ad libitum access to standard food and tap water. Following behavioral evaluations at P50, brain levels of TNF-α, neuregulin 1 (NRG1), glutamic acid decarboxylase 67 (GAD67), nerve growth factor (NGF), insulin-like growth factor 1 (IGF-1), and 5-hydroxyindoleacetic acid (5-HIAA) were measured. Histologically, hippocampal neuronal density and GFAP expression were assessed. RESULTS: Analysis of the behavioral tests (three-chamber social test, open field test, passive avoidance learning test and stereotypy test) revealed significant differences among the groups. Histologically, hippocampal CA1 and CA3 regions displayed significant alterations such as gliosis and neuronal cell death in fructose-exposed groups compare to controls. Biochemical measurements of the brain levels of TNF-α and neurodevelopmental markers showed significant differences between controls and fructose-exposed groups. CONCLUSION: These results suggest a possible link between the chronic maternal metabolic stress, such as long-term fructose intake, and neurodevelopmental disturbances in the offspring.

Evaluation of long-term effects of artificial sweeteners on rat brain: a biochemical, behavioral, and histological study.

The aim of the present study was to compare the effects of artificial sweeteners (aspartame, saccharin, and sucralose) on rat brain. Twenty-four adult male Sprague-Dawley rats were included in the study. The control group (n = 6) received regular tap water, whereas other groups received aspartame (3 mg/kg/day, n = 6,) or saccharin (3 mg/kg/day, n = 6) or sucralose (1.5 mg/kg/day, n = 6) in the drinking water. Following 6 weeks, the passive avoidance learning (PAL) test was performed to evaluate the neurobehavioral effects of sweeteners. The brains were assessed for lipid peroxides, neuron count, and Glial fibrillary acidic protein (GFAP) immunohistochemistry. Our results demonstrated that chronic intake of sweeteners significantly impaired PAL performance in all groups. Hippocampal CA1-CA3 areas revealed significantly lower neuronal count in aspartame and increased GFAP expression in all groups. Brain lipid peroxides were significantly higher in all groups. Our findings suggest that long-term consumption of artificial sweeteners may have harmful effects on cognition and hippocampal integrity in rats.

Measurement of Pain in Multiple Sclerosis.

life is pain. It is important to determine the features and the measurement of pain. Common types of pain are described in multiple sclerosis. One-dimensional and multi-dimensional pain scales, which are also used in different painful diseases, are used in the measurement of these pain. Scoring and recording in one-dimensional pain scales are easy and a better measurement is achieved in acute pain. However, the disadvantage of these scales is that they do not give detailed information about the nature of the pain. Multidimensional pain scales are used in chronic and complex pain. Multidimensional scales have some disadvantage about application by patients because of complexity. The development of specific scales for the better measurement of pain in multiple sclerosis is important for the effective treatment of pain in patients.