Chronic Variable Stress Is Responsible for Lipid and DNA Oxidative Disorders and Activation of Oxidative Stress Response Genes in the Brain of Rats

Abstract

Chronic environmental stress is associated with reactive oxygen species (ROS) overproduction and the pathogenesis of depression. The purpose of this study was to evaluate biochemical and molecular changes associated with ROS generation in the brains of rats submitted to chronic variable stress. Male Wistar rats (50–55 days old, weighing 200–250 g) were divided in two groups (n = 10): control and stressed. Rats in the stressed group were exposed to stress conditions for 40 days. The animals were decapitated and the brain samples were collected. In prefrontal cortex, we measured the following biochemical parameters: lipid peroxidation and concentration of glutathione—GSH, GSSG, GSH/GSSG ratio, glutathione peroxidase, and glutathione reductase activities. In the hippocampus marker of DNA, oxidative damage and expression of DNA-repairing genes (Ogg1, MsrA) and gene-encoding antioxidative transcriptional factor (Nrf2) were determined. The results demonstrate indirect evidence of ROS overproduction and presence of oxidative stress. They also reveal disruption of oxidative defense systems (decreased GR activity, diminished GSH/GSSG ratio, and decreased Nrf2 expression) and activation of the oxidative DNA repair system (increased Ogg1 and MsrA expression). Together, the presented data suggest that independent activation of oxidative stress response genes occurs in chronic variable stress conditions.

Altered expression of genes involved in brain energy metabolism as adaptive responses in rats exposed to chronic variable stress; changes in cortical level of glucogenic and neuroactive amino acids

“…Thus, the expression of glucose transporters can be raised in the brain as a response to an enhanced demand for glucose resulting in the support of energy metabolism. The research has shown that stress events have a significant impact on ROS generation in brain and it can cause an increase in energy demand (2,34). Repeated and unpredictable stress situations increase ROS generation, which can damage a variety of cell macromolecules, including those that constitute the electron transport system, therefore disrupting mitochondrial function (2,34,35).…”

“…The research has shown that stress events have a significant impact on ROS generation in brain and it can cause an increase in energy demand (2,34). Repeated and unpredictable stress situations increase ROS generation, which can damage a variety of cell macromolecules, including those that constitute the electron transport system, therefore disrupting mitochondrial function (2,34,35). It is possible that in chronic stress, we can observe a disturbance in energy production due to mitochondrial damage by excess ROS, which may activate signaling pathways involved in cellular adaptation to various types of stress.…”

“…Studies show that TFAM binds preferentially to oxidatively damaged DNA containing 8-oxoguanine (8-oxo-Gua), which is one of the most abundant DNA alterations induced by exposure to ROS (50). In our previous studies, we have shown a significant increase in AP-site accumulation in isolated DNA from the hippocampus of the rats subjected to CVS, which indicates an increase in oxidative damage of DNA (2). At the same time, we noticed upregulation of Ogg1 (the gene encodes the enzyme responsible for the excision of 8-oxoguanine) as increased efficiency of DNA repair.…”

“…To avoid predictability, rats were exposed to these stressors not at the same time each day. A specification has been presented in detail in part of our published study (2). In brief, two groups of rats, each consisted of 10 randomly selected animals, were used in the study.…”

“…Chronic or recurring stress is associated with overproduction of reactive oxygen species (ROS) and reactive nitrogen species (RNS), highly unstable molecules with unpaired electrons, leading to oxidative stress and development of depression through various biological change (1)(2)(3). Oxidative stress causes progressive oxidative damage to lipids, proteins and DNA in neurons and impairs synaptic function.…”