[Show abstract][Hide abstract] ABSTRACT: Previously, we have published that pharmacological induction of oxidative stress causes anxiety-like behavior in rats and also is associated with hypertension in these animals. Here, we report that sub-chronic induction of oxidative stress via pharmacological induction leads to i) reduction in glyoxalase (GLO)-1 and glutathione reductase (GSR)-1 expression; ii) calpain mediated reduction of brain derived neurotrophic factor (BDNF) levels; iii) NFκB mediated upregulation of proinflammatory factors interleukin (IL)-6 and tumor necrosis factor (TNF)-α and elevated angiotensin (AT)-1 receptor levels in hippocampus, amygdala and locus coeruleus regions of the brain. Acute oxidative stress has opposite effects. We speculate that regulation of GLO1, GSR1, BDNF, NFκB and AT-1 receptor may contribute to anxiety-like behavior and hypertension in rats.
[Show abstract][Hide abstract] ABSTRACT: Our previous work suggests that pharmacological induction of oxidative stress causes anxiety-like behavior in rats. Interestingly, sleep deprivation is reported to cause oxidative damage in the brain and is also reported to be anxiogenic. Minimal mechanistic insights are available. In this study, using a behavioral and biochemical approach, we investigated involvement of oxidative stress mechanisms in sleep deprivation-induced anxiety-like behavior of rats and the protective role of treadmill exercise in this process. We report that acute sleep deprivation (SD) increases oxidative stress in the cortex, hippocampus and amygdala while prior treadmill exercise prevents this increase. Serum corticosterones also increase with SD but its levels are normalized in exercised sleep-deprived rats. Also, anxiety-like behavior of rats significantly increases with SD while prior treadmill exercise prevents this increase. Protein expression of two enzymes involved in antioxidant defense, glyoxalase (GLO)-1 and glutathione reductase (GSR)-1 increased after 24h SD in the hippocampus, cortex and amygdala while their levels were normalized in exercised sleep-deprived rats. It is plausible that oxidative stress via regulation of GLO1 and GSR1 is involved in sleep deprivation-induced anxiety-like behavior of rats.
Full-text · Article · May 2011 · Behavioural brain research
[Show abstract][Hide abstract] ABSTRACT: Regulator of G-protein signaling protein (RGS)-2 is a modulator of anxiety and dysregulation of oxidative stress is implicated in anxiety. Also, RGS2 expression is reported to be induced by oxidative stress. Thus, if oxidative stress induces RGS2 expression and lack of RGS2 causes anxiety, then mechanisms that link RGS2 and oxidative stress potentially critical to anxiety must be revealed. Our study is the first to suggest role of RGS2 in regulation of enzymes involved in antioxidant defense namely glyoxalase-1 and glutathione reductase-1 via activation of p38 MAPK and PKC pathways in an Sp-1 dependent manner.
[Show abstract][Hide abstract] ABSTRACT: Exposure of rats to unpredictable, inescapable stress results in two distinct behaviors during subsequent escape testing. One behavior, suggestive of lack of stress resilience, is prolonged escape latency compared to non-stressed rats and is labeled learned helplessness (LH). The other behavior suggestive of stress resilience is normal escape latency and is labeled non-helpless (NH). This study examines the effects of unpredictable, inescapable tail-shock stress (TSS) on alpha(2)-adrenoceptor (α(2A)-AR) and corticotropin-releasing factor 1 receptor (CRF(1)-R) regulation as well as protein levels of G protein-coupled receptor kinase 3 (GRK3), GRK2, tyrosine hydroxylase (TH) plus carbonylated protein levels in locus coeruleus (LC), amygdala (AMG), cortex (COR) and striatum (STR). In NH rats, α(2A)-AR and CRF(1)-R were significantly down-regulated in LC after TSS. No changes in these receptor levels were observed in the LC of LH rats. GRK3, which phosphorylates receptors and thereby contributes to α(2A)-AR and CRF(1)-R down-regulation, was reduced in the LC of LH but not NH rats. GRK2 levels were unchanged. In AMG, GRK3 but not GRK2 levels were reduced in LH but not NH rats, and receptor regulation was impaired in LH rats. In STR, no changes in GRK3 or GRK2 levels were observed. Finally, protein carbonylation, an index of oxidative stress, was increased in the LC and AMG of LH but not NH rats. We suggest that reduced stress resilience after TSS may be related to oxidative stress, depletion of GRK3 and impaired regulation of α(2A)-AR and CRF(1)-R in LC.
Full-text · Article · Feb 2011 · Behavioural brain research
[Show abstract][Hide abstract] ABSTRACT: We recently reported involvement of oxidative stress in anxiety-like behavior of rats. Others in separate studies have demonstrated a link between oxidative stress and hypertension as well as with type 2 diabetes/insulin resistance. In the present study, we have tested a putative role of oxidative stress in anxiety-like behavior, hypertension and insulin resistance using a rat model of oxidative stress. Oxidative stress in rats was produced by xanthine (0.1%; drinking water) and xanthine oxidase (5 U/kg; i.p.). X+XO-treated rats had increased plasma and urinary 8-isoprostane levels (a marker of oxidative stress) and increased malondialdehyde (MDA) levels in the hippocampus and amygdala as compared to control rats. Serum corticosterone (a systemic marker of stress and anxiety) levels also increased with X+XO treatment. Moreover, anxiety-like behavior measured via open-field and light-dark exploration behavior tests significantly increased in X+XO-treated rats. Mean arterial blood pressure measured in anesthetized rats increased in X+XO-treated compared to control rats. Furthermore, plasma insulin but not glucose levels together with homeostasis model assessment (HOMA), an index of insulin resistance, were higher in X+XO-treated rats. Our studies suggest that oxidative stress is a common factor that link anxiety-like behavior, hypertension and insulin resistance in rats.
[Show abstract][Hide abstract] ABSTRACT: Recent work has suggested correlation of oxidative stress with anxiety-like behavior. There also is evidence for anxiolytic effects of physical exercise. However, a direct role of oxidative stress in anxiety is not clear and a protective role of physical exercise in oxidative stress-mediated anxiety has never been addressed. In this study, we have utilized rats to test direct involvement of oxidative stress with anxiety-like behavior and have identified oxidative stress mechanisms likely involved in anxiolytic effects of physical exercise. Intraperitoneal injections at non-toxic dose of l-buthionine-(S,R)-sulfoximine (BSO), an agent that increases oxidative stress markers, increased anxiety-like behavior of rats compared to vehicle-treated control rats. Prior 2 weeks treatment with the antioxidant, tempol attenuated BSO-induced anxiety-like behavior of rats suggesting a role of oxidative stress in this phenomenon. Moreover, moderate treadmill exercise prevented BSO-induced anxiety-like behavior of rats and also prevented BSO-mediated increase in oxidative stress markers in serum, urine and brain tissue homogenates from hippocampus, amygdala and locus coeruleus. Thus increasing oxidative stress increases anxiety-like behavior of rats. Moreover, antioxidant or treadmill exercise training both reduce oxidative stress in the rat brain regions implicated in anxiety response and prevent anxiety-like behavior of rats.
Full-text · Article · Apr 2010 · Behavioural brain research
[Show abstract][Hide abstract] ABSTRACT: A polymorphism of the human alpha(2B)-adrenoceptor (Del(301-303)-alpha(2B)-adrenoceptor) has been described, and this receptor exhibits reduced G-protein-coupled receptor kinase (GRK) phosphorylation and impaired short-term desensitization. Expression of the Del(301-303)-alpha(2B)-adrenoceptor also is associated with an increased risk for myocardial infarction in humans. Recent evidence from our laboratory suggests a quantitative relationship between cellular GRK3 expression levels and the sensitivity of the alpha(2B)-adrenoceptor to agonist-induced down-regulation. Therefore, the present study was undertaken to study agonist-induced down-regulation of the wild-type (WT)- and Del(301-303)-alpha(2B)-adrenoceptor in a neuronal cell model.
Haemagglutinin (HA) epitope-tagged WT- and Del(301-303)-alpha(2B)-adrenoceptor containing plasmids were constructed and the receptors were stably or transiently transfected in neuroblastoma/glioma hybrid NG108 cells. The expression levels in stable transfects were approximately 50 fmol x mg(-1). These cells were used to examine agonist-induced down-regulation and phosphorylation of the WT- and Del(301-303)-alpha(2B)-adrenoceptor.
The Del(301-303)-alpha(2B)-adrenoceptor, compared with the WT-alpha(2B-)adrenoceptor, displayed reduced adrenaline-stimulated (20 microM) phosphorylation and did not down-regulate in response to adrenaline (20-1000 microM). Using immunofluorescence labelling, we observed that transiently transfected WT-alpha(2B)-adrenoceptors internalized upon adrenaline treatment whereas the Del(301-303)-alpha(2B)-adrenoceptor did not. Finally, we determined the effect of adrenaline on the Del(301-303)-alpha(2B)-adrenoceptor in cells stably over-expressing GRK3 3-fold. In spite of the GRK3 over-expression, 20-1000 microM ADR failed to down-regulate or to increase phosphorylation of the Del(301-303)-alpha(2B)-adrenoceptor in these cells.
The results suggest that the 301-303 deletion mutation of the alpha(2B)-adrenoceptor eliminates agonist-induced down-regulation, an effect that cannot be overcome by increasing agonist concentration or by modest GRK3 over-expression.
Full-text · Article · Oct 2009 · British Journal of Pharmacology