Samina Salim

Depression, anxiety-like behavior and memory impairment are associated with increased oxidative stress and inflammation in a rat model of social stress

In the present study, we have examined the behavioral and biochemical effect of induction of psychological stress using a modified version of the resident-intruder model for social stress (social defeat). At the end of the social defeat protocol, body weights, food and water intake were recorded, depression and anxiety-like behaviors as well as memory function was examined. Biochemical analysis including oxidative stress measurement, inflammatory markers and other molecular parameters, critical to behavioral effects were examined. We observed a significant decrease in the body weight in the socially defeated rats as compared to the controls. Furthermore, social defeat increased anxiety-like behavior and caused memory impairment in rats (P<0.05). Socially defeated rats made significantly more errors in long term memory tests (P<0.05) as compared to control rats. Furthermore, brain extracellular signal-regulated kinase-1/2 (ERK1/2), and an inflammatory marker, interleukin (IL)-6 were activated (P<0.05), while the protein levels of glyoxalase (GLO)-1, glutathione reductase (GSR)-1, calcium/calmodulin-dependent protein kinase type (CAMK)-IV, cAMP-response-element-binding protein (CREB) and brain-derived neurotrophic factor (BDNF) were significantly less (P<0.05) in the hippocampus, but not in the prefrontal cortex and amygdala of socially defeated rats, when compared to control rats. We suggest that social defeat stress alters ERK1/2, IL-6, GLO1, GSR1, CAMKIV, CREB, and BDNF levels in specific brain areas, leading to oxidative stress-induced anxiety-depression-like behaviors and as well as memory impairment in rats.

Exercise prevents sleep deprivation-associated anxiety-like behavior in rats: Potential role of oxidative stress mechanisms

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.

Moderate treadmill exercise prevents oxidative stress-induced anxiety-like behavior in rats.

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.

Binding of amyloid β-peptide to mitochondrial hydroxyacyl-CoA dehydrogenase (ERAB): regulation of an SDR enzyme activity with implications for apoptosis in Alzheimer’s disease

The intracellular amyloid β‐peptide (Aβ) binding protein, ERAB, a member of the short‐chain dehydrogenase/reductase (SDR) family, is known to mediate apoptosis in different cell lines and to be a class II hydroxyacyl‐CoA dehydrogenase. The Aβ peptide inhibits the enzymatic reaction in a mixed type fashion with a K i of 1.2 μmol/l and a K iES of 0.3 μmol/l, using 3‐hydroxybutyryl‐CoA. The peptide region necessary for inhibition comprises residues 12–24 of Aβ1–40, covering the 16–20 fragment, which is the minimum sequence for the blockade of Aβ polymerization, but that minimal fragment is not sufficient for more than marginal inhibition. The localization of ERAB to the endoplasmic reticulum and mitochondria suggests a complex interaction with components of the programmed cell death machinery. The interaction of Aβ with ERAB further links oxidoreductase activity with both apoptosis and amyloid toxicity.

Oxidative Stress: A Potential Recipe For Anxiety, Hypertension and Insulin Resistance

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.

Chronic nicotine restores normal Aβ levels and prevents short-term memory and E-LTP impairment in Aβ rat model of Alzheimer's disease

Alzheimers disease (AD) is a devastating neurodegenerative disorder characterized by increased deposition of beta-amyloid (Aβ) peptides and progressive cholinergic dysfunction in regions of the brain involved in learning and memory processing. In AD, progressive accumulation of Aβ peptide impairs nicotinic acetylcholine receptor (nAChR) function by an unknown mechanism believed to involve α(7)- and α(4)β(2)-nAChR blockade. The three approaches of the current study evaluated the effects of chronic nicotine treatment in the prevention of Aβ-induced impairment of learning and short-term memory. Rat AD model was induced by 14-day i.c.v. osmotic pump infusion of a 1:1 mixture of 300 pmol/day Aβ(1-40)/Aβ(1-42) or Aβ(40-1) (inactive peptide, control). The effect of nicotine (2 mg/(kg day)) on Aβ-induced spatial learning and memory impairments was assessed by evaluation of performance in the radial arm water maze (RAWM), in vivo electrophysiological recordings of early-phase long-term potentiation (E-LTP) in urethane-anesthetized rats, and immunoblot analysis to determine changes in the levels of beta-site amyloid precursor protein (APP)-cleaving enzyme (BACE), Aβ and memory-related proteins. The results indicate that 6 weeks of nicotine treatment reduced the levels of Aβ(1-40) and BACE1 peptides in hippocampal area CA1 and prevented Aβ-induced impairment of learning and short-term memory. Chronic nicotine also prevented the Aβ-induced inhibition of basal synaptic transmission and LTP in hippocampal area CA1. Furthermore, chronic nicotine treatment prevented the Aβ-induced reduction of α(7)- and α(4)-nAChR. These effects of nicotine may be due, at least in part, to upregulation of brain derived neurotropic factor (BDNF).

Oxidative stress and psychological disorders.

Oxidative stress is an imbalance between cellular production of reactive oxygen species and the counteracting antioxidant mechanisms. The brain with its high oxygen consumption and a lipid-rich environment is considered highly susceptible to oxidative stress or redox imbalances. Therefore, the fact that oxidative stress is implicated in several mental disorders including depression, anxiety disorders, schizophrenia and bipolar disorder, is not surprising. Although several elegant studies have established a link between oxidative stress and psychiatric disorders, the causal relationship between oxidative stress and psychiatric diseases is not fully determined. Another critical aspect that needs much attention and effort is our understanding of the association between cellular oxidative stress and emotional stress. This review examines some of the recent discoveries that link oxidative status with anxiety, depression, schizophrenia and bipolar disorder. A discussion of published results and questions that currently exist in the field regarding a causal relationship between oxidative and emotional stress is also provided.

Expanded substrate screenings of human and Drosophila type 10 17beta-hydroxysteroid dehydrogenases (HSDs) reveal multiple specificities in bile acid and steroid hormone metabolism: characterization of multifunctional 3alpha/7alpha/7beta/17beta/20beta/21-HSD.

17beta-hydroxysteroid dehydrogenases (17beta-HSDs) catalyse the conversion of 17beta-OH (-hydroxy)/17-oxo groups of steroids, and are essential in mammalian hormone physiology. At present, eleven 17beta-HSD isoforms have been defined in mammals, with different tissue-expression and substrate-conversion patterns. We analysed 17beta-HSD type 10 (17beta-HSD10) from humans and Drosophila, the latter known to be essential in development. In addition to the known hydroxyacyl-CoA dehydrogenase, and 3alpha-OH and 17beta-OH activities with sex steroids, we here demonstrate novel activities of 17beta-HSD10. Both species variants oxidize the 20beta-OH and 21-OH groups in C21 steroids, and act as 7beta-OH dehydrogenases of ursodeoxycholic or isoursodeoxycholic acid (also known as 7beta-hydroxylithocholic acid or 7beta-hydroxyisolithocholic acid respectively). Additionally, the human orthologue oxidizes the 7alpha-OH of chenodeoxycholic acid (5beta-cholanic acid, 3alpha,7alpha-diol) and cholic acid (5beta-cholanic acid). These novel substrate specificities are explained by homology models based on the orthologous rat crystal structure, showing a wide hydrophobic cleft, capable of accommodating steroids in different orientations. These properties suggest that the human enzyme is involved in glucocorticoid and gestagen catabolism, and participates in bile acid isomerization. Confocal microscopy and electron microscopy studies reveal that the human form is localized to mitochondria, whereas Drosophila 17beta-HSD10 shows a cytosolic localization pattern, possibly due to an N-terminal sequence difference that in human 17beta-HSD10 constitutes a mitochondrial targeting signal, extending into the Rossmann-fold motif.

Moderate treadmill exercise rescues anxiety and depression-like behavior as well as memory impairment in a rat model of posttraumatic stress disorder.

Post-traumatic stress disorder (PTSD) is a condition which can develop from exposure to a severe traumatic event such as those occurring during wars or natural disasters. Benzodiazepines and selective serotonin reuptake inhibitors (SSRIs) are considered the gold standard for PTSD treatment, but their side effects pose a serious problem. While regular physical exercise is regarded as a mood elevator and known to enhance cognitive function, its direct role in rescuing core symptoms of PTSD including anxiety and depression-like behaviors and cognitive impairment is unclear. In the present study using the single-prolonged stress (SPS) rat model of PTSD (2h restrain, 20 min forced swimming, 15 min rest, and 1-2 min diethyl ether exposure), we examined the beneficial effect of moderate treadmill exercise on SPS-induced behavioral deficits including anxiety and depression-like behaviors and memory impairment. Male Wistar rats were randomly assigned into four groups: control (sedentary), exercised, SPS (no exercise), or SPS-exercised. Rats were exercised on a rodent treadmill for 14 consecutive days. Rats in all groups were tested for anxiety-like behaviors using open field (OF), light-dark and elevated-plus maze tests. All rats were tested for short-term and long-term memory in the radial arm water maze test. Rats were then sacrificed, blood was collected (for corticosterone levels), and individual organs (spleen, adrenals, and thymus) harvested. Results suggest that moderate physical exercise ameliorates SPS-induced behavioral deficits in rats.

Potential Contribution of Oxidative Stress and Inflammation to Anxiety and Hypertension

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.