Current Neuropharmacology (v.12, #2)

Editorial: Neurobiological Consequences of Oxidative Stress. by Karim Alkadhi, Samina Salim (99-99).

Glucocorticoid Regulates Parkin Expression in Mouse Frontal Cortex: Implications in Schizophrenia by Chirayu D. Pandya, Amanda Crider, Anilkumar Pillai (100-107).
Stress and glucocorticoid hormones, which are released into the circulation following stressful experiences,have been shown to contribute significantly to the manifestation of various psychiatric illnesses including schizophreniaand depression. Studies in rodents have reported dose and time dependent effects of glucocorticoids on the expression ofproteins related to neuroplasticity. However, the mechanism(s) involved in the regulation of proteins by glucocorticoidsare not clear. Ubiquitin ligases play important role in degradation, trafficking and stabilization of proteins. The presentstudy investigated the effect of glucocorticoid on ubiquitin-proteasome system in mouse frontal cortex. A significantincrease in mRNA and protein levels of parkin, an E3 ubiquitin ligase was found in cultured mouse primary corticalneurons following corticosterone treatment. An increase in parkin levels was also found in mouse frontal cortex in vivofollowing acute dexamethasone treatment. However, chronic treatment with corticosterone did not change parkin proteinlevels in mouse frontal cortex. Studies using postmortem brain samples from schizophrenia and control subjects indicateda significant increase in parkin protein levels in frontal cortex of schizophrenia subjects suggesting a response to increasedstress conditions in schizophrenia. These findings suggest a possible role of parkin in the pathophysiology of stress-relatedpsychiatric disorders.

Novel Therapeutic Targets in Depression and Anxiety: Antioxidants as a Candidate Treatment by Ying Xu, Chuang Wang, Jonathan J. Klabnik, James M. O' Donnell (108-119).
There is growing evidence that the imbalance between oxidative stress and the antioxidant defense system maybe associated with the development neuropsychiatric disorders, such as depression and anxiety. Major depression andanxiety are presently correlated with a lowered total antioxidant state and by an activated oxidative stress (OS) pathway.The classical antidepressants may produce therapeutic effects other than regulation of monoamines by increasing theantioxidant levels and normalizing the damage caused by OS processes. This chapter provides an overview of recent workon oxidative stress markers in the animal models of depression and anxiety, as well as patients with the aforementionedmood disorders. It is well documented that antioxidants can remove the reactive oxygen species (ROS) and reactivenitrogen species (RNS) through scavenging radicals and suppressing the OS pathway, which further protect againstneuronal damage caused oxidative or nitrosative stress sources in the brain, hopefully resulting in remission of depressionor anxiety symptoms. The functional understanding of the relationship between oxidative stress and depression andanxiety may pave the way for discovery of novel targets for treatment of neuropsychiatric disorders.

Association of Oxidative Stress to the Genesis of Anxiety: Implications for Possible Therapeutic Interventions by Waseem Hassan, Carlos Eduardo Barroso Silva, Imdad Ullah Mohammadzai, Joao Batista Teixeira da Rocha, J. Landeira-Fernandez (120-139).
Oxidative stress caused by reactive species, including reactive oxygen species, reactive nitrogen species, andunbound, adventitious metal ions (e.g., iron [Fe] and copper [Cu]), is an underlying cause of various neurodegenerativediseases. These reactive species are an inevitable by-product of cellular respiration or other metabolic processes that maycause the oxidation of lipids, nucleic acids, and proteins. Oxidative stress has recently been implicated in depression andanxiety-related disorders. Furthermore, the manifestation of anxiety in numerous psychiatric disorders, such as generalizedanxiety disorder, depressive disorder, panic disorder, phobia, obsessive-compulsive disorder, and posttraumatic stressdisorder, highlights the importance of studying the underlying biology of these disorders to gain a better understanding ofthe disease and to identify common biomarkers for these disorders. Most recently, the expression of glutathione reductase1 and glyoxalase 1, which are genes involved in antioxidative metabolism, were reported to be correlated with anxietyrelatedphenotypes. This review focuses on direct and indirect evidence of the potential involvement of oxidative stress inthe genesis of anxiety and discusses different opinions that exist in this field. Antioxidant therapeutic strategies are alsodiscussed, highlighting the importance of oxidative stress in the etiology, incidence, progression, and prevention ofpsychiatric disorders.

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

The autistic spectrum disorders (ASD) form a set of multi-faceted disorders with significant genetic, epigeneticand environmental determinants. Oxidative and nitrosative stress (O&NS), immuno-inflammatory pathways,mitochondrial dysfunction and dysregulation of the tryptophan catabolite (TRYCATs) pathway play significantinteractive roles in driving the early developmental etiology and course of ASD. O&NS interactions with immunoinflammatorypathways mediate their effects centrally via the regulation of astrocyte and microglia responses, includingregional variations in TRYCATs produced. Here we review the nature of these interactions and propose an earlydevelopmental model whereby different ASD genetic susceptibilities interact with environmental and epigeneticprocesses, resulting in glia biasing the patterning of central interarea interactions. A role for decreased local melatonin andN-acetylserotonin production by immune and glia cells may be a significant treatment target.

Myalgic Encephalomyelitis (ME) / Chronic Fatigue Syndrome (CFS) has been classified as a disease of thecentral nervous system by the WHO since 1969. Many patients carrying this diagnosis do demonstrate an almostbewildering array of biological abnormalities particularly the presence of oxidative and nitrosative stress (O&NS) and achronically activated innate immune system. The proposal made herein is that once generated chronically activated O&NSand immune-inflammatory pathways conspire to generate a multitude of self-sustaining and self-amplifying pathologicalprocesses which are associated with the onset of ME/CFS. Sources of continuous activation of O&NS and immuneinflammatorypathways in ME/CFS are chronic, intermittent and opportunistic infections, bacterial translocation,autoimmune responses, mitochondrial dysfunctions, activation of the Toll-Like Receptor Radical Cycle, and decreasedantioxidant levels. Consequences of chronically activated O&NS and immune-inflammatory pathways in ME/CFS arebrain disorders, including neuroinflammation and brain hypometabolism / hypoperfusion, toxic effects of nitric oxide andperoxynitrite, lipid peroxidation and oxidative damage to DNA, secondary autoimmune responses directed againstdisrupted lipid membrane components and proteins, mitochondrial dysfunctions with a disruption of energy metabolism(e.g. compromised ATP production) and dysfunctional intracellular signaling pathways. The interplay between all of thesefactors leads to self-amplifying feed forward loops causing a chronic state of activated O&NS, immune-inflammatory andautoimmune pathways which may sustain the disease.

Metformin Eased Cognitive Impairment Induced by Chronic L-methionine Administration: Potential Role of Oxidative Stress by Karem. H. Alzoubi, Omar. F. Khabour, Sayer I. Al-azzam, Murad H. Tashtoush, Nizar M. Mhaidat (186-192).
Chronic administration of L-methionine leads to memory impairment, which is attributed to increase in thelevel of oxidative stress in the brain. On the other hand, metformin is a commonly used antidiabetic drug with strongantioxidant properties. In the current study, we tested if chronic metformin administration prevents memory impairmentinduced by administration of L-methionine. In addition, a number of molecules related to the action of metformin oncognitive functions were examined. Both metformin and L-methionine were administered to animals by oral gavage.Testing of spatial learning and memory was carried out using radial arm water maze (RAWM). Additionally, hippocampallevels or activities of catalase, thiobarbituric acid reactive substances (TBARs), glutathione peroxidase (GPx), glutathione(GSH), oxidized glutathione (GSSG) and GSH/GSSG ratio were determined. Results showed that chronic L-methionineadministration resulted in both short- and long- term memory impairment, whereas metformin treatment prevented sucheffect. Additionally, L-methionine treatment induced significant elevation in GSSG and TBARs, along with reduction inGSH/GSSG ratio and activities of catalase, and GPx. These effects were shown to be restored by metformin treatment. Inconclusion, L-methionine induced memory impairment, and treatment with metformin prevented this impairmentprobably by normalizing oxidative stress in the hippocampus.

Oxidative Imbalance and Anxiety Disorders by R. Krolow, D. M. Arcego, C. Noschang, S. N. Weis, C. Dalmaz (193-204).
The oxidative imbalance appears to have an important role in anxiety development. Studies in both humans andanimals have shown a strong correlation between anxiety and oxidative stress. In humans, for example, the increasedmalondialdehyde levels and discrepancies in antioxidant enzymes in erythrocytes have been observed. In animals, severalstudies also show that anxiety-like behavior is related to the oxidative imbalance. Moreover, anxiety-like behavior can becaused by pharmacological-induced oxidative stress. Studies using knockout or overexpression of antioxidant enzymeshave shown a relationship between anxiety-like behavior and oxidative stress. Related factors of oxidative stress thatcould influence anxious behavior are revised, including impaired function of different mitochondrial proteins,inflammatory cytokines, and neurotrophic factors. It has been suggested that a therapy specifically focus in reducingreactive species production may have a beneficial effect in reducing anxiety. However, the neurobiological pathwaysunderlying the effect of oxidative stress on anxiety symptoms are not fully comprehended. The challenge now is toidentify the oxidative stress mechanisms likely to be involved in the induction of anxiety symptoms. Understanding thesepathways could help to clarify the neurobiology of the anxiety disorder and provide tools for new discovery in therapiesand preventive strategies.

Stress initiates a cascade of complex neural and peripheral changes that promote healthy adaption to stress, butwhen unabated, leads to pathology. Fascinating individual differences arise in the ability to cope with a stressor, renderingan individual more or less likely to develop stress-induced pathologies such as depression, anxiety, and cardiovasculardisease. In this review we evaluate recent findings that investigate the neural underpinnings of adopting a passive or activecoping response during social defeat stress. Because passive coping is associated with vulnerability to stress-relatedpathologies and active coping confers resiliency, understanding neurobiological adaptations associated with these diversecoping strategies may reveal biomarkers or targets impacting stress susceptibility. The co-occurrence of stress-induceddepression and cardiovascular disease is becoming increasingly clear. Therefore this review focuses on the centralmechanisms capable of contributing to psychopathology and cardiovascular disease such as corticotropin releasing factor,neuropeptide Y, monoamines, cytokines and oxidative stress. The impetus for this review is to highlight neurobiologicalsystems that warrant further evaluation for their contribution to the pathophysiology of depression-cardiovascular diseasecomorbidity.