Neuroglia of the central nervous system (CNS), represented by cells of neural (astrocytes, oligodendrocytes and NG2 glial cells) and myeloid (microglia) origins are fundamental for homeostasis of the nervous tissue. Astrocytes are critical for the development of the CNS, they are indispensable for synaptogenesis, and they define structural organisation of the nervous tissue, as well as the generation and maintenance of CNS-blood and cerebrospinal fluid-blood barriers. Astroglial cells control homeostasis of ions and neurotransmitters and provide neurones with metabolic support. Oligodendrocytes, through the process of myelination, as well as by homoeostatic support of axons provide for interneuronal connectivity. The NG2 cells receive direct synaptic inputs, and might be important elements of adult remyelination. Microglial cells, which originate from foetal macrophages invading the brain early in embryogenesis, shape the synaptic connections through removing of redundant synapses and phagocyting apoptotic neurones. Neuroglia also form the defensive system of the CNS through complex and context-specific programmes of activation, known as reactive gliosis. Many neurological diseases are associated with neurogliopathologies represented by asthenic and atrophic changes in glial cells that, through the loss or diminution of their homeostatic and defensive functions, assist evolution of pathology. Conceptually, neurological and psychiatric disorders can be regarded as failures of neuroglial homeostatic/
defensive responses, and, hence, glia represent a (much underappreciated) target for therapeutic intervention.
Astrocyte; microglia; neurodegeneration; neuroglia; neurological diseases; NG-2 cells; oligodendrocyte; psychiatric diseases; therapy.
Brain edema is a serious complication in ischemic stroke because even relatively small changes in brain volume can compromise cerebral blood flow or result in compression of vital brain structures on account of the fixed volume of the rigid skull. Literature data indicate that administration of either antagonists of the V1 vasopressin (AVP) receptor or the β1-adrenergic receptor are able to reduce edema or infarct size when administered after the onset of ischemia, a key advantage for possible clinical use. The present review discusses possible mechanisms, focusing on the role of NKCC1, an astrocytic cotransporter of Na+, K+, 2Cl- and water and its activation by highly increased extracellular K+ concentrations in the development of cytotoxic cell swelling. However, it also mentions that due to a 3/2 ratio between Na+ release and K+ uptake by the Na+,K+-ATPase driving NKCC1 brain extracellular fluid can become hypertonic, which may facilitate water entry across the blood-brain barrier, essential for development of edema. It shows that brain edema does not develop until during reperfusion, which can be explained by lack of metabolic energy during ischemia. V1 antagonists are likely to protect against cytotoxic edema formation by inhibiting AVP enhancement of NKCC1-mediated uptake of ions and water, whereas β1-adrenergic antagonists prevent edema formation because β1-adrenergic stimulation alone is responsible for stimulation of the Na+,K+-ATPase driving NKCC1, first and foremost due to decrease in extracellular Ca2+ concentration. Inhibition of NKCC1 also has adverse effects, e.g. on memory and the treatment should probably be of shortest possible duration.
Astrocyte; β1-adrenoceptor; brain edema; MCAO; memory; Na+; K+-ATPase; NKCC1; vasopressin.
Liver failure can lead to generalized hyperammonemia, which is thought to be the underlying cause of hepatic encephalopathy. This neuropsychiatric syndrome is accompanied by functional changes of astrocytes. These glial cells enter ammonia-induced self-amplifying cycle characterized by brain oedema, oxidative and osmotic stress that causes modification of proteins and RNA. Consequently, protein expression and function are affected, including that of glutamine synthetase and plasmalemmal glutamate transporters, leading to glutamate excitotoxicity; Ca2+-dependent exocytotic glutamate release from astrocytes contributes to this extracellular glutamate overload.
Astrocytes; exocytosis; glutamate release; hepatic encephalopathy.
The causal role of ammonium in hepatic encephalopathy was identified in 1930s. Astroglial cells are primary cellular elements of hepatic encephalopathy which conceptually, can be considered a toxic astrogliopathology. Previously we have reported that acute exposure to ammonium activated ouabain/Na,K-ATPase signalling pathway, which includes Src, EGF receptor, Raf, Ras, MEK and ERK1/2. Chronic incubation of astrocytes with ammonium increased production of endogenous ouabain-like compound. Ouabain antagonist canrenone abolished effects of ammonium on astrocytic swelling, ROS production, and upregulation of gene expression and function of TRPC1 and Cav1.2. However, ammonium induces multiple pathological modifications in astrocytes, and some of them may be not related to this signalling pathway. In this review, we focus on the effect of ammonium on ouabain/Na,K-ATPase signalling pathway and its involvement in ammonium-induced ROS production, cell swelling and aberration of Ca2+ signals in astrocytes. We also briefly discuss Na,K-ATPase, EGF receptor, endogenous ouabain and ouabain antagonist.
Ammonium; astrocytes; canrenone; Na; K-ATPase; ouabain.
It has been known for many years that the endogenous neurotransmitter noradrenaline (NA) exerts anti-inflammatory and neuroprotective effects both in vitro and in vivo. In many cases the site of action of NA are beta-adrenergic receptors (βARs), causing an increase in intracellular levels of cAMP which initiates a broad cascade of events including suppression of inflammatory transcription factor activities, alterations in nuclear localization of proteins, and induction of patterns of gene expression mediated through activity of the CREB transcription factor. These changes lead not only to reduced inflammatory events, but also contribute to neuroprotective actions of NA by increasing expression of neurotrophic substances including BDNF, GDNF, and NGF. These properties have prompted studies to determine if treatments with drugs to raise CNS NA levels could provide benefit in various neurological conditions and diseases having an inflammatory component. Moreover, increasing evidence shows that disruptions in endogenous NA levels occurs in several diseases and conditions including Alzheimer’s disease (AD), Parkinson’s disease (PD), Down’s syndrome, posttraumatic stress disorder (PTSD), and multiple sclerosis (MS), suggesting that damage to NA producing neurons is a common factor that contributes to the initiation or progression of neuropathology. Methods to increase NA levels, or to reduce damage to noradrenergic neurons, therefore represent potential preventative as well as therapeutic approaches to disease.
Alzheimer’s disease; amyloid; review; EAE; GFAP; locus coeruleus; multiple sclerosis; noradrenaline; transgenic mice; tyrosine hydroxylase.
It is generally assumed that the neuropathology of sporadic (late-onset or nonfamilial) Alzheimer’s disease (AD) is driven by the overproduction and spreading of first Amyloid-βx-42 (Aβ42) and later hyperphosphorylated (hp)-Tau oligomeric “infectious seeds”. Hitherto, only neurons were held to make and spread both oligomer types; astrocytes would just remove debris. However, we have recently shown that exogenous fibrillar or soluble Aβ peptides specifically bind and activate the Ca2+-sensing receptors (CaSRs) of untransformed human cortical adult astrocytes and postnatal neurons cultured in vitro driving them to produce, accrue, and secrete surplus endogenous Aβ42. While the Aβ-exposed neurons start dying, astrocytes survive and keep oversecreting Aβ42, nitric oxide (NO), and vascular endothelial growth factor (VEGF)-A. Thus astrocytes help neurons’ demise. Moreover, we have found that a highly selective allosteric CaSR agonist (“calcimimetic”), NPS R-568, mimics the just mentioned neurotoxic actions triggered by Aβ●CaSR signaling. Contrariwise, and most important, NPS 2143, a highly selective allosteric CaSR antagonist (“calcilytic”), fully suppresses all the Aβ●CaSR signaling-driven noxious actions. Altogether our findings suggest that the progression of AD neuropathology is promoted by unceasingly repeating cycles of accruing exogenous Aβ42 oligomers interacting with the CaSRs of swelling numbers of astrocyte-neuron teams thereby recruiting them to overrelease additional Aβ42 oligomers, VEGF-A, and NO. Calcilytics would beneficially break such Aβ/CaSR-driven vicious cycles and hence halt or at least slow the otherwise unstoppable spreading of AD neuropathology
Alzheimer’s disease; amyloid-beta oligomers; astrocyte-neuron teams; calcium-sensing receptor; calcilytics; calcimimetics.
Fluoxetine and other serotonin-specific re-uptake inhibitors (SSRIs) are generally thought to owe their therapeutic potency to inhibition of the serotonin transporter (SERT). However, research in our laboratory showed that it affects, with relatively high affinity the 5-HT2B receptor in cultured astrocytes; this finding was confirmed by independent observations showing that fluoxetine loses its ability to elicit SSRI-like responses in behavioral assays in mice in which the 5-HT2B receptor was knocked-out genetically or inhibited pharmacologically. All clinically used SSRIs are approximately equipotent towards 5-HT2B receptors and exert their effect on cultured astrocytes at concentrations similar to those used clinically, a substantial difference from their effect on SERT. We have demonstrated up-regulation and editing of astrocytic genes for ADAR2, the kainate receptor GluK2, cPLA2 and the 5-HT2B receptor itself after chronic treatment of cultures, which do not express SERT and after treatment of mice (expressing SERT) for 2 weeks with fluoxetine, followed by isolation of astrocytic and neuronal cell fractionation. Affected genes were identical in both experimental paradigms. Fluoxetine treatment also altered Ca2+ homeostatic cascades, in a specific way that differs from that seen after treatment with the anti-bipolar drugs carbamazepine, lithium, or valproic acid. All changes occurred after a lag period similar to what is seen for fluoxetine’s clinical effects, and some of the genes were altered in the opposite direction by mild chronic inescapable stress, known to cause anhedonia, a component of major depression. In the anhedonic mice these changes were reversed by treatment with SSRIs.
Astrocytes; gene expression; 5-HT2A receptor; 5-HT2B receptor; SSRIs.
Diabetic retinopathy (DR) is one of the major complications of diabetes causing vision loss and blindness worldwide. DR is widely recognized as a neurodegenerative disease as evidenced from early changes at cellular and molecular levels in the neuronal component of the diabetic retina, which is further supported by various retinal functional tests indicating functional deficits in the retina soon after diabetes progression. Diabetes alters the level of a number of neurodegenerative metabolites, which increases influx through several metabolic pathways which in turn induce an increase in oxidative stress and a decrease in neurotrophic factors, thereby damage retinal neurons. Loss of neurons may implicate in vascular pathology, a clinical signs of DR observed at later stages of the disease. Here, we discuss diabetes-induced potential metabolites known to be detrimental to neuronal damage and their mechanism of action. In addition, we highlight important neurotrophic factors, whose level have been found to be dysregulated in diabetic retina and may damage neurons. Furthermore, we discuss potential drugs and strategies based on targeting diabetes-induced metabolites, metabolic pathways, oxidative stress, and neurotrophins to protect retinal neurons, which may ameliorate vision loss and vascular damage in DR.
Metabolites; neurodegeneration; neurotrophic factor; neurons; retina.
Serine/threonine protein kinase C-related kinase (PKN/PRK) is a family of three isoenzymes (PKN1, PKN2,
PKN3), which are widely distributed in eukaryotic organisms and share the same overall domain structure. The Nterminal
region encompasses a conserved repeated domain, termed HR1a-c as well as a HR2/C2 domain. The
serine/threonine kinase domain is found in the C-terminal region of the protein and shows high sequence homology to
other members of the PKC superfamily.
In neurons, PKN1 is the most abundant isoform and has been implicated in a variety of functions including cytoskeletal
organization and neuronal differentiation and its deregulation may contribute to neuropathological processes such as
amyotrophic lateral sclerosis and Alzheimer’s disease. We have recently identified a candidate role of PKN1 in the
regulation of neuroprotective processes during hypoxic stress. Our key findings were that: 1) the activity of PKN1 was
significantly increased by hypoxia (1% O2) and neurotrophins (nerve growth factor and purine nucleosides); 2) Neuronal
cells, deficient of PKN1 showed a decrease of cell viability and neurite formation along with a disturbance of the F-actinassociated
cytoskeleton; 3) Purine nucleoside-mediated neuroprotection during hypoxia was severely hampered in PKN1
deficient neuronal cells, altogether suggesting a potentially critical role of PKN1 in neuroprotective processes.
This review gives an up-to-date overview of the PKN family with a special focus on the neuroprotective role of PKN1 in
Hypoxia; neuroprotection; PKN; PRK; protein kinase C-related kinase; purine nucleosides; review.
Schizophrenia is one of the most debilitating psychiatric diseases with a lifetime prevalence of approximately
1%. Although the specific molecular underpinnings of schizophrenia are still unknown, evidence has long linked its
pathophysiology to postsynaptic abnormalities.
The postsynaptic density (PSD) is among the molecular structures suggested to be potentially involved in schizophrenia.
More specifically, the PSD is an electron-dense thickening of glutamatergic synapses, including ionotropic and
metabotropic glutamate receptors, cytoskeletal and scaffolding proteins, and adhesion and signaling molecules. Being
implicated in the postsynaptic signaling of multiple neurotransmitter systems, mostly dopamine and glutamate, the PSD
constitutes an ideal candidate for studying dopamine-glutamate disturbances in schizophrenia. Recent evidence suggests
that some PSD proteins, such as PSD-95, Shank, and Homer are implicated in severe behavioral disorders, including
schizophrenia. These findings, further corroborated by genetic and animal studies of schizophrenia, offer new insights for
the development of pharmacological strategies able to overcome the limitations in terms of efficacy and side effects of
current schizophrenia treatment. Indeed, PSD proteins are now being considered as potential molecular targets against this
The current paper reviews the most recent hypotheses on the molecular mechanisms underlying schizophrenia
pathophysiology. First, we review glutamatergic dysfunctions in schizophrenia and we provide an update on postsynaptic
molecules involvement in schizophrenia pathophysiology by addressing both human and animal studies. Finally, the
possibility that PSD proteins may represent potential targets for new molecular interventions in psychosis will be
Dopamine; homer; kalirin; NMDA; PSD-95; psychosis; shank; synaptic plasticity.
Alzheimer’s disease (AD) is a complex neurodegenerative disorder with a multi-faceted pathogenesis. So far,
the therapeutic paradigm “one-compound-one-target” has failed and despite enormous efforts to elucidate the
pathophysiology of AD, the disease is still incurable.
The multiple factors involved in AD include amyloid aggregation to form insoluble neurotoxic plaques of Aβ,
hyperphosphorylation of tau protein, oxidative stress, calcium imbalance, mitochondrial dysfunction and deterioration of
synaptic transmission. These factors together, accentuate changes in the CNS homeostasis, starting a complex process of
interconnected physiological damage, leading to cognitive and memory impairment and neuronal death.
A recent approach for the rational design of new drug candidates, also called multitarget-directed ligand (MTDL)
approach, has gained increasing attention by many research groups, which have developed a variety of hybrid compounds
acting simultaneously on diverse biological targets. This review aims to show some recent advances and examples of the
exploitation of MTDL approach in the rational design of novel drug candidate prototypes for the treatment of AD.
Alzheimer’s disease; multi-target directed drugs; neurodegenerative disorders; rational drug design.
Dimethyl fumarate (BG-12, Tecfidera®) is a new oral drug approved by FDA and EMA in March
2013 for relapsing – remitting multiple sclerosis (RRMS). The drug was much anticipated because of its possible
superiority over currently available medications: fingolimod and teriflunomide as the only MS treatments currently
available in oral form.
The aim of this systematic review with meta-analysis was to assess the efficacy and safety of BG-12 in the
treatment of RRMS.
A systematic literature search was conducted in Medline/PubMed, EMBASE, and Cochrane Library up till 3rd
November, 2013. We sought all published randomized clinical trials evaluating the use of dimethyl fumarate for the
treatment of patients with RRMS. All included studies were critically appraised and analyzed with the use of Review
Manager 5.1.0. software according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses
(PRISMA) statement protocol.
Two trials, DEFINE and CONFIRM involved 2 651 patients and compared dimethyl fumarate taken either two or
three times daily with placebo in patients with RRMS. Additionally in CONFIRM trial third group of patients received
glatiramer acetate. The overall results of the meta-analysis showed that BG-12 (at both dosages) given to patients with
RRMS is safe and statistically significantly more effective than placebo in reducing the proportion of patients who had
a relapse by 2 years, the rate of disability progression and the mean number of gadolinium-enhancing lesions at 2 years.
The comparison between BG-12 and glatiramer acetate revealed that the analyzed agent could potentially be more
effective in the treatment of RRMS.
Despite limited RCTs data available, both analyzed BG-12 regimens showed their efficacy on clinical
disease parameters and other measures of disease activity in RRMS. The safety profile of the study agent was acceptable.
Autoimmune disorder; dimethyl fumarate; disease-modifying therapies; relapsing-remitting multiple sclerosis.
the last decades, the scientific interest in chemistry and pharmacology of
cannabinoids has increased. Most attention has focused on ∆9-tetrahydrocannabinol
(∆9-THC) as it is the psychoactive constituent of Cannabis sativa
(C. sativa). However, in previous years, the focus of interest in the second
plant constituent with non-psychotropic properties, cannabidiol (CBD) has been
enhanced. Recently, several groups have investigated the pharmacological
properties of CBD with significant findings; furthermore, this compound has
raised promising pharmacological properties as a wake-inducing drug. In the
current review, we will provide experimental evidence regarding the potential
role of CBD as a wake-inducing drug.
Dopamine; hypothalamus; marijuana; sleep; sleepiness.
Recent evidence has associated immune and inflammatory changes to cognitive performance in
many diseases, including schizophrenia. Since this is a new research field where concepts are not yet solid and new
questions and hypothesis are still arising, the present study aimed at summarizing the available clinical data associating
schizophrenia, cognition and inflammation/immune function.
A systematic review of the literature was made by searching the following terms in Medline: “schizophrenia or
psychosis or psychotic” AND “inflamm* or immun* or cytokine or IL-* or TNF-* or kynureni* or KYNA”, AND
“cognit* or attention or memory or executive function”.
Seventy five papers were identified using the selected terms, and seven papers were included in the review.
Papers excluded focused mainly on basic research or other neuropsychiatric disorders.
Recent findings link inflammatory markers to cognition in schizophrenia, suggesting that inflammation is
associated with worst cognitive performance. Microglial activation, monoaminergic imbalance, brain abnormalities and
the kynurenine pathway are possible mechanisms underlying cognitive impairment in schizophrenia. Clinical trials with
addition of immunomodulatory drugs have shown promising results, opening new windows to tackle cognition in
Cognition; immunology; inflammation; schizophrenia.
There has been a great deal
of interest recently in genetic effects on neurocognitive performance in the
healthy population. KIBRA –a postsynaptic protein from the WWC family of
proteins– was identified in 2003 in the human brain and kidney and has recently
been associated with memory performance and synaptic plasticity. Through
genome-wide screening, a single nucleotide polymorphism (SNP) was detected in
the ninth intron of KIBRA gene (T→ C substitution) and was implicated in human
memory and the underlying neuronal circuitry. This review presents a synopsis of
the current findings on the effects of the KIBRA SNP on human memory and
synaptic plasticity. Overall the findings suggest impaired memory performance
and less efficient or impaired hippocampal/medial temporal lobe (MTL) activation
in CC homozygotes (in comparison to T carriers) with some differences between
young and older subjects. This review also highlights limitations and potential
sources for variability of studies’ imaging findings along with future
perspectives and implications for the role of KIBRA in memory-related brain
Cognition; episodic memory; fMRI; genetic polymorphism; KIBRA; synaptic plasticity.
Insomnia is a common sleep
disorder which is prevalent in women and the elderly. Current insomnia drugs
mainly target the γ-aminobutyric acid (GABA) receptor, melatonin receptor,
histamine receptor, orexin, and serotonin receptor. GABAA receptor
modulators are ordinarily used to manage insomnia, but they are known to affect
sleep maintenance, including residual effects, tolerance, and dependence. In an
effort to discover new drugs that relieve insomnia symptoms while avoiding side
effects, numerous studies focusing on the neurotransmitter GABA and herbal
medicines have been conducted. Traditional herbal medicines, such as Piper
methysticum and the seed of Zizyphus jujuba Mill var. spinosa,
have been widely reported to improve sleep and other mental disorders. These
herbal medicines have been applied for many years in folk medicine, and extracts
of these medicines have been used to study their pharmacological actions and
mechanisms. Although effective and relatively safe, natural plant products have
some side effects, such as hepatotoxicity and skin reactions effects of Piper
methysticum. In addition, there are insufficient evidences to certify the
safety of most traditional herbal medicine. In this review, we provide an
overview of the current state of knowledge regarding a variety of natural plant
products that are commonly used to treat insomnia to facilitate future studies.
Hypnotic; insomnia; natural products; sedatives; γ-aminobutyric acid.
Chronic administration of L-methionine leads to memory impairment, which is attributed to increase in the level of oxidative stress in the brain. On the other hand, metformin is a commonly used antidiabetic drug with strong antioxidant properties. In the current study, we tested if chronic metformin administration prevents memory impairment induced by administration of L-methionine. In addition, a number of molecules related to the action of metformin on cognitive 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, hippocampal levels 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-methionine administration resulted in both short- and long- term memory impairment, whereas metformin treatment prevented such effect. Additionally, L-methionine treatment induced significant elevation in GSSG and TBARs, along with reduction in GSH/GSSG ratio and activities of catalase, and GPx. These effects were shown to be restored by metformin treatment. In conclusion, L-methionine induced memory impairment, and treatment with metformin prevented this impairment probably by normalizing oxidative stress in the hippocampus.
Memory; learning; hippocampus; maze; oxidative stress; L-methionine; metformin.
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 schizophrenia and depression. Studies in rodents have reported dose and time dependent effects of glucocorticoids on the expression of proteins related to neuroplasticity. However, the mechanism(s) involved in the regulation of proteins by glucocorticoids are not clear. Ubiquitin ligases play important role in degradation, trafficking and stabilization of proteins. The present study investigated the effect of glucocorticoid on ubiquitin-proteasome system in mouse frontal cortex. A significant increase in mRNA and protein levels of parkin, an E3 ubiquitin ligase was found in cultured mouse primary cortical neurons following corticosterone treatment. An increase in parkin levels was also found in mouse frontal cortex in vivo following acute dexamethasone treatment. However, chronic treatment with corticosterone did not change parkin protein levels in mouse frontal cortex. Studies using postmortem brain samples from schizophrenia and control subjects indicated a significant increase in parkin protein levels in frontal cortex of schizophrenia subjects suggesting a response to increased stress conditions in schizophrenia. These findings suggest a possible role of parkin in the pathophysiology of stress-related psychiatric disorders.
Parkin; glucocorticoid; cortex; schizophrenia; neurons.
There is growing evidence that the imbalance between oxidative stress and the antioxidant defense system may be associated with the development neuropsychiatric disorders, such as depression and anxiety. Major depression and anxiety 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 the antioxidant levels and normalizing the damage caused by OS processes. This chapter provides an overview of recent work on oxidative stress markers in the animal models of depression and anxiety, as well as patients with the aforementioned mood disorders. It is well documented that antioxidants can remove the reactive oxygen species (ROS) and reactive nitrogen species (RNS) through scavenging radicals and suppressing the OS pathway, which further protect against neuronal damage caused oxidative or nitrosative stress sources in the brain, hopefully resulting in remission of depression or anxiety symptoms. The functional understanding of the relationship between oxidative stress and depression and anxiety may pave the way for discovery of novel targets for treatment of neuropsychiatric disorders.
Oxidative stress; Antioxidants; Depression and anxiety; Oxidative stress pathway; Antidepressants.
Oxidative stress caused by reactive species, including reactive oxygen species, reactive nitrogen species, and unbound, adventitious metal ions (e.g., iron [Fe] and copper [Cu]), is an underlying cause of various neurodegenerative diseases. These reactive species are an inevitable by-product of cellular respiration or other metabolic processes that may cause the oxidation of lipids, nucleic acids, and proteins. Oxidative stress has recently been implicated in depression and anxiety-related disorders. Furthermore, the manifestation of anxiety in numerous psychiatric disorders, such as generalized anxiety disorder, depressive disorder, panic disorder, phobia, obsessive-compulsive disorder, and posttraumatic stress disorder, highlights the importance of studying the underlying biology of these disorders to gain a better understanding of the disease and to identify common biomarkers for these disorders. Most recently, the expression of glutathione reductase 1 and glyoxalase 1, which are genes involved in antioxidative metabolism, were reported to be correlated with anxiety-related phenotypes. This review focuses on direct and indirect evidence of the potential involvement of oxidative stress in the genesis of anxiety and discusses different opinions that exist in this field. Antioxidant therapeutic strategies are also discussed, highlighting the importance of oxidative stress in the etiology, incidence, progression, and prevention of psychiatric disorders.
Antioxidant therapy; anxiety disorders; oxidative stress; toxicity.
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.
Psychological stress; oxidative stress; anxiety; depression.
The autistic spectrum disorders (ASD) form a set of multi-faceted disorders with significant genetic, epigenetic and environmental determinants. Oxidative and nitrosative stress (O&NS), immuno-inflammatory pathways, mitochondrial dysfunction and dysregulation of the tryptophan catabolite (TRYCATs) pathway play significant interactive roles in driving the early developmental etiology and course of ASD. O&NS interactions with immuno-inflammatory pathways mediate their effects centrally via the regulation of astrocyte and microglia responses, including regional variations in TRYCATs produced. Here we review the nature of these interactions and propose an early developmental model whereby different ASD genetic susceptibilities interact with environmental and epigenetic processes, resulting in glia biasing the patterning of central interarea interactions. A role for decreased local melatonin and N-acetylserotonin production by immune and glia cells may be a significant treatment target.
Autism; Oxidative stress; Nitrosative stress; glia; Immuno-inflammation; tryptophan; melatonin.
Myalgic Encephalomyelitis (ME) / Chronic Fatigue Syndrome (CFS) has been classified as a disease of the central nervous system by the WHO since 1969. Many patients carrying this diagnosis do demonstrate an almost bewildering array of biological abnormalities particularly the presence of oxidative and nitrosative stress (O&NS) and a chronically activated innate immune system. The proposal made herein is that once generated chronically activated O&NS and immune-inflammatory pathways conspire to generate a multitude of self-sustaining and self-amplifying pathological processes which are associated with the onset of ME/CFS. Sources of continuous activation of O&NS and immune-inflammatory pathways in ME/CFS are chronic, intermittent and opportunistic infections, bacterial translocation, autoimmune responses, mitochondrial dysfunctions, activation of the Toll-Like Receptor Radical Cycle, and decreased antioxidant levels. Consequences of chronically activated O&NS and immune-inflammatory pathways in ME/CFS are brain disorders, including neuroinflammation and brain hypometabolism / hypoperfusion, toxic effects of nitric oxide and peroxynitrite, lipid peroxidation and oxidative damage to DNA, secondary autoimmune responses directed against disrupted 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 these factors leads to self-amplifying feed forward loops causing a chronic state of activated O&NS, immune-inflammatory and autoimmune pathways which may sustain the disease.
Autoimmune; chronic fatigue syndrome; cytokines; inflammation; myalgic encephalomyelitis; nitrosative stress; oxidative.
The oxidative imbalance appears to have an important role in anxiety development. Studies in both humans and animals have shown a strong correlation between anxiety and oxidative stress. In humans, for example, the increased malondialdehyde levels and discrepancies in antioxidant enzymes in erythrocytes have been observed. In animals, several studies also show that anxiety-like behavior is related to the oxidative imbalance. Moreover, anxiety-like behavior can be caused by pharmacological-induced oxidative stress. Studies using knockout or overexpression of antioxidant enzymes have shown a relationship between anxiety-like behavior and oxidative stress. Related factors of oxidative stress that could 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 reducing reactive species production may have a beneficial effect in reducing anxiety. However, the neurobiological pathways underlying the effect of oxidative stress on anxiety symptoms are not fully comprehended. The challenge now is to identify the oxidative stress mechanisms likely to be involved in the induction of anxiety symptoms. Understanding these pathways could help to clarify the neurobiology of the anxiety disorder and provide tools for new discovery in therapies and preventive strategies.
Antioxidants; anxiety disorders; anxiolytics drugs; genetics; inflammation; mitochondrial; neurotrophic factor; reactive species.