Oxidative stress and anxiety
They found that, in the brain, the expression of glutathione reductase 1 and glyoxalase 1, which are
genes involved in antioxidative metabolism, is highly correlated
with anxiety-related phenotypes. Furthermore, they also found
that the activity of these enzymes is highest in the most anxious
mice and lowest in the least anxious strains.
We found that anxiety in mice is accompanied
by markedly elevated levels of ROS in neuronal and glial cells
within the cerebellum and hippocampus, as well as in neurons
of the cerebral cortex and in blood monocytes, granulocytes and
As a consequence, we suggest that an
imbalance in the redox system of anxious mice plays a role in
neuroinflammation and neurodegeneration, predisposing them to
recurrent infection and chronic inflammation.
In agreement with our recent findings observed a significant relationship between trait anxiety and ROS
formation in monocytes of hypertensive(!) individuals.
They found that treating mice with buthionine-
S,R-sulfoximine (BSO), an inducer of oxidative stress, induces anxious behavior through the NADPH oxidase pathway.
Masood et al.29 induced oxidative
stress in mice by depleting glutathione, glutathione depletion
causes a myriad of cellular stresses, including oxidative, nitrosative
and carbonyl stresses, as glutathione is an important determinant
of the oxygen, nitrogen and dicarbonyl metabolisms.
Excessive production of ROS induces oxidative damage of cellular
structures, production of reactive nitrogen species triggers
nitrosylation reactions, which can alter the structure of proteins
to inhibit their normal function, excessive accumulation
of reactive dicarbonyl compounds leads to damage of protein and
nucleotides by dicarbonyl glycation.
Showed that vitamin E deficiency in the mouse brain significantly
increases the levels of central oxidative stress markers, resulting
in anxiogenic behavior without abnormalities in the locomotor
performance of the mice. Souza et al.48 demonstrated in rats that
the consumption of a highly palatable diet enriched with sucrose
leads to an obese phenotype, increases protein oxidation in the
frontal cortex and induces anxiety-like behavior in the dark/
light choice test without altering locomotion in an open field
Masood et al. were able to show that oxidative stress-related anxiety can be
reversed in mice upon inhibition of NADPH oxidase or phosphodiesterase-
2, enzyme that is indirectly implicated in oxidative stress
Mechanism of oxidative stress-induced intracellular acidosis in
rat cerebellar astrocytes and C6 glioma cells.
We have found that H202 induces a significant intracellular acidosis
in both cultured rat cerebellar astrocytes and C6 glioma cells.
Two membrane-crossing ferrous iron chelators, phenanthroline and deferoxamine, almost
completely inhibited H202-induced intracellular acidosis, while the non-membrane-crossing
iron chelator apo-transferrin had no effect. Furthermore, the acidosis was completely inhibited
by two potent membrane-crossing OH scavengers, N-(2-mercaptopropionyl)-glycine (N-MPG)
and dimethyl thiourea (DMTU).
Our results suggest that OH inhibits glycolysis, leading to ATP hydrolysis and intracellular
"Is H202-induced acidosis caused by an increase in
intracellular Ca2+ levels?" (maybe why is some calcium blockers used in treat anxiety?)
C. glioma cells: inhibition of the citric acid cycle and
The reason for the initial acidosis
induced by cyanide or rotenone is not clear, but it has
recently been suggested that, in the presence of glucose,
these inhibitors may stimulate anaerobic glycolysis and
over-production of lactate (Smith, Donoso, Bauer & Eisner,
1993) or deplete mitochondrial ATP, resulting in ATP
hydrolysis (Gevers, 1977).
Pyruvate is a substrate in the tricarboxylic acid cycle (TCA),
but is also a potent peroxide-ion scavenger.
We found, both in the presence and absence
of glucose, that 10 mm pyruvate completely blocked the
Primary cultures of astrocytes: inhibition of the
the results using IAA (0'5 mM), DOG (10 mM) or glucosefree
medium (Table 2) were similar to those seen in C6 cells.
Primary cultures of astrocytes: inhibition of the TCA
cycle and respiratory chain.
Secondly, H202 reversibly inhibits the glycolytic enzyme
H202 only partially inhibits GAPDH (Hyslop et
leaving some glycolytic ATP production intact and
also inhibits the glycolytic pathway, resulting in accumulation
of sugar phosphates and increased H+ production.
Initiation of neuronal damage by complex I deficiency and oxidative stress in Parkinson's disease.
Oxidative stress and partial deficiencies of mitochondrial complex I appear to be key factors in the pathogenesis of Parkinson's disease. They are interconnected; complex I inhibition results in an enhanced production of reactive oxygen species (ROS), which in turn will inhibit complex I. Partial inhibition of complex I in nerve terminals is sufficient for in situ mitochondria to generate more ROS. H2O2 plays a major role in inhibiting complex I as well as a key metabolic enzyme, alpha-ketoglutarate dehydrogenase. The vicious cycle resulting from partial inhibition of complex I and/or an inherently higher ROS production in dopaminergic neurons leads over time to excessive oxidative stress and ATP deficit that eventually will result in cell death in the nigro-striatal pathway.
Mitochondrial Complex I Deficiency in Parkinson's Disease
The structure and function of mitochondrial respiratory-chain enzyme proteins were studied postmortem in the substantia nigra of nine patients with Parkinson's disease and nine matched controls. Total protein and mitochondrial mass were similar in the two groups. NADH-ubiquinone reductase (Complex I) and NADH cytochrome c reductase activities were significantly reduced, whereas succinate cytochrome c reductase activity was normal. These results indicated a specific defect of Complex I activity in the substantia nigra of patients with Parkinson's disease. This biochemical defect is the same as that produced in animal models of parkinsonism by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and adds further support to the proposition that Parkinson's disease may be due to an environmental toxin with action(s) similar to those of MPTP.
Mitochondrial Complex I and IV Dysfunction of Leukocytes in Parkinson’s Disease
The observed respiratory chain enzyme deficiency supports the hypothesis that systemic mitochondrial dysfunction is important in the pathogenesis of idiopathic PD.
Reversal of Oxidative Stress-Induced Anxiety by Inhibition of Phosphodiesterase-2 in Mice
Treatment of mice with l-buthionine-(S,R)-sulfoximine (300 mg/kg), an inducer of oxidative stress, caused anxiety-like behavioral effects in elevated plusmaze, open-field, and hole-board tests through the NADPH oxidase pathway; these effects were antagonized by Bay 60-7550 (3 mg/kg) and apocynin (3 mg/kg), an inhibitor of NADPH oxidase. The Bay 60-7550-mediated decrease in oxidative stress (i.e., superoxide anion and reactive oxygen species generation in cultured neurons and total antioxidant capacity and lipid peroxides in amygdala and hypothalamus) and expression of NADPH oxidase subunits (i.e., p47 phox and gp91 phox expression in amygdala, hypothalamus, and cultured neurons) was associated with increased cGMP and phosphorylation of vasodilator-stimulated phosphoprotein at Ser239, suggesting an important role of cGMP-protein kinase G signaling in reduction of anxiety. Overall, the present results indicate that oxidative stress induces anxiety-like behavior in mice and that PDE2 inhibition reverses it through an increase in cGMP signaling. Thus, PDE2 may be a novel pharmacological target for treatment of anxiety in neuropsychiatric and neurodegenerative disorders that involve oxidative stress.
Glutamate transporters are oxidant-vulnerable: a molecular link between oxidative and excitotoxic neurodegeneration?
Increasing evidence indicates that glutamate transporters are vulnerable to the action of biological oxidants, resulting in reduced uptake function. This effect could contribute to the build-up of neurotoxic extracellular glutamate levels, with major pathological consequences. Specific 'redox-sensing' elements, consisting of cysteine residues, have been identified in the structures of at least three transporter subtypes (GLT1, GLAST and EAAC1) and shown to regulate transport rate via thiol-disulphide redox interconversion. In particular, they review evidence suggesting a possible involvement of oxidative alterations of glutamate transporters in specific pathologies, including amyotrophic lateral sclerosis, Alzheimer's disease, brain trauma and ischaemia.
Glutamate-dependent inhibition of dopamine release in striatum is mediated by a new diffusible messenger, H2O2.(!!!)