The interplay between oxidative stress and bioenergetic failure in neuropsychiatric illnesses: can we explain it and can we treat it?

Nitro-oxidative stress and lowered antioxidant defences play a key role in neuropsychiatric disorders such as major depression, bipolar disorder and schizophrenia. The first part of this paper details mitochondrial antioxidant mechanisms and their importance in reactive oxygen species (ROS) detoxification, including details of NO networks, the roles of H2O2 and the thioredoxin/peroxiredoxin system, and the relationship between mitochondrial respiration and NADPH production. The second part highlights and identifies the causes of the multiple pathological sequelae arising from self-amplifying increases in mitochondrial ROS production and bioenergetic failure. Particular attention is paid to NAD+ depletion as a core cause of pathology; detrimental effects of raised ROS and reactive nitrogen species on ATP and NADPH generation; detrimental effects of oxidative and nitrosative stress on the glutathione and thioredoxin systems; and the NAD+-induced signalling cascade, including the roles of SIRT1, SIRT3, PGC-1α, the FOXO family of transcription factors, Nrf1 and Nrf2. The third part discusses proposed therapeutic interventions aimed at mitigating such pathology, including the use of the NAD+ precursors nicotinamide mononucleotide and nicotinamide riboside, both of which rapidly elevate levels of NAD+ in the brain and periphery following oral administration; coenzyme Q10 which, when given with the aim of improving mitochondrial function and reducing nitro-oxidative stress in the brain, may be administered via the use of mitoquinone, which is in essence ubiquinone with an attached triphenylphosphonium cation; and N-acetylcysteine, which is associated with improved mitochondrial function in the brain and produces significant decreases in oxidative and nitrosative stress in a dose-dependent manner.

Preliminary survey of potato virus Y (PVy) strains in potato samples from Kurdistan (Iran).

Potato virus Y (PVY) is the type species in the potyvirus genus of the family potyviridae. This plant pathogenic virus is transmitted through plant sap inoculation by stem and core grafting and by at least 25 aphid species in a non-persistent manner. According to potato specialists in most parts of the world, PVY is currently considered as the most harmful virus in cultivated potatoes. This is also the case for potato production in Iran. In this project we investigated potato leaves that were collected in the Kurdistan province in Iran for the presence of PVY with use of different biochemical/molecular techniques as ELISA, RT-PCR and qPCR. The different PVY strains, including PVY-O, PVY-N, PVYN-TN, PVY-NWi, were determined by using a triplex RT-PCR. In conclusion, the results demonstrated the presence of PVY-NWi strains in the potato leaf samples from Kurdistan (Iran). The data are discussed in relation to prevalence of PVY strains in Iran.

Lower high-density lipoprotein cholesterol and increased omega-6 polyunsaturated fatty acids in first-degree relatives of bipolar patients.

BACKGROUND: Lower serum high-density lipoprotein cholesterol and increased ratio of omega-6/omega-3 fatty acids have been reported in unipolar and bipolar depressed patients. Changes in cholesterol and fatty acids have been suggested to affect membrane viscosity and consequently serotonergic neurotransmitter expression. The goal of this study was to investigate whether lower baseline cholesterol and increased omega-6 and lower omega-3 fatty acids are present in healthy first-degree relatives of bipolar patients compared with controls and whether these changes were associated with neuroendocrine responses to an i.v. tryptophan challenge or mood. METHOD: Baseline cholesterol, fatty acids and mood were determined in healthy first-degree relatives of patients with bipolar disorders (N = 30) and healthy matched controls (N = 15) (parallel-group design). Prolactin and cortisol were measured following tryptophan infusion. RESULTS: First-degree relatives showed significantly lower plasma high-density lipoprotein cholesterol and increased total omega-6 fatty acids in phospholipids. Lower total omega-3 and higher total omega-6 fatty acids in phospholipids were positively correlated with peak prolactin response to tryptophan. Lower total omega-3 fatty acids in phospholipids and cholesteryl esters were associated with lower mood. CONCLUSIONS: Abnormalities of lower plasma high-density lipoprotein cholesterol and increased total omega-6 fatty acids in phospholipids in these subjects are in agreement with findings in bipolar and major depressed patients. Changes in fatty acids show an association with central serotonergic parameters. It is suggested that these abnormalities in cholesterol and fatty acids may constitute a trait marker for bipolar disorders.

Experiences and perspectives for the use of a Paenibacillus strain as a plant protectant.

A study on the microbial ecology in an active slow sand filter, used for disinfecting the circulating plant nutrient solutions, showed that spore-forming plant-associated bacteria belonging to the Bacillus-Paenibacillus complex are well adapted for transmission in the solutions and passage through the filter. Therefore, strains from this bacterial group were suitable candidates for biological control in irrigated and closed plant growth systems. The spore-forming Paenibacillus polymyxa strain PpDGB was selected in in vitro tests as a potent pathogen-antagonist and was tested as a prophylactic protection agent in the plant rhizosphere, especially for cultures stages that are highly susceptible to stress and disease. Plant cuttings, in vitro plants and seeds of different plant types were bacterized and planted in their typical disease-conducive environment where nutrient solutions or water irrigation was applied and further plant development was monitored. Observed plant parameters were plant survival, weight, chlorophyll concentration in the leaf mesophyl, root health and root hair formation. The PpDGB treatment initially induced stress in the plants, which was observed as a transient stop in plant transpiration. This effect caused some necrosis in the most stress-sensitive in vitro plant species. In the other plants this stress period was followed by a significant enhancement in plant growth. In case of seed treatment, more seeds germinated and seedling growth was faster. In the tested formulation, PpDGB enhanced growth but not disease resistance, probably due to simultaneous activation of the residual plant pathogens. Therefore variant formulations have to be tested. The influence of PpDGB on the composition of the bacterial communities in the rhizosphere was assessed by DGGE profiling. In soilless plant cultures, PpDGB-driven profile changes could be observed from the 5th day after the initial treatment. P. polymyxa bacteria were shown to be widely present in association with plants and specific PpDGB detection in plant and rhizosphere was only possible with newly developed strain-specific PCR primers based on Nif H gene sequences. Quantitative PCR based on SYBR Green fluorescence enabled detection of low PpDGB concentrations in the plant rhizosphere.

Serotonergic markers and lowered plasma branched-chain-amino acid concentrations in fibromyalgia.

The aims of the present study were to examine serotonergic markers, i.e. [3H]paroxetine binding characteristics and the availability of plasma tryptophan, the precursor of serotonin (5-HT), and the plasma concentrations of the branched chain amino acids (BCAAs), valine, leucine and isoleucine, in fibromyalgia. The [3H]paroxetine binding characteristics, B(max) and K(d) values, and tryptophan and the competing amino acids (CAA), known to compete for the same cerebral uptake mechanism (i.e. valine, leucine, isoleucine, phenylalanine and tyrosine), were determined in fibromyalgia patients and normal controls. There were no significant differences in the [3H]paroxetine binding characteristics (B(max) and K(d)) between fibromyalgia and control subjects. There were no significant differences in plasma tryptophan or the tryptophan/CAA ratio between fibromyalgia patients and normal controls. In the fibromyalgia patients, there were no significant correlations between [3H]paroxetine binding characteristics or the availability of tryptophan and myalgic or depressive symptoms. Patients with fibromyalgia had significantly lower plasma concentrations of the three BCAAs (valine, leucine and isoleucine) and phenylalanine than normal controls. It is hypothesized that the relative deficiency in the BCAAs may play a role in the pathophysiology of fibromyalgia, since the BCAAs supply energy to the muscle and regulate protein synthesis in the muscles. A supplemental trial with BCAAs in fibromyalgia appears to be justified.

High-dose growth hormone treatment of short children born small for gestational age.

The effect of GH administration was evaluated over 2 yr in 50 short, prepubertal, non-GH deficient children born small for gestational age, who had been randomly allocated to a group receiving no treatment or daily sc GH treatment at a dose of 0.2 or 0.3 IU/kg. At the start of the study, mean age was 5.2 yr, bone age was 4.0 yr, height SDS was -3.5, height velocity SDS was -0.8, weight SDS was -2.7, and body mass index SDS was -1.9. Catch-up growth was observed in none of the untreated and all of the treated children. The response to GH treatment included a near doubling of growth velocity and of weight gain and a mean height increment of more than 2 SDS. GH treatment was associated with a distinct acceleration of bone maturation. The differences between the growth responses evoked by the two GH doses were minor. The prepubertal GH-induced catch-up growth was associated with elevated serum concentrations of insulin, insulin-like growth factor-I, insulin-like growth factor binding protein-3, and osteocalcin, whereas insulin-like growth factor-II levels remained unaltered. GH treatment was well tolerated. In conclusion, high-dose GH administration over 2 yr is emerging as a potential therapy to increase the short stature that results from insufficient catch-up growth in young children born small for gestational age. The long-term impact of this approach remains to be delineated.

Increased serum interleukin-1-receptor-antagonist concentrations in major depression.

Recently, it has been shown that major depression may be accompanied by an increased production of interleukin-1 beta (IL-1 beta), an acute phase (AP) response and simultaneous signs of activation and suppression of cell-mediated immunity. The interleukin-1-receptor antagonist (IL-1-rA) is released in vivo during an AP response and serum levels are increased in many immune disorders. The release of IL-1-rA may limit the pro-inflammatory effects of IL-1. This study has been carried out to examine serum IL-1-Ra in 68 depressed subjects (21 minor, 25 simple major and 22 melancholic subjects) vs. 22 normal controls. Depressed subjects showed significantly higher serum IL-1-rA concentrations than healthy controls. 29% of all depressed subjects had serum IL-1-rA levels higher than the mean value +2 standard deviations of normal controls; 44% depressed subjects had IL-1-rA values greater than 0.215 ng/ml with a specificity of 90%. In depressed subjects, there was a significant and positive relationship between serum IL-1-rA and severity of illness. In depression, there were no significant relationships between serum IL-1-rA concentrations and indicants of hypothalamic-pituitary-adrenal (HPA)-axis activity, such as 24-h urinary cortisol and postdexamethasone cortisol values. Women had significantly higher serum IL-1-rA levels than men. The findings support the thesis that depression is accompanied by an immune-inflammatory response.

Increased plasma concentrations of interleukin-6, soluble interleukin-6, soluble interleukin-2 and transferrin receptor in major depression.

Recently, it was found that major depression may be accompanied by significant changes in cell-mediated and humoral immunity. The purpose of this study was to investigate the plasma concentrations of interleukin (IL)-6, soluble IL-6 receptor (sIL-6R), sIL-2R and transferrin receptor (TfR) in patients with major depression in an acute phase of illness, in remission and during antidepressive treatment. Plasma concentrations of IL-6, sIL-6R, sIL-2R and TfR were significantly higher in major depressed subjects than in healthy controls. In major depressed subjects, but not in normal controls, there were significant positive correlations between the plasma concentrations of IL-6 and sIL-6R, IL-6 and sIL-2R, IL-6 and TfR, and between sIL-2R and TfR. Subchronic treatment with antidepressive drugs, such as fluoxetine or tricyclic antidepressants, did not significantly affect plasma IL-6, sIL-6R, sIL-2R or TfR. The latter did not significantly differ between major depressed patients in an acute phase of illness or in complete clinical remission. It is suggested that: (1) a coordinated and upregulated production of IL-6, sIL-6R, sIL-2R and TfR may constitute a trait marker of major depression; and that (2) an upregulated production of IL-6 may represent a contributing factor to the various immune disorders encountered in major depression and maybe to the pathophysiology or pathogenesis of that illness.

Psychoimmune investigation in obsessive-compulsive disorder: assays of plasma transferrin, IL-2 and IL-6 receptor, and IL-1 beta and IL-6 concentrations.

This study was carried out to investigate the immune function in obsessive-compulsive disorder (OCD). Plasma levels of interleukin (IL)-1 beta, IL-6, soluble IL-6 receptor (sIL-6R), sIL-2R, and transferrin receptor (TfR), and baseline plasma cortisol levels were measured in 19 OCD patients and 19 normal controls. No significant differences in any of the above immune variables were found between subjects with OCD and normal controls. There was a significant positive correlation between IL-6 or sIL-6R concentrations and severity of compulsive--but not obsessive--symptoms. In subjects with OCD, there was a significant negative relationship between sIL-2R concentrations and plasma cortisol values. In subjects with OCD and in the study group as a whole, there were significant positive relationships between sIL-2R and TfR concentrations.

Relationships between interleukin-6 activity, acute phase proteins, and function of the hypothalamic-pituitary-adrenal axis in severe depression.

Recent studies from this laboratory have provided some evidence that major depression, in particular melancholia, may be accompanied by an immune response. The present study was designed to investigate whether severe depression is characterized by increased interleukin-6 (Il-6) activity and whether Il-6 production is related to altered levels of acute phase reactants and to abnormal function of the hypothalamic-pituitary-adrenal (HPA) axis. Measurements were made in 8 healthy control subjects and 24 depressed inpatients of Il-6 production in culture supernatants of mitogen-stimulated peripheral leukocytes and plasma levels of haptoglobin (Hp), transferrin (Tf), and postdexamethasone cortisol. Il-6 activity was significantly higher in melancholic subjects than in healthy control subjects and in patients with minor depression or nonmelancholic major depression. Il-6 production was significantly correlated with Hp (positively) and Tf (negatively) plasma levels. There were significant and positive correlations between Il-6 activity and postdexamethasone cortisol values. The findings may suggest that increased Il-6 activity in severe depression is related to hypotransferrinemia, hyperhaptoglobinemia, and hyperactivity of the HPA axis.

Psychomotor retardation, anorexia, weight loss, sleep disturbances, and loss of energy: psychopathological correlates of hyperhaptoglobinemia during major depression.

Recently, we have established that major depression is characterized by hyperhaptoglobinemia, which may be regarded as an index of an "acute" phase response in that illness. The present study investigates the psychopathological correlates of increased plasma concentrations of haptoglobin (Hp) in major depression. To this end, the authors studied the Hp levels in relation to depressive items of the Structured Clinical Interview for DSM-III (SCID) and the Hamilton Rating Scale for Depression (HRSD) in 90 depressed subjects. There was a significant positive relationship between the SCID symptoms anorexia/weight loss, sleep, and psychomotor disorders and Hp plasma concentrations. Hp plasma levels were significantly and positively correlated with overall severity of illness (HRSD). The HRSD symptom correlates of higher Hp levels were loss of interest, middle insomnia, and psychomotor retardation. Up to 31.4% of the variance in Hp plasma values could be explained by psychomotor disorders, anorexia, weight loss, middle insomnia, and less diurnal variation of mood. It is suggested that hyperhaptoglobinemia, as an index of an "acute" phase response in major depression, is related to the somatic dimension of depressive illness.

Immune disorders in depression: higher T helper/T suppressor-cytotoxic cell ratio.

This study investigated the leukocyte T helper and T suppressor-cytotoxic cell (sub)set profile of minor, simple major and melancholic depressives versus normal controls. Using both monoclonal antibody staining and flow cytometry, we determined the absolute numbers and percentages of the following T cell immune subsets: T helper (CD4+), T virgin (CD4+CD45+), T memory (CD4+CD45-), T suppressor/cytotoxic (CD8+), CD8+ T suppressor (CD8+CD57-) and CD8+ T cytotoxic (CD8+CD57+) cells. After computing the CD4+/CD8+ ratio, we detected a significantly increased ratio in depressed patients as compared with healthy controls. Depression per se is characterized by a higher percentage of CD4+ and a lower percentage of CD8+CD57- cells. Melancholic depressed subjects exhibit a significantly increased number of CD4+ and CD4+CD45- cells. The combined use of various percentages of CD4+ and CD8+ (sub)sets yields a high degree of marker positivity for melancholia: through cumulative evaluation of those percentages, the marker positivity increases to 68% (sensitivity) and the specificity is 95%. These results together with our previous reports may refer to a depression-related state of T cell activation.