Piotr Gałecki

A review on the oxidative and nitrosative stress (O&NS) pathways in major depression and their possible contribution to the (neuro)degenerative processes in that illness.

This paper reviews the body of evidence that major depression is accompanied by a decreased antioxidant status and by induction of oxidative and nitrosative (IO&NS) pathways. Major depression is characterized by significantly lower plasma concentrations of a number of key antioxidants, such as vitamin E, zinc and coenzyme Q10, and a lowered total antioxidant status. Lowered antioxidant enzyme activity, e.g. glutathione peroxidase (GPX), is another hallmark of depression. The abovementioned lowered antioxidant capacity may impair protection against reactive oxygen species (ROS), causing damage to fatty acids, proteins and DNA by oxidative and nitrosative stress (O&NS). Increased ROS in depression is demonstrated by increased levels of plasma peroxides and xanthine oxidase. Damage caused by O&NS is shown by increased levels of malondialdehyde (MDA), a by-product of polyunsaturated fatty acid peroxidation and arachidonic acid; and increased 8-hydroxy-2-deoxyguanosine, indicating oxidative DNA damage. There is also evidence in major depression, that O&NS may have changed inactive autoepitopes to neoantigens, which have acquired immunogenicity and serve as triggers to bypass immunological tolerance, causing (auto)immune responses. Thus, depression is accompanied by increased levels of plasma IgG antibodies against oxidized LDL; and increased IgM-mediated immune responses against membrane fatty acids, like phosphatidyl inositol (Pi); oleic, palmitic, and myristic acid; and NO modified amino-acids, e.g. NO-tyrosine, NO-tryptophan and NO-arginine; and NO-albumin. There is a significant association between depression and polymorphisms in O&NS genes, like manganese superoxide dismutase, catalase, and myeloperoxidase. Animal models of depression very consistently show lowered antioxidant defences and activated O&NS pathways in the peripheral blood and the brain. In animal models of depression, antidepressants consistently increase lowered antioxidant levels and normalize the damage caused by O&NS processes. Antioxidants, such as N-acetyl-cysteine, compounds that mimic GPX activity, and zinc exhibit antidepressive effects. This paper reviews the pathways by which lowered antioxidants and O&NS may contribute to depression, and the (neuro)degenerative processes that accompany that illness. It is concluded that aberrations in O&NS pathways are--together with the inflammatory processes--key components of depression. All in all, the results suggest that depression belongs to the spectrum of (neuro)degenerative disorders.

Depression and sickness behavior are Janus-faced responses to shared inflammatory pathways

It is of considerable translational importance whether depression is a form or a consequence of sickness behavior. Sickness behavior is a behavioral complex induced by infections and immune trauma and mediated by pro-inflammatory cytokines. It is an adaptive response that enhances recovery by conserving energy to combat acute inflammation. There are considerable phenomenological similarities between sickness behavior and depression, for example, behavioral inhibition, anorexia and weight loss, and melancholic (anhedonia), physio-somatic (fatigue, hyperalgesia, malaise), anxiety and neurocognitive symptoms. In clinical depression, however, a transition occurs to sensitization of immuno-inflammatory pathways, progressive damage by oxidative and nitrosative stress to lipids, proteins, and DNA, and autoimmune responses directed against self-epitopes. The latter mechanisms are the substrate of a neuroprogressive process, whereby multiple depressive episodes cause neural tissue damage and consequent functional and cognitive sequelae. Thus, shared immuno-inflammatory pathways underpin the physiology of sickness behavior and the pathophysiology of clinical depression explaining their partially overlapping phenomenology. Inflammation may provoke a Janus-faced response with a good, acute side, generating protective inflammation through sickness behavior and a bad, chronic side, for example, clinical depression, a lifelong disorder with positive feedback loops between (neuro)inflammation and (neuro)degenerative processes following less well defined triggers.

Lipid peroxidation and antioxidant protection in patients during acute depressive episodes and in remission after fluoxetine treatment

Increasing numbers of studies indicate that free radicals and their derivatives play a role in some neuropsychiatric disorders, such as depression. The aim of this study was to investigate the activities of antioxidant enzymes, lipid peroxidation and total antioxidant status (TAS) in patients suffering from major depressive disorder (MDD) as compared to healthy controls. Specifically, we wanted to estimate how fluoxetine influences antioxidant defense and lipid peroxidation. Fifty MDD patients and thirty healthy controls participated in the study. Antioxidant enzyme activities and lipid peroxidation levels were measured in erythrocytes, while TAS was measured in plasma. All measurements were taken during an acute depressive episode and then again during depression remission after a three-month fluoxetine treatment. During acute depressive episodes, patients had significantly higher activity levels of antioxidant enzymes, such as copper-zinc superoxide dismutase (SOD1) and catalase (CAT), as compared to healthy controls. Concentrations of malondialdehyde (MDA) were also significantly higher during depressive episodes. Activity levels of glutathione peroxidase (GPx) did not differ significantly between depressed patients and healthy control subjects. Moreover, the plasma total antioxidant status of the depressed patients was decreased in comparison to control subjects. After three months of fluoxetine treatment, the above parameters did not change significantly. Major depressive disorder is accompanied by disturbances in the balance between pro- and anti-oxidative processes; however, these disturbances do not improve in patients in remission after three months of fluoxetine therapy.

Oxidative stress parameters after combined fluoxetine and acetylsalicylic acid therapy in depressive patients.

There are numerous reports indicating disturbed equilibrium between oxidative processes and antioxidative defense in patients with depression. Moreover, depressive patients are characterized by the presence of elements of an inflammatory process, which is one of the sources of reactive oxygen species (ROS). In view of the above, it was decided to study both the effect of fluoxetine monotherapy and that of fluoxetine co‐administered with acetylsalicylic acid on lipid peroxidation and antioxidative defense in patients with the first depressive episode in their life.

(Neuro)inflammation and neuroprogression as new pathways and drug targets in depression: from antioxidants to kinase inhibitors.

In 1993 the first review on the inflammatory findings in depression was published (Maes, 1993). The second review on this topic (Maes, 1995) appeared in this journal that now publishes a special state-of-the art issueon the inflammatorypathways indepression. The initial so-called “monocyte-T lymphocyte”, “cytokine” or “inflammatory” hypothesis was based on findings on increased levels of proinflammatory cytokines produced bymonocytic cells/macrophages, e.g. interleukin-1β (IL-1β), IL6, and tumor necrosis factor-α (TNFα); and T lymphocytes, e.g. interferon-γ (IFNγ) and IL-2, in depression, and entailed 6 statements (Maes, 1995, 1997; Maes et al., 1995):

The expression of genes encoding for COX-2, MPO, iNOS, and sPLA2-IIA in patients with recurrent depressive disorder

BACKGROUND There is evidence that inflammation, oxidative and nitrosative stress (IO&NS) play a role in the pathophysiology of depression. There are also data indicating altered inflammatory gene expression in depressive disorder and that genetic variants of IO&NS genes are associated with increased risk of the disease in question. The aim of this study was to explore mRNA expression of four IO&NS genes PTGS2, MPO, NOS2A, and PLA2G2A coding respectively: cyclooxygenase-2 (COX-2), myeloperoxidase (MPO), inducible nitric oxide synthase (iNOS) and secretory phospholipase A2 type IIA (sPLA2-IIA). METHOD Expression of the mRNA was determined using quantitative real-time PCR, in peripheral blood cells of patients with recurrent depressive disorder (rDD) and normal controls. RESULTS The mRNA expressions of the genes encoding for COX-2, MPO, iNOS and sPLA2-IIA were significantly increased in the peripheral blood cells of depressed patients versus controls. LIMITATIONS Patients were treated with antidepressants. CONCLUSION Our results indicate and may confirm the role of peripheral IO&NS pathways in the pathophysiology of depression. The results represent a promising way to investigate biological markers of depression.

The glutathione system: a new drug target in neuroimmune disorders.

Glutathione (GSH) has a crucial role in cellular signaling and antioxidant defenses either by reacting directly with reactive oxygen or nitrogen species or by acting as an essential cofactor for GSH S-transferases and glutathione peroxidases. GSH acting in concert with its dependent enzymes, known as the glutathione system, is responsible for the detoxification of reactive oxygen and nitrogen species (ROS/RNS) and electrophiles produced by xenobiotics. Adequate levels of GSH are essential for the optimal functioning of the immune system in general and T cell activation and differentiation in particular. GSH is a ubiquitous regulator of the cell cycle per se. GSH also has crucial functions in the brain as an antioxidant, neuromodulator, neurotransmitter, and enabler of neuron survival. Depletion of GSH leads to exacerbation of damage by oxidative and nitrosative stress; hypernitrosylation; increased levels of proinflammatory mediators and inflammatory potential; dysfunctions of intracellular signaling networks, e.g., p53, nuclear factor-κB, and Janus kinases; decreased cell proliferation and DNA synthesis; inactivation of complex I of the electron transport chain; activation of cytochrome c and the apoptotic machinery; blockade of the methionine cycle; and compromised epigenetic regulation of gene expression. As such, GSH depletion has marked consequences for the homeostatic control of the immune system, oxidative and nitrosative stress (O&NS) pathways, regulation of energy production, and mitochondrial survival as well. GSH depletion and concomitant increase in O&NS and mitochondrial dysfunctions play a role in the pathophysiology of diverse neuroimmune disorders, including depression, myalgic encephalomyelitis/chronic fatigue syndrome and Parkinson’s disease, suggesting that depleted GSH is an integral part of these diseases. Therapeutical interventions that aim to increase GSH concentrations in vivo include N-acetyl cysteine; Nrf-2 activation via hyperbaric oxygen therapy; dimethyl fumarate; phytochemicals, including curcumin, resveratrol, and cinnamon; and folate supplementation.

Increased autoimmune responses against auto-epitopes modified by oxidative and nitrosative damage in depression: implications for the pathways to chronic depression and neuroprogression.

OBJECTIVE There is evidence that major depression is characterized by oxidative and nitrosative stress (O&NS). The aim of this study is to examine IgM-mediated autoimmune responses against a variety of modified neo-epitopes formed by O&NS damage to self-epitopes in chronic depression. METHODS Serum IgM antibodies directed against conjugated oleic and azelaic acid, malondialdehyde (MDA), phosphatidyl inositol (Pi), and conjugated nitric-oxide (NO) adducts, i.e., NO-tryptophan, NO-tyrosine, NO-arginine, and NO-cysteinyl, were determined in 33 healthy controls and 74 depressed patients subdivided into 28 patients with chronic (duration >2 year) and 46 without chronic depression. RESULTS Serum IgM levels against all neoepitopes were significantly higher in depressed patients than in healthy controls. Moreover, the IgM levels were significantly higher, except Pi, in chronically depressed patients than in non-chronically depressed patients. CONCLUSIONS Depression is characterized by IgM-related autoimmune responses directed against neo-epitopes that are normally hidden from the immune system but that became immunogenic secondary to damage by O&NS. The results show that the generation of neoantigenic determinants that lead to (auto)immune responses is strongly associated with chronic depression. DISCUSSION The damage caused by O&NS to auto-epitopes and the consequent formation of O&NS modified neoantigenic determinants may increase the risk to develop depression and in particular chronic depression through transition to autoimmune reactions. This has implications for understanding the immuno-inflammatory and oxidative-autoimmune pathways that lead to chronic depression and neuroprogression in that illness.

Single‐nucleotide polymorphisms and mRNA expression for melatonin synthesis rate‐limiting enzyme in recurrent depressive disorder

Abstract:  Depressive disorder (DD) is characterised by disturbances in blood melatonin concentration. It is well known that melatonin is involved in the control of circadian rhythms, sleep included. The use of melatonin and its analogues has been found to be effective in depression therapy. Melatonin synthesis is a multistage process, where the last stage is catalysed by acetylserotonin methyltransferase (ASMT), the reported rate‐limiting melatonin synthesis enzyme. Taking into account the significance of genetic factors in depression development, the gene for ASMT may become an interesting focus for studies in patients with recurrent DD. The goal of the study was to evaluate two single‐nucleotide polymorphisms (SNPs) (rs4446909; rs5989681) of the ASMT gene, as well as mRNA expression for ASMT in recurrent DD‐affected patients. We genotyped two polymorphisms in a group of 181 recurrent DD patients and in 149 control subjects. The study was performed using the polymerase chain reaction/restriction fragment length polymorphism method. The distribution of genotypes in both studied SNPs in the ASMT gene differed significantly between DD and healthy subjects. The presence of AA genotype of rs4446909 polymorphism and of GG genotype of rs5989681 polymorphism was associated with lower risk for having recurrent DD. In turn, patients with depression were characterised by reduced mRNA expression for ASMT. In addition, ASMT transcript level in both recurrent DD patients and in healthy subjects depended significantly on genotype distributions in both polymorphisms. In conclusion, our results suggest the ASMT gene as a susceptibility gene for recurrent DD.

Association between inducible and neuronal nitric oxide synthase polymorphisms and recurrent depressive disorder

BACKGROUND Major depression is characterised by increased nitric oxide (NO) levels. Inhibition of the NO synthesizing enzymes, neuronal nitric oxide synthase (nNOS) and inducible nitric oxide synthase (iNOS), results in antidepressant-like effects, whereas the expression of iNOS and nNOS is increased in depression. Recent studies have indicated that NOS participates in the mechanisms of antidepressants. The aim of this study was to examine whether a single nucleotide polymorphism (SNP) present in the genes encoding iNOS and nNOS can contribute to the risk of developing recurrent depressive disorder (rDD). METHODS The study was carried out in a group of 181 depressive patients and 149 control subjects of Polish origin. SNPs were assessed using polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) analyses. RESULTS The genotype distributions of the polymorphisms in exon 22 of the NOS2A gene and in exon 29 of the nNOS gene were significantly different between rDD patients and controls. The results showed that the G/A SNP of the gene encoding iNOS was associated with an increased susceptibility to rDD, whereas A/A homozygous carriers had a decreased risk of developing rDD. There was also a significant association between the C/T SNP of the gene encoding nNOS; the presence of the CC homozygous genotype decreased the risk of rDD, whereas the T allele and T/T homozygous genotype increased the vulnerability to rDD. CONCLUSIONS Our results suggest that polymorphisms in the iNOS and nNOS genes confer an increased susceptibility or resistance to rDD. Future research should examine genetic variants and their associations to the expression of NOSs and NO level in depressive patients.