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Suppression of interleukin-1 action by phospholipase-A2 inhibitors in helper T lymphocytes
Abstract
The mechanism by which interleukin 1 (IL-1) and T cell receptor (TCR) activation co-stimulate T helper (Th) cells is not clear. In chondrocytes, fibroblasts and several other cell types, much of the evidence suggests a linkage between IL-1 action and increased phospholipase-A2 (PLA2) activity. Although Th cells have very low levels of PLA2, they are well known targets for IL-1. We studied the effects of PLA2 inhibitors, i.e., lipocortin-1 (LC-1) and the synthetic peptide antiflammin-P2 (AF-2), on the enhancing effect of IL-1 upon activation of TCR. When murine D10.G4.1 Th2 cells were stimulated by their clonotypic anti-TCR antibody 3D3, both LC-1 and AF-2 inhibited the biological response to IL-1. This blockade was not seen when D10 cells were induced to proliferate with interleukin-2 (IL-2) and 3D3 in the presence of the same inhibitors, LC-1 or AF-2. These results strongly suggest that PLA2 also plays a central role in mediating the actions of IL-1 in the helper T cell.
... ANXA1 is a pleiotropic molecule with a number of antiinflammatory actions of relevance to the regulation of neutrophil-driven inflammatory processes (10±13, reviewed in 14). In addition, and of potential relevance to the regulation of immune function, ANXA1 and peptides derived from its primary sequence have been shown to exert suppressive effects on mitogen-stimulated murine thymocytes [15], rodent T cell lines [16] and an immortalized T cell line [17]. Although preliminary experiments suggest possible effects of ANXA1 on mitogen-activated T cells in humans [18,19], the effects of ANXA1 on antigen-driven human T cell proliferation and cytokine production have never been examined. ...
... Its effects on T cell proliferation have not been examined. A second peptide, antiflammin-2 (AF-2), comprising amino acids 246±254 of ANXA1, is also anti-inflammatory in rodents [36] and also suppresses proliferation of an immortalized T-cell line [17]. ...
... Although Ac2±26 and AF-2 inhibited T cell proliferation, high concentrations were needed to produce an effect. This is in accord with published studies [10,16,17,35] showing that, in a variety of systems in vitro, ANXA1derived peptides are less potent than intact ANXA1 and may act as partial agonists. Given the modest size of the peptides compared to the intact protein, this could reflect the absence of critical structural features needed to increase affinity for the binding site and/or to evoke a signalling response. ...
Annexin-1 (ANXA1, lipocortin 1) is a pleiotrophic protein produced by many cell types including peripheral blood leucocytes. Although it has been shown to inhibit "macroscopic" inflammatory processes in animal models, its direct effects on antigen-activated human T cells have not been studied.
To test the hypothesis that ANXA1-derived peptides inhibit antigen-driven prototype Th1 and Th2-type human T cell responses of clinical relevance and lectin-driven responses in vitro.
Peripheral blood mononuclear cells (PBMC) were isolated from 14 atopic subjects sensitized to house dust mite allergen (Dermatophagoides pteronyssinus, Der p) and purified protein derivative (PPD) of Mycobacterium tuberculosis. PBMC (1 x 106/mL) were cultured with phytohaemagglutinin (PHA; 5 microg/mL; 4 days), Der p (25 microg/mL; 6 days), PPD (10 microg/mL, 6 days) or medium control. Two ANXA1-derived peptides, Ac2-26 and AF-2 (5-500 microM), were assessed for possible inhibition of PHA-and antigen-induced T cell proliferation (measured by 3H-thymidine uptake), while Ac2-26 was assessed for inhibition of Der p-induced interleukin (IL)-5 release and PPD-induced interferon-gamma (IFN-gamma) release (measured by ELISA). Comparison was made with dexamethasone as an established inhibitory control. Endogenous production by PBMC of cell surface-associated and intracellular ANXA1 in response to PHA, Der p and PPD in the presence and absence of dexamethasone was measured by specific ELISA.
Both PHA- and antigen-induced T cellular proliferation were inhibited by dexamethasone. Although neither ANXA1-derived peptide significantly altered PHA-induced proliferation, both effected concentration-dependent reductions in antigen-induced proliferation, Ac2-26 being the more potent. Peptides of identical amino acid composition to Ac2-26 and AF-2, but of random sequence, were ineffective at equivalent concentrations. In addition, Ac2-26 and dexamethasone inhibited Der p-induced IL-5 release and PPD-induced IFN-gamma release in a concentration-dependent fashion. Endogenous ANXA1 was detectable in PBMC, but at concentrations approximately 104-fold lower, in molar terms, than the effective concentrations of the exogenously added, ANXA1-derived inhibitory peptides. Endogenous production was not significantly altered by any of the T cell stimuli employed in this study, in the presence or absence of dexamethasone.
In prototype Th1 and Th2-type human T cell responses, ANXA1-derived peptides can inhibit antigen-driven cellular proliferation and cytokine production.
... This result is in agreement with the study done by Oczan et al, [17] Kuloglu et al, [15] Machado-Vieira et al [28] and Andreazza et al [29] which also showed the higher value for MDA in patients than controls. Increased MDA levels disable cellular membrane function by stimulating phospholipase-A 2 and thus release interleukins by stimulating the immune system [30]. The majority of pre-treatment patients (21 out of 32) were experiencing severe acute manic episode with psychotic symptoms. ...
Aim: Brain is more vulnerable to oxidative free radicals than other tissues. Oxidative stress might primarily or secondarily be involved in the pathogenesis of bipolar affective disorder. Therefore this study was aimed to estimate & compare parameters of oxidative stress and antioxidant levels in bipolar patients and healthy controls. Methods: A total of 32 bipolar patients and 30 healthy subjects were recruited in this study. Serum MDA level was measured as indicator of lipid peroxidation and vitamin C, E & glutathione were determined as a measure of antioxidant status. Results: Significantly (p<0.001) elevated MDA level was found in patient before treatment (7.11 ± 1.62 nmol/ml) as compared to control (3.02 ± 1.30 nmol/ml) group. Patients on follow-up also had significantly increased MDA level (5.37 ± 1.36 nmol/ml) as compared to control group and decrease in level was significant (p<0.001) in comparison to before treatment patients. Vitamin C (0.82 ± 0.32 mg/dl), E (0.77 ± 0.20 mg/dl) and glutathione (4.44 ± 0.91 µmol/gm Hb) levels were significantly (p<0.001) reduced in patient group compared with those of control (1.53 ± 0.56 mg/dl), (1.27 ± 0.37 mg/dl) and (9.66 ± 1.79 µmol/gm Hb) respectively. Conclusion: The findings suggest that there is increased oxidative stress in bipolar patients in comparison to controls.
... As a result of those alterations, the biological membranes induce cytokine production [1]. On the other hand, elevation of LP induces phospholipase A2, which changes receptor functions in the cell membranes, induces immune cells, and leads to secretion of interleukins from T cells [30] and it may increase LP [5,16]. After administrating venlafaxine, the results demonstrate treatment of rat with venlafaxine effectively protected the rats against depressioninduced brain damage, shown by increased cortex brain GSH-Px activities and GSH levels and decreased LP and XO levels. ...
Venlafaxine is an approved antidepressant that is an inhibitor of both serotonin and norepinephrine transporters. Medical
treatment with oral venlafaxine can be beneficial to depression due to reducing free radical production in the brain and medulla
of depression- induced rats because oxidative stress may a play role in some depression. We investigated the effect of venlafaxine
administration and experimental depression on lipid peroxidation and antioxidant levels in cortex brain, medulla and erythrocytes
of rats. Thirty male wistar rats were used and were randomly divided into three groups. Venlafaxine (20mg/kg) was orally
supplemented to depression-induced rats constituting the first group for four week. Second group was depression-induced group
although third group was used as control. Depressions in the first and second groups were induced on day zero of the study
by chronic mild stress. Brain, medulla and erythrocytes samples were taken from all animals on day 28. Depression resulted
in significant decrease in the glutathione peroxidase (GSH-Px) activity and vitamin C concentrations of cortex brain, glutathione
(GSH) value of medulla although their levels were increased by venlafaxine administration to the animals of depression group.
The lipid peroxidation levels in the three tissues and nitric oxide value in cortex brain elevated although their levels were
decreased by venlafaxine administration. There were no significant changes in cortex brain vitamin A, erythrocytes vitamin
C, GSH-Px and GSH, medulla vitamin A, GSH and GSH-Px values. In conclusion, cortex brain within the three tissues was most
affected by oxidative stress although there was the beneficial effect of venlafaxine in the brain of depression-induced rats
on investigated antioxidant defenses in the rat model. The treatment of depression by venlafaxine may also play a role in
preventing oxidative stress.
... Sierra-Honigmann and Murphy were the first to investigate the effects of hrAnx-A1 on T helper cells [26]. The authors tested the inhibitory effect of Anx-A1 and its derived peptide anti-inflammin-F2 (AF-2), on IL-1- induced PLA 2 activation in the Th2 cell line D10.G4 and showed that both compounds efficiently inhibited the biological response to IL-1. ...
Studies over the last decade have provided us with a wealth of evidence showing that Annexin-1 is a homeostatic endogenous anti-inflammatory mediator of the innate immune system. However, as in Robert Louis Stevenson's novel 'The Strange Case of Dr Jekyll and Mr Hyde', recent investigations on the role of this protein in the adaptive immune response have revealed a previous unknown 'dark side' as positive modulator of T cell activation. This review will be focusing on these recent findings providing further evidences for the promising therapeutic potential of drugs targeting Annexin-1.
... As a result of these changes, the biological membranes induce cytokine production. 18,22 On the other hand, elevation of LP induces phospholipase A2, which changes receptor functions in the cell membranes, induces immune cells, and leads to secretion of interleukins from T-cells, 34 which may increase LP. 24 Treatment of the MTX-induced toxicity rats with CAPE drug effectively protected the rats against depression-induced testes damage, increased testes CAT activities and decreased LP levels in testes. It has been reported that CAPE treatment may partially suppress immune cells including T-cells. ...
The aim of this study was to investigate the possible protective role of caffeic acid phenethyl ester on testicular toxicity of methotrexate in rats. Nineteen male rats were divided into three groups as follows: group I, control; group II, methotrexate-treated; group III, methotrexate + caffeic acid phenethyl ester-treated. In the second day of experiment, a single dose of methotrexate was intraperitoneally administered to groups II and III, although a daily single dose of caffeic acid phenethyl ester was intraperitoneally administered to group III for 7 days. At the end of the experiment, the testes of the animals were removed and weighed. In the tissue, the level of lipid peroxidation as malondialdehyde and activities of superoxide dismutase were higher in the methotrexate group than in the control group. Lipid peroxidation levels and superoxide dismutase activities were decreased in caffeic acid phenethyl ester + methotrexate group compared with methotrexate group. The activities of catalase in the methotrexate group decreased insignificantly although its activities were significantly increased by caffeic acid phenethyl ester administration. The activity of glutathione peroxidase did not change in the groups. There was significant difference in body weight between control and methotrexate-induced groups. In conclusion, the administration of methotrexate causes elevation of oxidative stress although treatment with caffeic acid phenethyl ester has protective effects on the oxidative stress in testes.
... Increased MDA levels disable cellular membrane functions by stimulating phospholipase A 2 and thus release interleukins by stimulating the immune system. 35 Free radicals can also react with membrane-associated proteins, altering enzyme and neurotransmitter receptor function. 36 We suggest that these effects may be associated with the aetiology of bipolar disorder because changes of neurotransmitter-receptor functions are considered to be responsible for the aetiopathogenesis of bipolar disorder. ...
Recent data from several reports indicate that free radicals are involved in aetiopathogenesis of many human pathologies including neuropsychiatric disorders such as schizophrenia, bipolar disorder etc. In the present study, we aimed at determining and evaluating levels of malondialdehyde (MDA), a product of lipid peroxidation, and antioxidant enzyme superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activity levels in patients diagnosed with schizophrenia (n = 25) and bipolar disorder (n = 23). The control group was composed of 20 healthy subjects. There was a significant increase in MDA levels of patients with schizophrenia and bipolar disorder compared with controls. SOD and GSH-Px activity levels were significantly higher in the schizophrenic group compared with controls. SOD activity levels in bipolar the group were significantly higher than controls whereas there were no significant changes in GSH-Px activity levels in the bipolar group and controls. Significant differences between lipid peroxidation product and antioxidant enzyme (SOD and GSH-Px) activity levels in schizophrenic and bipolar disorder patients compared with controls leads us to believe that these differences are related to the heterogenities in aetiologies of these disorders.
... Recombinant ANXA1 and peptides derived from its primary sequence have been shown to exhibit anti-proliferative activity on mitogenstimulated T cell lines and human PBMC. Purified ANXA1 suppresses the proliferation of murine thymocytes (Hirata et al. 1983), and recombinant ANXA1 and the synthetic peptide antiflamin-2 (AF-2; corresponding to amino acid sequence 246-254) inhibit IL-1-stimulated activity in murine Th2-like cell lines (Sierra-Honigmann et al. 1992). Recombinant ANXA1 also demonstrates anti-proliferative activity in mitogen-stimulated human PBMC cultures (Almawi et al. 1996, Koseki et al. 1997. ...
The concept of anti-inflammation is currently evolving with the definition of several endogenous inhibitory circuits that are important in the control of the host inflammatory response. Here we focus on one of these pathways, the annexin 1 (ANXA1) system. Originally identified as a 37 kDa glucocorticoid-inducible protein, ANXA1 has emerged over the last decade as an important endogenous modulator of inflammation. We review the pharmacological effects of ANXA1 on cell types involved in inflammation, from blood-borne leukocytes to resident cells. This review reveals that there is scope for more research, since most of the studies have so far focused on the effects of the protein and its peptido-mimetics on neutrophil recruitment and activation. However, many other cells central to inflammation, e.g. endothelial cells or mast cells, also express ANXA1: it is foreseen that a better definition of the role(s) of the endogenous protein in these cells will open the way to further pharmacological studies. We propose that a more systematic analysis of ANXA1 physio-pharmacology in cells involved in the host inflammatory reaction could aid in the design of novel anti-inflammatory therapeutics based on this endogenous mediator.
... In the period II, plasma TBARS levels were found to be significantly lower than those in the period I and in the pre-treatment phase. Increased TBARS levels without treatment of the disorder have been reported to disable cellular membrane functions by stimulating phospholipase A 2 and thus release interleukins by stimulating the immune system (Sierra and Murphy 1992). ...
The changes in antioxidant-oxidant balance play important roles in the pathophysiology of neuropsychiatric conditions. Bipolar disorder (BD) is a psychiatric condition with recurrent mood disturbances. This study evaluates the effects of treatment with lithium, alone or in combination with antipsychotic olanzapine, on oxidant-antioxidant status and atherogenic character in patients with BD. The blood samples from 15 patients were tested before the treatment (pre-treatment phase) and at the ends of two consecutive treatment periods: period I, treatment with lithium and an antipsychotic drug, olanzapine (first 6 months) and period II, treatment with only lithium (6 months following period I). We measured serum atherogenic lipids (total cholesterol, triglycerides, and LDL-cholesterol), plasma lipid peroxides (thiobarbituric acid-reactive substances), antioxidant enzymes (glutathione peroxidase, superoxide dismutase, and catalase) in neutrophils and lymphocytes, and total antioxidant status in plasma. Compared with pre-treatment phase, the lipid parameters were increased with each treatment; especially, LDL-cholesterol was significantly increased only with lithium treatment. These findings alert to be cautious about use of lithium in patients with atherogenic conditions. Moreover, plasma lipid peroxides were decreased significantly after the combination therapy and further decreased with lithium treatment. Antioxidant enzyme activities in lymphocytes were decreased after both types of treatment. Importantly, plasma total antioxidant status was increased only with lithium treatment. Thus, treatment with lithium alone decreases already up-set oxidant status in BD. In conclusion, the combination therapy with olanzapine is better in terms of atherogenic profile, while lithium alone produces better antioxidant status in patients with BD.
Agomelatine (AGOM) as an antidepressant acts both as a melatonin-receptor agonist and a selective serotonin-receptor antagonist. As a potent melatonin derived antioxidant, AGOM might modulate depression-induced lipid peroxidation and pro-inflammatory cytokines in brain, kidney and liver. The present study explores whether AGOM protects against experimental depression-induced brain, kidney and liver oxidative stress, and plasma cytokine production in rats with chronic mild stress (CMS)-induced depression. Thirty-six rats were divided into four groups. The first group was used as an untreated control. The second group received AGOM for 4 weeks. The third group was exposed to chronic mild stress (CMS) of 4 weeks for induction depression. The fourth group received 40 mg/kg AGOM and CMS for 4 weeks. Liver and kidney lipid peroxidation levels were high in the CMS group although they were low in AGOM treatments. AGOM and AGOM + CMS treatments increased the lowered glutathione peroxidase activity and reduced glutathione levels in brain, kidney and liver of CMS group. β-carotene, vitamin A and vitamin E concentrations in the brain, kidney and liver of the four groups were not changed by CMS and AGOM treatments. However, plasma TNF-α, interleukin (IL)-1β, and IL-4 levels were high in the CMS and AGOM group and their levels were further increased by the AGOM + CMS treatment. In conclusions, AGOM induced protective effects against experimental depression-induced brain, kidney, and liver oxidative injuries through regulation of the glutathione concentrations and glutathione peroxidase activity. However, plasma cytokine productions were increased by the AGOM treatment.
Aim: Brain is more vulnerable to oxidative free radicals than other tissues. Oxidative stress might primarily or secondarily be involved in the pathogenesis of bipolar affective disorder. Therefore this study was aimed to estimate & compare parameters of oxidative stress and antioxidant levels in bipolar patients and healthy controls. Methods: A total of 32 bipolar patients and 30 healthy subjects were recruited in this study. Serum MDA level was measured as indicator of lipid peroxidation and vitamin C, E & glutathione were determined as a measure of antioxidant status. Results: Significantly (p<0.001) elevated MDA level was found in patient before treatment (7.11 ± 1.62 nmol/ml) as compared to control (3.02 ± 1.30 nmol/ml) group. Patients on follow-up also had significantly increased MDA level (5.37 ± 1.36 nmol/ml) as compared to control group and decrease in level was significant (p<0.001) in comparison to before treatment patients. Vitamin C (0.82 ± 0.32 mg/dl), E (0.77 ± 0.20 mg/dl) and glutathione (4.44 ± 0.91 µmol/gm Hb) levels were significantly (p<0.001) reduced in patient group compared with those of control (1.53 ± 0.56 mg/dl), (1.27 ± 0.37 mg/dl) and (9.66 ± 1.79 µmol/gm Hb) respectively. Conclusion: The findings suggest that there is increased oxidative stress in bipolar patients in comparison to controls.
We investigated the effects of lamotrigine, aripiprazole and escitalopram administration and experimental depression on lipid peroxidation (LP) and antioxidant levels in cortex of the brain in rats. Forty male wistar rats were randomly divided into five groups. First group was used as control although second group was depression-induced group. Aripiprazole, lamotrigine and escitalopram per day were orally supplemented to chronic mild stress (CMS) depression-induced rats constituting the third, fourth and fifth groups for 28 days, respectively. Depression resulted in significant decrease in the glutathione peroxidase (GSH-Px) activity, reduced glutathione and vitamin C of cortex of the brain although their levels and beta-carotene concentrations were increased by the three drugs administrations to the animals of CMS induced depression group. The LP levels in the cortex of the brain and plasma of depression group were elevated although their levels were decreased by the administrations. The increases of antioxidant values in lamotrigine group were higher according to aripiprazole and escitalopram supplemented groups. Vitamin A level did not change in the five groups. In conclusion, the experimental depression is associated with elevated oxidative stress although treatment with lamotrigine has most protective effects on the oxidative stress within three medicines.
Annexin I is a phospholipid and actin binding protein which may play a role in signal transduction to the cytoskeleton. Previous work reported the differential expression of annexin I mRNA among rat adenocarcinoma cell lines of various metastatic potential (MTLn3, MTLn2, MTC.4: highest to lowest, respectively) (Pencil et al. 1993, Breast Cancer Res Treat, 25, 165-74). This relationship has been extended to the protein level in in vitro cultures using Western blotting and flow cytometry. Annexin I protein levels in MTLn3 cells are 3- to 5-fold higher than in MTC.4 cells. The weakly metastatic cell line MTLn2 shows levels 1.5- to 2.5-fold higher than MTC.4. In vivo tumors were produced by injecting 1 x 10(6) cells into mammary fat pads of syngeneic rats and necropsies were performed 40 days later. Semiquantitative immunohistochemical color image analysis was performed using a polyclonal rat annexin I specific antibody. Annexin I protein expression was highest in lung metastases of MTLn3, at 8-fold the levels observed in the MTC.4 primary tumors. MTLn3 cells in the primary tumor had an annexin I specific optical density 3-fold higher than that of cells in the MTC.4 primary tumor. MTLn2 primary tumors had an annexin I specific optical density 1.5-fold higher than MTC.4. A proportion of human mammary adenocarcinomas also have positive annexin I immunoreactivity, often with more uniform annexin I staining in the lymph node metastases. These results suggest that there may be survival advantages for nascent metastatic cells with high annexin I levels.
Die Bedeutung des oxidativen Stresses als ätiologischer Faktor in der Pathogenese der schizophrenen Psychosen und affektiven Störungen wird mehrfach diskutiert. In der vorliegenden Studie wurden die Konzentrationen zweier Isoenzyme der Superoxiddismutase (SOD), Cu/Zn-SOD und Mn-SOD, mittels ELISA in verschiedenen kortikalen und subkortikalen Regionen in post mortem Gehirngewebe von Patienten mit einer Erkrankung aus dem schizophrenen Formenkreis, mit einer depressiven Verstimmung und bei neuropsychiatrisch unauffälligen Individuen bestimmt. Die Ergebnisse dieser Arbeit stützen die Befunde anderer Studien, die auf eine Erhöhung des oxidativen Stresses hinweisen und eine Beteiligung freier Radikale in der Pathogenese der Schizophrenie und unipolaren Depression vermuten Impaired oxidative stress defense has been reported in patients suffering from schizophrenic psychosis or depressive disorder, indicating the involvement of free radical metabolism in the pathogenetic processes of these diseases. In this study, the concentrations of two isoenzymes of superoxide dismutase (SOD), Cu, Zn- and MnSOD, were determined with ELISA in various cortical and subcortical areas of post-mortem brain tissue from patients diagnosed with a schizophrenia spectrum disorder or depressive disorder and compared with post-mortem brain tissue from individuals without neuropsychiatric disorders. The results of this study support previous reports of impaired antioxidative defense system and suggest that increased oxidative stress plays a important role in the etiopathogenesis of major psychosis.
produces significant morbidity and some mortality. Three major pathobiological phenomenon contribute to the eventual progressive joint destruction: inflammation, abnormal cellular and humoral immune responses and synovial hyperplasia.t.2 The treatment of RA presents a tremendous challenge and currently consists of combination of non-steroidal anti-inflammatory drugs (NSAIDs) and slow-acting antirheumatic drugs (SAARDs) such as chloroquine. gold salts, d-penicillamine, sulfasalazine. azathioprine and methotrexate also referred to as second line drugs.3 NSAlDs provide some symptomatic relief but do not suppress cartilage erosion or the outcome of the disease. Side effects, especially gastrointestinal, are also relatively common with most NSAIDs. The SAARDs may alter disease outcome but their efficacy is di~puted.~ Furthermore, most patients treated with SAARDs drop out over a five-year period due to either lack of efficacy or adverse reaction^.^
Antiflammins are synthetic peptides derived from the region of highest local similarity between uteroglobulin and lipocortin. These peptides have shown anti-inflammatory activity on carrageenan-induced rat footpad edema. They are potent inhibitors for phospholipase A2 activation both in vitro and in vivo. Previously, we have demonstrated the effectiveness of topical antiflammins in suppressing acute ocular inflammation and allergic response in rodent endotoxin-induced uveitis and murine allergic conjunctivitis. The mechanisms by which antiflammins protect against inflammation and allergy in these ocular models may involve inhibition of phospholipase A2 and inducible nitric oxide synthase (iNOS) as well as the production of proinflammatory cytokine, interleukin-6.
Uteroglobin/Clara cell 10-kDa protein (UG/CC10) is a hormonally regulated small secretory protein that has a variety of in vitro and in vivo pharmacological effects. These include a potent anti-inflammatory activity and inhibitory effects on neutrophil migration, thrombin-induced platelet aggregation, in vitro chemoinvasion, as well as "tumor suppressor"-like effects and other properties. Several mechanisms of action have been proposed for these effects. Pharmacological properties suggest that UG itself or substances derived from it may be used as experimental drugs for several indications. The group of oligopeptides collectively known as "antiflammins" (AFs) were originally described in 1988. Their design was derived from the region of highest sequence similarity between UG and another group of proteins with anti-inflammatory properties, the lipocortins or annexins. Nanomolar concentrations of these peptides can reproduce several of the pharmacological activities of UG, including its in vivo anti-inflammatory effects and inhibition of platelet aggregation. The AFs have been safely and effectively used to suppress inflammation and fibrosis in several animal models. Progress in clarifying the mechanism of action of the AFs may facilitate the structure-based design of a novel class of potent anti-inflammatory, antichemotactic drugs.
Reactive oxygen species (ROS) may play a role in some neuropsychiatric disorders. There is some evidence that the activation of immune-inflammatory process, increase of monoamines catabolism, and abnormalities in lipid compounds may cause overproduction of ROS and, in turn, antioxidative enzyme activities (AEAs) and lipid peroxidation (LP), and that these phenomena may be related to pathophysiology of major depression.
The aims of this study were (i) to examine the AEAs and LP levels of the major depressed (MD) patients, and to compare these with healthy controls; and (ii) to investigate the effect of subchronic treatment with selective serotonin reuptake inhibitors (SSRIs) on AEAs and LP levels in MD subjects. Thirty MD patients, and 32 healthy controls (HC) participated in this study. AEAs and LP levels were determined by measuring several antioxidative enzymes and malondialdehyde (MDA) levels in plasma and/or in red blood cells.
Major depressed patients, especially melancholic patients, had higher AEA and LP levels than those of healthy controls. After treatment for 3 months with SSRIs, AEA and LP levels of the patients were significantly decreased to normal levels.
These findings suggest that (i) major depression, especially with melancholia, is associated with elevated AEAs and LP, and that (ii) subchronic treatment with SSRIs may have a suppressive effect on AEA and LP. CLINICAL IMPLICATION AND LIMITATION: AEAs might be used for monitoring SSRIs effects.
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