自由基代谢与精神分裂症临床症状和药物治疗的关系

目的：探讨自由基代谢与精神分裂症临床症状和药物治疗的关系。方法：是否治疗的慢性精神分裂症患者各４０例分别评定定阳性和阴性症状量表（ＰＡＮＳＳ）,并测定膜脂质过氧化物丙二醛（ＭＤＡ）含量、铜／锌超氧化物歧化酶（Ｇｕ－ＺｎＳＯＤ）和谷胱苷肽过氧化物酶（ＧＳＨ－Ｐｘ）活性。结果：与健康对照组相比,未治疗组患者ＭＤＡ含量和ＧＳＨ－Ｐｘ活性显著增加,治疗组患者无显著改变;而两组患者ＳＯＤ活性显著降低;未治疗     

Serum Oxidative Stress Marker Levels in Unmedicated and Medicated Patients with Schizophrenia

Oxidative stress has been suggested to be involved in schizophrenia, but studies have demonstrated inconsistent results on oxidative stress marker level/activity in patients with schizophrenia. In order to clarify the circulating oxidative stress marker level/activity in patients with schizophrenia, this study recruited 80 schizophrenia patients (40 first-episode, drug-free and 40 chronically medicated patients) and 80 controls to analyze serum activities of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and total antioxidant capacity (T-AOC), and levels of lipid peroxidation marker malondialdehyde (MDA) in schizophrenia patients, and whether they associate with the severity of the disease. We showed that only serum GSH-Px activity was significantly reduced in unmedicated patients with schizophrenia when compared with control subjects, whereas the other three analyzed oxidative stress markers did not show significant differences between cases and controls. Moreover, our results demonstrated that chronic medication increased GSH-Px activity and MDA levels in patients with schizophrenia, but reduced SOD activity in the patients. We also found that short-term antipsychotic treatments on the patients with schizophrenia reduced the SOD activity. Correlation analyses indicated that the oxidative stress marker activity/level is not significantly associated with the severity of schizophrenia, except that SOD level correlated with PANSS positive score significantly. Taken together, the data from the present study suggested that the dysfunctions of oxidative stress markers in patients with schizophrenia were mainly caused by antipsychotics, emphasizing increased oxidative stress as a potential side effect of antipsychotics on the patients.     

Bcl-2 associated with positive symptoms of schizophrenic patients in an acute phase

B cell lymphoma protein-2 (Bcl-2) may contribute to the pathophysiology of schizophrenia in the brain. The aim of this study was to investigate the serum levels of Bcl-2 in schizophrenic patients in an acute phase, and evaluate Bcl-2 level changes after antipsychotic treatment. We consecutively enrolled 41 schizophrenia patients in an acute phase; 28 were followed up with a 4-week antipsychotic treatment. Serum Bcl-2 levels were measured with assay kits. All patients were evaluated by examining the correlation between Bcl-2 levels and Positive and Negative Syndrome Scale (PANSS) scores, using Pearson correlation coefficients. In schizophrenic patients in an acute phase, positive PANSS subscores were significantly negatively correlated with Bcl-2 levels. In addition, we found Bcl-2 levels had a significantly negative correlation with PANSS total scores and positive subscores in male patients in an acute phase. Using the paired t-test, we found no significant changes in Bcl-2 levels in schizophrenia patients who had received the 4-week treatment with antipsychotic drugs (n=28). In conclusion, our results suggest that Bcl-2 might be an indicator of schizophrenia severity in the acute phase. In addition, Bcl-2 levels might be associated with positive symptoms in male patients with schizophrenia.     

Antioxidant intervention attenuates oxidative stress in children and teenagers with Down syndrome

We previously demonstrated that systemic oxidative stress is present in Down syndrome (DS) patients. In the present study we investigated the antioxidant status in the peripheral blood of DS children and teenagers comparing such status before and after an antioxidant supplementation. Oxidative stress biomarkers were evaluated in the blood of DS patients (n = 21) before and after a daily antioxidant intervention (vitamin E 400 mg, C 500 mg) during 6 months. Healthy children (n = 18) without DS were recruited as control group. The activity of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GR), glutathione S-transferase (GST), gamma-glutamyltransferase (GGT), glucose-6-phosphate dehydrogenase (G6PD) and myeloperoxidase (MPO), as well as the contents of reduced glutathione (GSH), uric acid, vitamin E, thiobarbituric acid reactive substances (TBARS), and protein carbonyls (PC) were measured. Before the antioxidant therapy, DS patients presented decreased GST activity and GSH depletion; elevated SOD, CAT, GR, GGT and MPO activities; increased uric acid levels; while GPx and G6PD activities as well as vitamin E and TBARS levels were unaltered. After the antioxidant supplementation, SOD, CAT, GPx, GR, GGT and MPO activities were downregulated, while TBARS contents were strongly decreased in DS. Also, the antioxidant therapy did not change G6PD and GST activities as well as uric acid and PC levels, while it significantly increased GSH and vitamin E levels in DS patients. Our results clearly demonstrate that the antioxidant intervention with vitamins E and C attenuated the systemic oxidative damage present in DS patients.     

The Combined Effect of Sleep Deprivation and Western Diet on Spatial Learning and Memory: Role of BDNF and Oxidative Stress

Either sleep deprivation or Western diet can impair learning and memory via induction of oxidative stress, which results in neuronal damage and interference with the neurotransmission. In this study, we examined the combined effect of sleep deprivation and Western diet on hippocampus-dependent spatial learning and memory. In addition, possible molecular targets for sleep deprivation and Western diet-induced cognitive impairments were investigated. Sleep deprivation was induced in rats using the modified multiple platform model simultaneous with the administration of Western diet for 6 weeks. Thereafter, spatial learning and memory were tested using radial arm water maze. At the molecular level, BDNF protein and antioxidant markers including superoxide dismutase (SOD), catalase, glutathione peroxidase (GPx), glutathione (GSH), oxidized glutathione (GSSG), GSH/GSSG, and thiobarbituric acid reactive substances (TBARS) were assessed. The results of this study revealed that sleep deprivation, Western diet, or a combination of both impair short- and long-term memory (P?<?0.05). The magnitude of the impairment induced by the combined treatment at the 24-h long-term memory was higher than that caused by each factor alone (P?<?0.05). In addition, the combined treatment reduced the levels of hippocampal BDNF, a reduction that was not detected with each factor alone. Moreover, the combined treatment reduced the hippocampal activities of SOD, catalase, GPx, ratio of GSH/GSSG, and elevated TBARS level (P?<?0.05). In conclusion, the combination of sleep deprivation and Western diet decreases BDNF levels and increases oxidative stress in the hippocampus, thus inducing memory impairment that is greater than the impairment produced by each factor alone.     

Risperidone reverses phencyclidine induced decrease in glutathione levels and alterations of antioxidant defense in rat brain

Perinatal phencyclidine (PCP) administration to rats represents one of the actual animal models of schizophrenia. Numerous data suggest redox dysregulation in this disease. We have previously demonstrated decreased content of the reduced glutathione (GSH) and complex disbalance of antioxidant enzymes in the brain of rats perinatally treated with PCP. The aim of this study was to elucidate whether chronic risperidone treatment can reverse these changes. The Wistar rats were perinatally treated with either PCP (10mg/kg; PCP, two groups) or saline (0.9% NaCl, two groups). At postnatal day (PN) 35, two groups of rats one NaCl and one PCP have started to receive risperidone in drinking water for nine weeks (NaCl-RSP and PCP-RSP groups). Animals were sacrificed on PN100 and the levels of GSH, the activities of γ-glutamate cysteine ligase (GCL), glutathione peroxidase (GPx), glutathione reductase (GR) and superoxide dismutase (SOD), as well as, the concentration of lipid peroxides were determined in the different brain structures. Risperidone restored decreased GSH levels, as well as decreased γ-GCL activity in cortex and hippocampus of animals perinatally treated with PCP. Alterations in GPx and GR activities caused by perinatal PCP treatment were also reversed by risperidone in most investigated brain structures. Furthermore, chronic risperidone treatment caused the decrease in SOD activity both in control and in PCP perinatally treated groups. Increased levels of lipid peroxides noticed in hippocampus and thalamus were reversed after chronic risperidone treatment. The results of the present study demonstrate that risperidone treatment restores GSH levels and to great measure reverses antioxidant defense alterations in the brain of perinatally PCP treated rats. Further studies are necessary in order to clarify the significance of risperidone influence on oxidative stress parameters in schizophrenia.     

Elevated plasma superoxide dismutase in first-episode and drug naive patients with schizophrenia: inverse association with positive symptoms

Excessive free radical production or oxidative stress may be involved in the pathophysiology of schizophrenia as evidenced by increased superoxide dismutase (SOD) activities, a critical enzyme in the detoxification of superoxide radicals. This study compared plasma SOD activities in 78 never-medicated first-episode and 100 medicated chronic schizophrenia patients to 100 healthy control subjects and correlated these SOD activities with the Positive and Negative Syndrome Scale (PANSS) among the schizophrenic patients. We found that both first-episode and chronic patients had significantly increased plasma SOD activities compared to controls, and that chronic schizophrenic patients on antipsychotic medication had significantly higher SOD activities than first episode schizophrenic patients. Plasma SOD activities were also negatively correlated with positive symptoms of schizophrenia, but only in first-episode patients. Thus, oxidative stress appears to be greater in first episode schizophrenic patients with fewer positive symptoms and may become greater as schizophrenia becomes more chronic, although we cannot exclude the possibility that chronic antipsychotic treatment may increase SOD activities and presumed oxidative stress in schizophrenia.     

Decreased antioxidant enzymes and membrane essential polyunsaturated fatty acids in schizophrenic and bipolar mood disorder patients

Oxidative stress-mediated cell damage has been considered in the pathophysiology of schizophrenia. Abnormal findings have often been considered related to differences in ethnicity, life style, dietary patterns and medications, all of which influence indices of oxidative stress and oxidative cell damage. To minimize these confounds, schizophrenic patients were compared with age-matched control subjects with the same ethnic background and similar lifestyle, as well as with bipolar mood disorder (BMD) patients. Levels of antioxidant defense enzymes (i.e. superoxide dismutase, SOD; catalase, CAT; and glutathione peroxidase, GPx) were lower in schizophrenic patients than in controls, indicating conditions for increased oxidative stress. The contents of plasma thiobarbituric acid reactive substances (TBARS) were only marginally higher in schizophrenic patients, who had normal levels of arachidonic acid (AA), a major source of TBARS, indicating no significant oxidative membrane lipid peroxidation. Levels of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), however, were significantly lower in schizophrenic patients. When the same indices in BMD patients were compared with findings in matched controls, levels of only SOD and CAT were lower in the patients, whereas GPx was not. Again, as in schizophrenia, the contents of TBARS were marginally higher in BMD patients with no change in levels of AA. Levels of alpha-linolenic acid and EPA were significantly lower and levels of DHA were slightly lower in BMD patients. These data indicate that certain biochemical characteristics may be common to a spectrum of psychiatric disorders, and suggest supplementation of antioxidants and essential fatty acids might affect clinical outcome.     

Serum S100B and antioxidant enzymes in bipolar patients

Bipolar disorder (BD) is a chronic, severe, and highly disabling psychiatric disorder; peripheral markers have been used to assess biochemical alterations associated with BD and/or possibly involved in its pathophysiology. Beyond neuronal commitment, many groups have proposed the involvement of glial activity in psychiatric disorders. Other biochemical markers, particularly associated with oxidative stress, have been studied in BD. In the present study, we evaluated glial involvement and oxidative stress in patients with BD. Glial activity was assessed by measuring serum S100B content; oxidative stress was assessed using serum thiobarbituric acid reactive substances (TBARS) and activities of antioxidant enzymes in BD patients during different episodes of disease. We found a significant increment of serum S100B during episodes of mania and depression, but not in euthymic patients. Superoxide dismutase (SOD) activity, as well the SOD/glutathione peroxidase plus catalase ratio, was also increased in manic and depressed patients. On the other hand, TBARS levels were increased in BD patients regardless of the phase of the disorder. These findings suggest a potential oxidative damage in BD patients. This peripheral oxidative imbalance indicates that systemic changes are taking place during the active phases of the illness. Such changes appear to relate to astrocyte function, as indicated by serum S100B elevation.     

Persistence of the benefit of an antioxidant therapy in children and teenagers with Down syndrome

This study examined the effect of an antioxidant intervention in biomarkers of inflammation and oxidative stress (OS) in the blood of Down syndrome (DS) children and teenagers during four different stages. A control group was composed by healthy children (n = 18), assessed once, and a Down group composed by DS patients (n = 21) assessed at the basal period (t₀), as well as after 6 months of antioxidant supplementation (t₁), after 12 months (after interruption of the antioxidant intervention for 6 months) (t₂), and again after further 6 months of antioxidant supplementation (t₃). Biomarkers of inflammation (myeloperoxidase activity – MPO and levels of IL-1β and TNF-α) and OS (thiobarbituric acid reactive substances – TBARS, protein carbonyls – PC), reduced glutathione (GSH), uric acid (UA) and vitamin E levels, as well as antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT), glutathione reductase (GPx), glutathione reductase (GR), glutathione-S-transferase (GST) and gamma-glutamyltransferase (GGT) activities, were measured after each period. After the antioxidant supplementation, the activities of SOD, CAT, GPx, GR, GGT and MPO were downregulated, while TBARS contents were strongly decreased, the contents of GSH and vitamin E were significantly increased, and no changes in G6PD and GST activity as well as in UA and PC levels were detected. After the interruption of the antioxidant therapy for 6 months, DS patients showed elevated GPx and GGT activities and also elevated UA and TBARS levels. No changes in SOD, CAT, GR, GST, G6PD and MPO activities as well as in GSH, vitamin E, PC, TNF-α and IL-1β levels were detected. The results showed that the antioxidant intervention persistently attenuated the systemic oxidative damage in DS patients even after a relatively long period of cessation of the antioxidant intervention.