Elevated activity of superoxide dismutase in male late-life schizophrenia and its correlation with clinical symptoms and cognitive deficits.

BACKGROUND: Despite inconsistent findings, accumulative evidence has shown abnormalities of the key antioxidant enzyme, superoxide dismutase (SOD), in patients with schizophrenia. However, few studies explored SOD in late-life schizophrenia (LLS). Our work aimed to investigate changes in SOD activity and the relationship between SOD activity and psychotic symptoms or cognitive deficits in LLS. METHODS: 32 geriatric male patients with schizophrenia (age ≥ 60) and 28 age-matched male normal controls were recruited in the study. We assessed cognitive functions with the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), evaluated the severity of clinical symptoms with the Positive and Negative Syndrome Scale (PANSS), and measured the plasma levels of SOD. RESULTS: Patients with LLS presented with higher total levels of SOD compared to the controls (81.70 vs. 65.26 U/ml, p < .001). Except for the visuospatial index, the cognitive performance was significantly worse on RBANS total and other domain scores in the schizophrenia group than the control group. In the schizophrenia group, SOD levels were positively correlated with subscores of general psychopathology and negative symptoms and total scores of the PANSS (all p < .05), and inversely associated with performance in immediate memory, language, and RBANS total scores (all p < .05). CONCLUSIONS: Our findings suggest that patients with LLS display disturbances in the antioxidant system, which may underlie the pathological process of cognitive impairments and negative symptoms in the late stage of schizophrenia. Supplementing with antioxidants could be a potential treatment.

Effect of the complete replacement of dietary fish meal by soybean meal on histopathology and immune response of the hindgut in grass carp (Ctenopharyngodon idellus).

A 14-day experiment was conducted to explore the pathological process and immune response of soybean meal (SBM) induced enteritis (SBMIE) in grass carp (Ctenopharyngodon idellus). The complete replacement of dietary fish meal (FM) with SBM resulted in a remarkable reduction in final body weight, weight gain ratio, and feed conversion efficiency (p < 0.05). The typical histopathological changes of SBMIE appeared starting at day 4, and progressively increased in severity until day 8, then gradually subsided after day 11. The course of SBMIE could be divided into incubation period (days 1-2), prodromal period (days 3-6), symptomatic period (days 7-10), and convalescent period (days 11-14). Transcription levels of pro-inflammatory cytokines, including IL-1ß, TNF-α, IL-6, IL-8, IL-17A/F1 and IFN-γ2, were up-regulated during the prodromal period, and then down-regulated during the convalescent period. Transcript levels of anti-inflammatory cytokines (IL-10 and TGFß1) and their receptors (IL-10R1 and TßRII), were up-regulated during the prodromal and convalescent periods. Transcript levels of MHCIIß, Igµ, Igτ, TCRδ, TCRß, CD4, and CD8α were altered in SBMIE. Furthermore, expression levels of T-bet, IFN-γ2, RORγ2 and IL-17A/F1 were significantly increased in the initiation of enteritis, whereas the transcript levels of Foxp3 and IL-2/15Ra were significantly up-regulated in the repair of enteritis. In conclusion, grass carp SBMIE is regulated by the adjustment of SBM-based diet intake, and the changes of the above-mentioned genes expression suggest that these genes may be involved in SBMIE.

Ginkgo biloba leaf extract and alpha-tocopherol attenuate haloperidol-induced orofacial dyskinesia in rats: Possible implication of antiapoptotic mechanisms by preventing Bcl-2 decrease and Bax elevation.

BACKGROUND: Tardive dyskinesia (TD) is a serious side effect of long-term administration of typical neuroleptics, such as haloperidol. The pathophysiology of TD remains unclear, but the experimental evidence suggests that free radical-induced neuronal apoptosis in the basal ganglia may play an important role. PURPOSE: This study was to investigate changes in Bax and Bcl-2 expression levels in TD-associated brain regions and the effects of the antioxidant EGb761 on Bax and Bcl-2 levels in an animal model of TD. METHODS: Thirty-two rats were randomly divided into four study groups: saline control (saline), haloperidol-alone (haloperidol), EGb761-haloperidol (EGb), and alpha-tocopherol-haloperidol (vitamin E). Rats were treated with daily intraperitoneal haloperidol injections (2 mg/kg/day) for 5 weeks. EGb761 (50 mg/kg/day) and alpha-tocopherol (20 mg/kg/day) were then administered for another 5 weeks during the withdrawal period. Behavioral assessments were performed, and Bax and Bcl-2 protein expression levels were immunohistochemically analyzed in four brain regions, including the prefrontal cortex, striatum, substantia nigra, and globus pallidum. RESULTS: We found that increased vacuous chewing movements (VCMs) were associated with increased proapoptotic Bax protein expression, decreased antiapoptotic Bcl-2 protein expression, and an increased Bax/Bcl-2 ratio. EGb761 and alpha-tocopherol treatment reversed the increase in VCMs, decreased Bax expression, increased Bcl-2 expression, and decreased the Bax/Bcl-2 ratio. CONCLUSIONS: These results demonstrate that long-term haloperidol administration may affect Bcl-2 protein family expression and promote neuronal apoptosis in the basal ganglia. In combination with their antioxidant capacity, EGb761 and alpha-tocopherol's antiapoptotic effects through Bcl-2 might account for the symptom improvement observed in haloperidol-induced TD rats.

Ginkgo biloba and vitamin E ameliorate haloperidol-induced vacuous chewingmovement and brain-derived neurotrophic factor expression in a rat tardive dyskinesia model.

Neurodegeneration may be involved in the development of tardive dyskinesia (TD), and low levels of brain-derived neurotrophic factor (BDNF) may play a role. Ginkgo biloba (EGb761), a potent antioxidant, may have neuroprotective effects. We hypothesized that there would be decreased BDNF expression in TD, but that treatment with EGb761 would increase BDNF expression and reduce TD manifestations in a rat model. Forty rats were treated with haloperidol (2mg/kg/day via intraperitoneal injections) for 5weeks. EGb761 (50mg/kg/day) and vitamin E (20mg/kg/day) were then administered by oral gavage for another 5weeks, and we compared the effects of treatment with EGb761 or vitamin E on haloperidol-induced vacuous chewing movements (VCMs) and BDNF expression in four brain regions: prefrontal cortex (PFC), striatum (ST), substantia nigra (SNR), and globus pallidus (GP). Our results showed that haloperidol administration led to a progressive increase in VCMs, but both EGb761 and vitamin E significantly decreased VCMs. Haloperidol also decreased BDNF expression in all four brain regions, but both EGb761 and vitamin E administration significantly increased BDNF expression. Our results showed that both EGb761 and VE treatments exerted similar positive effects in a rat model of TD and increased BDNF expression levels in the four tested brain regions, suggesting that both EGb761 and vitamin E improve TD symptoms, possibly by enhancing BDNF in the brain and/or via their free radical-scavenging actions.

Beneficial effects of EGb761 and vitamin E on haloperidol-induced vacuous chewing movements in rats: Possible involvement of S100B mechanisms.

Tardive dyskinesia (TD) is a serious side effect induced by the long-term administration of typical antipsychotics. The pathophysiology of TD remains unclear, but experimental evidence suggests that neurodegeneration caused by free radicals may play an important role in TD development. S100B is considered a potential biomarker of structural neural and glial damage. This study investigated S100B expression in TD-related brain regions and assessed the effect of antioxidants Gingko biloba leaf extract (EGb761) and vitamin E (VE) on S100B in TD rats. A total of 32 rats were randomly divided into 4 study groups: saline control (saline), haloperidol alone group (Hal), EGb761-haloperidol (EGb-Hal), and vitamin E-haloperidol (VE-Hal). Rats were treated with haloperidol intraperitoneal injections (2mg/kg/day) each day for 5 weeks. EGb761 (50mg/kg/day) and VE (20mg/kg/day) were then administered during a 5-week withdrawal period. We performed behavioral assessments and immunohistochemically analyzed S100B expression in four TD-related brain regions. Our findings demonstrated that haloperidol administration led to a progressive increase in VCMs and in S100B expression in all four brain regions. Both EGb761 and VE reversed these changes, and there were no group differences between the EGb761 and VE groups. Our results indicated that long-term administration of haloperidol may induce VCMs and increase S100B expression in TD-related brain regions, and S100B may be a significant biomarker related to TD pathophysiology. Moreover, the antioxidant capacity of EGb761 and VE coupled with the possible neuroprotective effects of S100B may account for their success in improving the symptoms of haloperidol-induced TD.

Biological evaluation of a novel Herceptin-platinum (II) conjugate for efficient and cancer cell specific delivery.

Platinum-based drugs have been widely used for the treatment of malignant tumors. However, their applications are limited by severe side effects for their lack of selectivity for cancer cells. The development of antibody drug conjugates (ADCs) have provided a platform to reduce drug toxicity and improve drug efficacy. Here we describe a nover conjugate comprising of Herceptin (an anti-HER2 antibody) and platinum drug via a cathepsin B cleavable dipetide for enhancing drug accumulation and HER2-positive cancer cell specific delivery. This conjugate is believed to be cleaved by cathepsin B, leading to a 1,6-elimination reaction and activation of drug release. Herceptin-Pt(II) is evaluated to have approximately loaded with 6.4 moles platinum drugs per mole of antibody. We demonstrate that Herceptin-Pt(II) retain high and selective binding affinity for HER2 protein and HER2-positive SK-BR-3 cancer cells. The in vitro cytotoxicity tests indicate that Herceptin-Pt(II) exhibits much higher cytotoxicity than oxaliplatin against SK-BR-3 cells. More importantly, Herceptin-Pt(II) shows no obvious inhibition against the growth of both MCF-7 and MDA-MB-231 cells, which express lower levels of HER2. Furthermore, compared with free oxaliplatin, Herceptin significantly improved the cellular uptake of platinum drugs in SK-BR-3 cells. In summary, Herceptin-platinum (II) conjugate is a remarkable and potent platform for efficient and cancer cell specific delivery.

Extract of Ginkgo biloba is equivalent to vitamin E in attenuating and preventing vacuous chewing movements in a rat model of tardive dyskinesia.

Free radical-mediated abnormalities may contribute toward the pathogenesis of tardive dyskinesia (TD). Many studies have reported the protective antioxidant and free radical-scavenging activities of extract of Ginkgo biloba (EGb761) against free radical-induced cell damage and dysfunction. This study aimed to compare the efficacy of EGb761 with that of vitamin E for the prevention and treatment of TD in a rat model. We carried out two studies. First, rats were injected with haloperidol (2 mg/kg intraperitoneally) daily for 5 weeks. EGb761 (50 mg/kg/day) or vitamin E (20 mg/kg/day) were then administered for another 5 weeks, and their effects on vacuous chewing movements (VCMs) were compared. Second, we compared 10 weeks of haloperidol alone with 10 weeks of haloperidol plus EGb761 or vitamin E. The administration of haloperidol led to a progressive increase in VCMs, which peaked at week 5. In study one, EGb761 and vitamin E, administered by an oral gavage for 5 weeks during withdrawal from chronic haloperidol treatment, decreased VCMs significantly, showing 83.8 and 91.0% reduction, respectively, compared with the haloperidol-alone group. In study two, the concomitant administration of EGb761 and vitamin E led to significantly fewer VCMs, by 64.4 and 73.9%, respectively, compared with the haloperidol-alone group. There was no significant difference in either study between EGb761 and vitamin E treatment. EGb761 shows promise for the prevention and treatment of TD in a rat model with a magnitude that was similar to that of vitamin E.

Consolidation therapy is necessary following successful biofeedback treatment for pubertal chronic prostatitis patients: a 3-year follow-up study.

OBJECTIVE: To assess long-term effects of biofeedback training on pubertal chronic prostatitis (CP). METHODS: Pubertal CP patients received 12-week intensive biofeedback training and were divided into two groups: group 1 received further monthly training ≥ 24 (26-36) months; group 2 received further monthly training <24 (13-23) months. National Institutes of Health-CP Symptom Index (NIH-CPSI) scores, maximum urinary flow rate (Qmax) and postvoid residual urine volume (PVR) were recorded monthly. RESULTS: Total NIH-CPSI scores decreased significantly in group 1 (n = 10; mean age ± SD 16.5 ± 1.1 years) together with all subdomain scores (pain, urination, life impact). Total NIH-CPSI scores increased significantly in group 2 (n = 12; mean age ± SD 16.3 ± 1.2 years) at 30 and 36 months, and were significantly different from group 1 at these time points. Urination and life-impact scores increased significantly and Qmax decreased significantly in group 2 at 30 and 36 months. PVR was unchanged in either group. CONCLUSIONS: Twelve-week intensive biofeedback training requires lengthy consolidation sessions to achieve long-term success. Further investigation should assess longer intervals between consolidation sessions, for improving patient compliance and outcome.

Brain-derived neurotrophic factor levels and its Val66Met gene polymorphism predict tardive dyskinesia treatment response to Ginkgo biloba.

BACKGROUND: Tardive dyskinesia (TD) has no well-accepted treatments or known pathophysiology, but low brain-derived neurotrophic factor (BDNF) may play an important role in its pathophysiology. Ginkgo biloba (EGb-761) is a potent antioxidant that has neuroprotective effects mediated through enhancing BDNF levels. We hypothesized that treatment with EGb-761 would increase serum BDNF levels and reduce TD, particularly among schizophrenia patients who have the BDNF valine 66 to methionine (Val66Met) genotype (Val/Val). METHODS: Serum BDNF levels and genotyping for the BDNF gene Val66Met polymorphism were assessed in Chinese schizophrenic patients with (n = 368) and without (n = 563) TD as well as healthy control subjects (n = 546). About half of the TD patients (n = 157) then participated in a double-blind, randomized, placebo-control 12-week treatment with 240 mg per day of EGb-761. Serum BDNF levels were measured again at posttreatment. Clinical efficacy was determined using the Abnormal Involuntary Movement Scale (AIMS). RESULTS: TD patients had lower BDNF levels than the non-TD patients and healthy controls. EGb-761 treatment improved symptoms of TD and increased BDNF levels compared with placebo treatment. Moreover, the improvement of AIMS total score correlated with the increase in BDNF levels. Furthermore, improvement in the AIMS score was greatest in those with the Val/Val allele and lowest with the Met/Met allele. CONCLUSIONS: The BDNF system may be implicated in the pathophysiology of TD and its improvement with antioxidant treatment. Furthermore, patients with the genetic potential for greater BDNF release (Val/Val at 66) may obtain a greater reduction in TD from EGb-761 treatment.

Extract of Ginkgo biloba treatment for tardive dyskinesia in schizophrenia: a randomized, double-blind, placebo-controlled trial.

OBJECTIVE: Free radicals may be involved in the pathogenesis of tardive dyskinesia (TD). Extract of Ginkgo biloba (EGb) is a potent antioxidant possessing free radical-scavenging activities. The aim of the study was to evaluate the efficacy of EGb-761, a standardized extract given in capsule form, in treating TD in schizophrenia patients. METHOD: Inpatients with DSM-IV-diagnosed schizophrenia and TD (n = 157) in a mainland China Veterans Affairs psychiatric hospital were randomly assigned to 12 weeks of treatment with either EGb-761, 240 mg/d (n = 78) or a placebo (n = 79) in a double-blind manner. Primary outcome measures were (1) change from baseline in the Abnormal Involuntary Movement Scale (AIMS) score and (2) proportion of patients with a ≥ 30% reduction in their AIMS total score at week 12. Secondary outcome measures included the Positive and Negative Syndrome Scale (PANSS) and cognitive performance as measured by the Continuous Performance Test-37 Version and the 3-card Stroop task. Patients were recruited for the study between December 2006 and May 2007. RESULTS: Of the 157 patients who were randomly assigned, 152 (96.8%) completed the study. EGb-761 treatment significantly decreased the AIMS total score in patients with TD compared to those who were given a placebo (2.13 ± 1.75 vs -0.10 ± 1.69; P < .0001), with 40 (51.3%) and 4 (5.1%) patients achieving response in the EGb-761 and placebo treatment groups, respectively. There were no between-group differences in the PANSS total score or cognitive measures from baseline to week 12. CONCLUSIONS: EGb-761 appears to be an effective treatment for reducing the symptoms of TD in schizophrenia patients, and improvement may be mediated through the well-known antioxidant activity of this extract. TRIAL REGISTRATION: clinicaltrials.gov identifier: NCT00672373.

Effect of rapamycin on cue-induced drug craving in abstinent heroin addicts.

The mammalian target of rapamycin is an evolutionarily conserved serine-threonine kinase (mTOR), which controls protein synthesis and catabolism in response to environmental cues. This randomized double-blind clinical trial enrolled 60 abstinent heroin addicts and randomly assigned them to three groups: placebo, 2.5 mg and 5 mg rapamycin. The participants were given the cue-reactivity paradigm with 5 min exposures to neutral and drug-related imagery while craving, anxiety, blood pressure and heart rate pre- and post-exposure were assessed. We found that drug-related cues increased both craving and anxiety of abstinent heroin addicts, and had no effect on blood pressure and heart rate. A single high-dose of rapamycin significantly reduced the craving, but not anxiety induced by drug-related cues. Our findings suggested that rapamycin merits outpatient clinical trials as a potential pharmacotherapy for relapse prevention from drug-related cue induced craving.

Circadian alteration in neurobiology during 30 days of abstinence in heroin users.

BACKGROUND: Previous studies have shown that individuals withdrawn from chronic opiate administration undergo substantial elevations of cortisol levels with blunted corticotropin (ACTH) rhythms and that these changes persist beyond the 7-10 days of acute withdrawal symptoms. However, there are no published studies of changes in expression of clock genes or of other neuropeptides related to circadian-rhythm regulation, which may influence relapse susceptibility. METHODS: Blood samples were collected from 8 healthy control subjects and 16 heroin addicts during pharmacologically unassisted withdrawal on the 3rd, 10th, and 30th days of abstinence at 3-hour intervals for 24 hours. Outcome measures were the relative expression of clock gene mRNA (hperiod1, hperiod2, hclock) and the levels of serum cortisol, plasma ACTH, beta-endorphin (beta-EP), leptin, neuropeptide Y, interleukin-2 (IL-2), and tumor necrosis factor (TNF) in these subjects. RESULTS: Compared with healthy volunteers, abstinent addicts showed disruptions in diurnal rhythms of hPER1 and hPER2 mRNA expression, along with disruptions in diurnal rhythms of cortisol, ACTH, beta-endorphin, leptin, and IL-2 release. Several of these disruptions (hPER1, hPER2, ACTH, beta-endorphin, and IL-2) persisted for the 30-day testing period, as did elevation of 24-hour levels of cortisol and decreases in 24-hour IL-2 and TNF levels. CONCLUSIONS: These prolonged neurobiological changes may play a role in protracted opiate withdrawal symptoms and contribute to relapse vulnerability.

[Changes of sperm chromatin in oligo-astheno-teratozoospermia syndrome patients after treated by integrated Chinese and Western medicine].

OBJECTIVE: To observe the changes of sperm chromatin in patients with oligo-astheno-teratozoospermia (OAT) syndrome after treated by integrated Chinese and Western medicine. METHODS: Sixty patients with OAT syndrome were treated by integrated Chinese and Western medicine for 3 months. Their sperm samples were collected before and after the treatment, subjected to acridine orange staining and analyzed by fluorescent microscopy, flow cytometry and sperm routine detection. RESULTS: Significant differences were shown in the master-group sperm signals (P < 0.01) and at and COMPalphat (P < 0.05) by flow cytometry, as well as in the green and the red groups (P < 0.05) by fluorescent microscopy before and after the treatment. Changes in sperm concentration, motility, vitality and deformity were noted after the treatment, with statistic difference between pre- and post-treatment (P < 0.05) except in forward sperm concentration. CONCLUSION: Treatment by integrated Chinese and Western medicine can improve sperm chromatin in patients with OAT syndrome. Flow cytometry, along with fluorescent microscopy and sperm routine detection, plays an important role in the evaluation of male infertility therapy.

The effects of Ginkgo biloba extract added to haloperidol on peripheral T cell subsets in drug-free schizophrenia: a double-blind, placebo-controlled trial.

OBJECTIVE: To investigate the effects of Ginkgo biloba extract (EGb) administration on T lymphocyte subsets and superoxide dismutase (SOD) levels in schizophrenia. METHODS: One hundred and nine schizophrenic inpatients were randomly assigned to 12 weeks of treatment with 360 mg/day of EGb plus a stable dose of 0.25 mg kg(-1) day(-1) of haloperidol and placebo plus the same dose of haloperidol using a double-blind design. Clinical efficacy was determined using the Brief Psychiatric Rating Scale (BPRS), Scale for Assessment of Positive Symptoms, and Scale for Assessment of Negative Symptoms. T lymphocytes (CD3+), T helper cells (CD4+), T suppressor cells (CD8+), and IL-2-secreting cells were measured using the alkaline phosphatase/antialkaline phosphatase technique; and SOD levels were measured by radioimmunometric assay at baseline and at posttreatment, as compared to 30 sex- and age-matched normal subjects. RESULTS: Patients demonstrated significantly lower CD3+, CD4+, and IL-2-secreting cells, together with CD4/CD8 ratio, and significantly higher blood SOD levels than did healthy controls at baseline. There was a significantly negative relationship between SOD and CD4+ cells in the schizophrenic group at baseline. After a 12-week treatment, CD3+, CD4+, and IL-2-secreting cells, together with CD4/CD8 ratio, showed a significant increase, but a significant decrease in SOD levels in the EGb group. There was only a significant increase in CD4+ cells but no change in SOD levels in the placebo group. There was a significant correlation between the change in CD4+ cells at posttreatment vs pretreatment and a reduction of BPRS total score in the whole patient group. CONCLUSIONS: EGb may improve the decreased peripheral immune functions in schizophrenia. The beneficial effects of EGb on the immune systems and the improvement of schizophrenic symptoms may be medicated through its antioxidant activity.