Background: Increasing evidence indicates that oxidative injury exists in schizophrenia. Although it may not be the main cause, oxidative damage has been suggested to contribute to the pathophysiology and may account for deteriorating course and poor outcome in schizophrenia. There is increasing interest in the neuroprotective efficacy of antioxidants in modulating such processes with at least one polyphenolic being tested as a prophylactic in Alzheimer's disease. Beneficial effects of adjunctive ω-3 (n-3 series) polyunsaturated fatty acids with combined intakes of vitamin C and E on both the positive and negative symptoms of schizophrenia have been reported. Robust in vitro systems are desirable, enabling a mechanistic investigation of the molecular mechanisms underpinning such effects and identification of further potentially efficacious nutraceuticals. Materials and Method: Comparative studies employing a lymphoblastoid cell line of schizophrenic origin, a neuroblastoma IMR-32 cell line and the lymphoma U937 cell line was undertaken. The cytoprotective effects of phenolic antioxidants and essential fatty acids in affording protection to cellular DNA, protein and lipids from an oxidative challenge were assessed in the three cell lines. In addition, two human studies were undertaken. The first study utilised the non-invasive technique of breath hydrocarbon analysis and the lipid peroxidation products in a population of schizophrenic patients were compared to a population of apparently healthy aged-matched control subjects, while the second study investigated possible differences in biomarkers of DNA, lipid and protein oxidation in schizophrenic and control subjects. Plasma vitamin C levels were also compared in both groups. Results and Conclusion: Cell Culture Studies: Pre-treatment of peripheral and neuronal cells with antioxidant or ω-3 fatty acids followed by an oxidative challenge significantly reduced the levels of DNA damage. Treatment with H₂O₂ alone and following pre-treatment with EPA or DHA had no effect on the levels of protein carbonyls in U937 cells, however, DHA supplementation did appear to reduce endogenous and H2O2-induced protein carbonylation. Marked differences in the uptake of fatty acids by the cell types were found and the IMR-32 cell line was most susceptible to the oxidant challenge. Hydroxytyrosol gave significant cytoprotection in all three cell lines and this possible neuroprotective efficacy warrants further investigation, both in vitro and in vivo. Treatment of the three cell lines with a high concentration of H2O2 for 30min or 4 hours did not induce a significant increase in MDA. U937 cells were supplemented for 24 hours with fatty acids followed by a 4 hour oxidative stress. Both EPA and DHA treatment appeared to reduce LOOH levels in the U937 cells but not significantly. Cytoplasmic PLA2 activity in the three human cell lines was examined and the basal level of cPLA2 activity was found to be comparable in the lymphoblastoid and IMR-32 cells but significantly lower than that measured in the U937 cells. Supplementation of the U937 cell line with EPA caused a significant decrease (p<0.05) in cPLA2 activity relative to the vehicle treated control but neither EPA nor DHA supplementation appeared to have any significant effect on either total PLA2 or cPLA2 activity in IMR-32 or lymphoblastoid cell lines. Abstract v Human Studies: No significant difference was found between the levels of ethane and pentane in the breath from the schizophrenic patients and control samples. In addition, no significant difference in the levels of plasma MDA between the two groups was detected. Ethane levels and MDA levels were higher in the male schizophrenic samples than in the female schizophrenic samples but the results were not statistically significant. The pentane levels were higher in the female schizophrenic samples when compared to the male schizophrenia samples but again, these were not significantly greater. Finally, results of study 2 revealed that cellular DNA damage and plasma protein carbonyl levels were increased in the schizophrenic group compared to control subjects but not significantly. However, DNA damage in lymphocytes from the male schizophrenic group was significantly higher than the female group. Biomarkers of lipid peroxidation and plasma vitamin C levels also revealed no significant difference between the two groups under investigation, although a significant elevation in plasma vitamin C was observed in the female control group when compared to the male groups. Treatment of cells with EPA, DHA and hydroxytyrosol to reduce levels of oxidative damage warrants further investigation. Ultimately, it is important to investigate a range of biomarkers to determine whether the measurement of oxidative damage to lipids, proteins and DNA has clinical significance. This will enable better understanding of the disease of interest and allow these biomarkers to become potentially useful clinical tools.

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A gravidade da síndrome isquemia/reperfusão determina o prognóstico da lesão renal aguda (LRA). Agentes como o citrato de sildenafil (Sil) e a N-acetilcisteína (NAC) tem demonstrado efeito renoprotetor na LRA isquêmica com resultados ainda inconclusivos. Esse estudo investigou o efeito do Sil e da NAC na LRA com diferentes tempos de isquemia. Foram utilizados grupos de ratos Wistar, adultos e machos: SHAM; Isquemia 30 min (clampeamento dos pedículos renais por 30 min); Isquemia 30 + Sil (Sil 0,25 mg/kg 60 min antes da isquemia renal); Isquemia 30 + NAC (NAC 150 mg/kg antes e após a isquemia renal); Isquemia 45 (clampeamento dos pedículos renais por 45 min); Isquemia 45 + Sil e Isquemia 45 + NAC. Foram avaliadas a função renal (clearance de creatinina e fração de excreção de sódio-FENa); a lesão oxidativa (peróxidos urinários; substâncias reativas ao ácido tiobarbitúrico - TBARS; óxido nítrico - NO e tióis no tecido renal); a síntese protéica da óxido nítrico sintase induzível iNOS e da heme oxigenase-1 HO-1 (western blotting) e análise histológica renal (área intersticial relativa - AIR e lesão tubulointersticial). Os grupos 30 min tratados com Sil e NAC demonstraram melhora da função renal, redução dos índices oxidantes e NO, ausência de iNOS e presença de HO-1. Nos grupos 45 min, o Sil manteve a função renal, porém demonstrou proteção tubular e oxidante; a NAC não demonstrou efeito protetor em nenhum dos parâmetros avaliados. Quanto à histologia, apenas o Sil induziu redução da AIR e da lesão tubulointersticial nos tempos 30 e 45 min. O estudo confirmou que as características funcionais e histológicas induzidas pelo tempo de isquemia na LRA determinam as respostas às manobras farmacológicas de prevenção. A expressão HO-1 pode ser considerada um mediador de proteção renal. / Severity of ischemic/reperfusion injury syndrome determines the prognosis of acute kidney injury (AKI). Agents such as sildenafil citrate (Sil) and N-acetylcysteine (NAC) have demonstrated renoprotective effect on ischemic AKI which data is still inconclusive. This study investigated the protective action of Sil and NAC in the AKI with different time of ischemia. Adult, male, Wistar rats were divided: SHAM, Ischemia 30 min (renal pedicles clamping for 30 min), Ischemia 30 + Sil (Sil 0,25 mg/kg 60 min before renal ischemia), Ischemia 30 + NAC (NAC 150 mg/kg before and after renal ischemia), Ischemia 45 min (renal pedicles clamping for 45 min), Ischemia 45 + Sil, Ischemia 45 + NAC. Renal function (creatinine clearance and urine sodium fractional excretion - FENa); oxidative injury (urinary peroxides, thiobarbituric acid reactive substances - TBARS, nitric oxide - NO and thiols in renal tissue); expression of inducible nitric oxide synthase - iNOS and heme oxygenase-1 HO-1 (western blotting) and kidney histological analysis (fractional interstitial area - FIA and tubuleinterstitial injury) were evaluated. Sil and NAC treatment in 30 min renal ischemia induced increase in renal function, decrease in the rate of oxidation and NO levels, iNOS absence and HO-1 expression. In the Ischemia 45 groups, Sil it maintained renal function, however demonstrated tubular and oxidative protection; NAC produced no renoprotective effect on any of the parameters evaluated. Histology studies showed that, only Sil induced reduction in FIA and tubuleinterstitial injury at 30 and 45 min ischemic time. The study confirmed that the functional and histological characteristics induced by time of ischemia determine the renoprotective pharmacological agent action in the AKI. HO-1 expression can be a renal protection mediator.

A gravidade da síndrome isquemia/reperfusão determina o prognóstico da lesão renal aguda (LRA). Agentes como o citrato de sildenafil (Sil) e a N-acetilcisteína (NAC) tem demonstrado efeito renoprotetor na LRA isquêmica com resultados ainda inconclusivos. Esse estudo investigou o efeito do Sil e da NAC na LRA com diferentes tempos de isquemia. Foram utilizados grupos de ratos Wistar, adultos e machos: SHAM; Isquemia 30 min (clampeamento dos pedículos renais por 30 min); Isquemia 30 + Sil (Sil 0,25 mg/kg 60 min antes da isquemia renal); Isquemia 30 + NAC (NAC 150 mg/kg antes e após a isquemia renal); Isquemia 45 (clampeamento dos pedículos renais por 45 min); Isquemia 45 + Sil e Isquemia 45 + NAC. Foram avaliadas a função renal (clearance de creatinina e fração de excreção de sódio-FENa); a lesão oxidativa (peróxidos urinários; substâncias reativas ao ácido tiobarbitúrico - TBARS; óxido nítrico - NO e tióis no tecido renal); a síntese protéica da óxido nítrico sintase induzível iNOS e da heme oxigenase-1 HO-1 (western blotting) e análise histológica renal (área intersticial relativa - AIR e lesão tubulointersticial). Os grupos 30 min tratados com Sil e NAC demonstraram melhora da função renal, redução dos índices oxidantes e NO, ausência de iNOS e presença de HO-1. Nos grupos 45 min, o Sil manteve a função renal, porém demonstrou proteção tubular e oxidante; a NAC não demonstrou efeito protetor em nenhum dos parâmetros avaliados. Quanto à histologia, apenas o Sil induziu redução da AIR e da lesão tubulointersticial nos tempos 30 e 45 min. O estudo confirmou que as características funcionais e histológicas induzidas pelo tempo de isquemia na LRA determinam as respostas às manobras farmacológicas de prevenção. A expressão HO-1 pode ser considerada um mediador de proteção renal. / Severity of ischemic/reperfusion injury syndrome determines the prognosis of acute kidney injury (AKI). Agents such as sildenafil citrate (Sil) and N-acetylcysteine (NAC) have demonstrated renoprotective effect on ischemic AKI which data is still inconclusive. This study investigated the protective action of Sil and NAC in the AKI with different time of ischemia. Adult, male, Wistar rats were divided: SHAM, Ischemia 30 min (renal pedicles clamping for 30 min), Ischemia 30 + Sil (Sil 0,25 mg/kg 60 min before renal ischemia), Ischemia 30 + NAC (NAC 150 mg/kg before and after renal ischemia), Ischemia 45 min (renal pedicles clamping for 45 min), Ischemia 45 + Sil, Ischemia 45 + NAC. Renal function (creatinine clearance and urine sodium fractional excretion - FENa); oxidative injury (urinary peroxides, thiobarbituric acid reactive substances - TBARS, nitric oxide - NO and thiols in renal tissue); expression of inducible nitric oxide synthase - iNOS and heme oxygenase-1 HO-1 (western blotting) and kidney histological analysis (fractional interstitial area - FIA and tubuleinterstitial injury) were evaluated. Sil and NAC treatment in 30 min renal ischemia induced increase in renal function, decrease in the rate of oxidation and NO levels, iNOS absence and HO-1 expression. In the Ischemia 45 groups, Sil it maintained renal function, however demonstrated tubular and oxidative protection; NAC produced no renoprotective effect on any of the parameters evaluated. Histology studies showed that, only Sil induced reduction in FIA and tubuleinterstitial injury at 30 and 45 min ischemic time. The study confirmed that the functional and histological characteristics induced by time of ischemia determine the renoprotective pharmacological agent action in the AKI. HO-1 expression can be a renal protection mediator.

Background and objective: By reviewing our current understanding of oxidative injury as a cause of focal segmental glomerulosclerosis (FSGS), we hope to advance the use of antioxidants as a promising treatment in addition to the other therapeutic modalities to slow the rate of progression. Methods: Key references from the past concerning oxidative injury and FSGS were analyzed, together with those from a PubMed search of the literature from 1997 to 2007, to form the basis of this commentary. Results: In animal studies in FSGS produced by subtotal nephrectomy or puromycin injections, evidence of oxidant injury provided the rationale for disease reversal with an antioxidant such as high dose vitamin E. Clinical trial in children with FSGS using vitamin E resulted in significant reduction in proteinuria. Other treatment modalities in children with FSGS over the past four decades were reviewed. These consisted of one or more of the following medications: oral prednisone, angiotensin converting enzyme inhibitors, angiotensin receptor blockers, and intravenous methylprednisolone with and without cyclophosphamide or cyclosporine. The prognosis with these recent therapeutic interventions improved the outcome of children with FSGS compared to no treatment as advocated earlier. However, when the current regimen of combined treatment was compared with the regimen of prednisone plus cyclophosphamide, there was no difference in Kaplan-Meier kidney survival rate at a mean follow-up of 12 to 16 years. Conclusion: In reviewing current concepts of oxidant injury and other mechanisms of injury in the development of FSGS and the available modalities of treatment, we call into question, whether the cost and side effects of intravenous methylprednisolone is justifiable on the basis of unchanged kidney survival rates with continuing this particular mode of intervention.