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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.

Presbycusis, or age-related hearing loss, is one of the most common conditions impacting the aging population, characterized by progressive sensorineural hearing loss and impairment in speech discrimination capability. Current management is limited to auditory rehabilitation with the assistance of hearing aids or cochlear implants in advanced cases. There currently exists no effective treatments available for the prevention or attenuation of hearing loss in association with presbycusis. The purpose of this study was to evaluate the potential of a combination antioxidant therapy in the prevention and treatment of presbycusis. The objectives of this randomized controlled animal study were to: identify an anesthetic which would allow for repeated reliable longitudinal auditory brainstem response (ABR) testing in a mouse model, identify a combination antioxidant which targets multiple sites within the oxidative pathway and assess its ability to prevent age-related threshold shifts and to arrest further age-related threshold shifts in C57BL6 mice with documented age-related threshold shifts. Mice were randomized to one of three groups: an early treatment group, a late treatment group, or a control group. The treatment groups of mice were fed with a combination agent comprised 6 antioxidant agents. ABRs were performed comparing Avertin to ketamine/xylazine with no significant difference in test thresholds. ABR thresholds were recorded at baseline and every 3 months following initiation of treatment in the 3 randomized groups. Threshold shifts from baseline were decreased in the treatment groups when compared to the control group at all tested frequencies and time points.Presbycusis, or age-related hearing loss, is one of the most common conditions impacting the aging population, characterized by progressive sensorineural hearing loss and impairment in speech discrimination capability. Current management is limited to auditory rehabilitation with the assistance of hearing aids or cochlear implants in advanced cases. There currently exists no effective treatments available for the prevention or attenuation of hearing loss in association with presbycusis. The purpose of this study was to evaluate the potential of a combination antioxidant therapy in the prevention and treatment of presbycusis. The objectives of this randomized controlled animal study were to: identify an anesthetic which would allow for repeated reliable longitudinal auditory brainstem response (ABR) testing in a mouse model, identify a combination antioxidant which targets multiple sites within the oxidative pathway and assess its ability to prevent age-related threshold shifts and to arrest further age-related threshold shifts in C57BL6 mice with documented age-related threshold shifts. Mice were randomized to one of three groups: an early treatment group, a late treatment group, or a control group. The treatment groups of mice were fed with a combination agent comprised 6 antioxidant agents. ABRs were performed comparing Avertin to ketamine/xylazine with no significant difference in test thresholds. ABR thresholds were recorded at baseline and every 3 months following initiation of treatment in the 3 randomized groups. Threshold shifts from baseline were decreased in the treatment groups when compared to the control group at all tested frequencies and time points.

The metabotropic glutamate receptors are G-protein coupled receptors with many cell signaling functions in the central and peripheral nervous systems. The type 3 metabotropic glutamate receptor (mGluR3) is particularly important to survival signaling, and has been implicated in a wide range of neurological disorders. Activating mGluR3 protects dorsal root ganglion neurons from glucose-induced oxidative injury by increasing antioxidant defenses. During hyperglycemia, oxidative injury and programmed cell death in dorsal root ganglion neurons underlies the formation and progression of diabetic sensory neuropathy. Using a rat embryo cell culture model of sensory neuropathy, the toxic effects of elevated glucose concentrations were examined in dorsal root ganglion neurons, and the neuroprotective potential of mGluR3-activating compounds was explored through 3 central hypotheses: (1) Does mGluR3 activation protect dorsal root ganglion neurons from glucose-induced cell death? (2) Does mGluR3 activation prevent glucose-induced oxidative injury? (3) Is mGluR3 neuroprotection mediated through increased glutathione antioxidant defense systems? Neurons exposed to excess glucose experienced oxidative damage, including reactive oxygen species accumulation, mitochondrial membrane depolarization, and programmed cell death. Initial experiments found that activating mGluR3 prevents oxidative damage, and that protection only occurs in neurons co-cultured with Schwann cells. Glial cells may facilitate synthesis of the antioxidant glutathione in neurons; subsequent experiments determined that activating mGluR3 increases glutathione concentration in both neurons and Schwann cells, and that protection requires glutathione synthesis. These results suggest that activating mGluR3 increases glutathione synthesis, thereby countering free radical production and glucose-induced oxidative damage in dorsal root ganglion neurons. Increasing endogenous antioxidant defenses in this manner is a potential therapeutic target for diabetic sensory neuropathy.

Epoxy lipids are a relatively little studied class of oxidized phospholipids in comparison with their γ-hydroxy(oxo)-α,β-unsaturated analogs. Most of the known epoxy lipids were first studied in foods. Recent studies indicate that epoxy lipids are relevant to human diseases. Some of them readily form etheno adducts upon reaction with DNA’s bases. These etheno adducts were detected in tissues from cancer patients. Thus it is important to know the chemistry of epoxylipid formation and their reactivity with other biomolecules. Epoxy phospholipids had not been reported. However the chemistry underlying the formation of known epoxy lipids seemed likely to produce such phospholipids. To assess the natural occurrence and biological properties of these putative epoxy phospholipids, one member of this class was prepared by total synthesis. The route developed can be easily modified to allow the production of other epoxy phospholipids. The production of the new phospholipid from oxidation of linoleic acid was demonstrated in vitro. The presence of this epoxy phospholipid was further detected in rat retina.Extensive literature precedent suggests that 9-hydroperoxy-10,12 octadienoic acid and 13-hydroperoxy-9,11-octadienoic acid are the primary first generation oxidation products from linoleic acid. They can fragment to produce epoxy-truncated lipids, such as 4,5-epoxy-2(E)-decenal, the most studied representative of the class. Several mechanism and putative intermediates have been proposed for the formation of epoxy lipids from these lipid peroxide precursors. By examining the autoxidation of one putative intermediate, 13-hydroperoxy-9,10-cis-epoxyoctadeca-11-enoic acid, we concluded that the proposed epoxy hydroperoxide mechanism involving this intermediate is a feasible pathway for the formation of epoxy lipids.