Aldose reductase-deficient mice are protected from delayed motor nerve conduction velocity, increased c-Jun NH2-terminal kinase activation, depletion of reduced glutathione, increased superoxide accumulation, and DNA damage.

The exaggerated flux through polyol pathway during diabetes is thought to be a major cause of lesions in the peripheral nerves. Here, we used aldose reductase (AR)-deficient (AR(-/-)) and AR inhibitor (ARI)-treated mice to further understand the in vivo role of polyol pathway in the pathogenesis of diabetic neuropathy. Under normal conditions, there were no obvious differences in the innervation patterns between wild-type AR (AR(+/+)) and AR(-/-) mice. Under short-term diabetic conditions, AR(-/-) mice were protected from the reduction of motor and sensory nerve conduction velocities observed in diabetic AR(+/+) mice. Sorbitol levels in the sciatic nerves of diabetic AR(+/+) mice were increased significantly, whereas sorbitol levels in the diabetic AR(-/-) mice were significantly lower than those in diabetic AR(+/+) mice. In addition, signs of oxidative stress, such as increased activation of c-Jun NH(2)-terminal kinase (JNK), depletion of reduced glutathione, increase of superoxide formation, and DNA damage, observed in the sciatic nerves of diabetic AR(+/+) mice were not observed in the diabetic AR(-/-) mice, indicating that the diabetic AR(-/-) mice were protected from oxidative stress in the sciatic nerve. The diabetic AR(-/-) mice also excreted less 8-hydroxy-2'-deoxyguanosine in urine than diabetic AR(+/+) mice. The structural abnormalities observed in the sural nerve of diabetic AR(+/+) mice were less severe in the diabetic AR(-/-) mice, although it was only mildly protected by AR deficiency under short-term diabetic conditions. Signs of oxidative stress and functional and structural abnormalities were also inhibited by the ARI fidarestat in diabetic AR(+/+) nerves, similar to those in diabetic AR(-/-) mice. Taken together, increased polyol pathway flux through AR is a major contributing factor in the early signs of diabetic neuropathy, possibly through depletion of glutathione, increased superoxide accumulation, increased JNK activation, and DNA damage.

Supplementation with a combination of omega-3 fatty acids and antioxidants (vitamins E and C) improves the outcome of schizophrenia.

Reduced levels of membrane essential polyunsaturated fatty acids (EPUFAs), namely, arachidonic acid (AA), eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA) and docosahexaenoic acids (DHAs), and their association with psychopathology have been consistently reported in both chronic-medicated schizophrenic patients as well as in never-medicated patients soon after the first episode of psychosis. Past supplementation studies with either omega-6 or omega-3 or both EPUFAs generally in chronic-medicated-older patients have reported varying degrees of therapeutic effects, and have suggested that supplementation with primarily omega-3 EPUFAs (EPA>DHA) may be preferable. We report the supplementation with a mixture of EPA/DHA (180:120 mg) and antioxidants (vitamin E/C, 400 IU:500 mg) orally morning and evening to schizophrenic patients (N=33) for 4 months. The red blood cell (RBC) membrane fatty acid levels, plasma lipid peroxides and clinical measures were carried out by established procedures at pretreatment, posttreatment and after 4 months of postsupplementation period to determine the stability of treatment effects within patients. Levels of fatty acids and lipid peroxides were compared with their levels in normal controls (NC) (N=45).Posttreatment levels of RBC EPUFAs were significantly higher than pretreatment levels as well as levels in normal controls without any significant increase in plasma peroxides. Concomitantly, there was significant reduction in psychopathology based on reduction in individual total scores for brief psychiatric rating scale (BPRS) and positive and negative syndrome scale (PANSS), general psychopathology-PANSS and increase in Henrich's Quality of Life (QOL) Scale. The EPUFA levels returned to pretreatment levels after 4 months of supplementation washout. However, the clinical improvement was significantly retained. Future studies need be done in placebo-controlled trials and also with a comparison group supplemented with fatty acids alone in a larger number of patients, both chronic as well as never medicated, and for a longer duration of treatment while the dietary intake is monitored. This may establish the EPUFA supplementation a very effective treatment to improve the outcome for an extended period of time.

Essential polyunsaturated fatty acid and lipid peroxide levels in never-medicated and medicated schizophrenia patients.

BACKGROUND: Reduced levels of membrane essential polyunsaturated fatty acids (EPUFAs) and increased levels of lipid peroxidation products (thiobarbituric acid reactive substances; TBARS) have been observed in chronic medicated schizophrenics. The relationship of EPUFA and TBARS to psychopathology is unclear, since their levels may be altered differentially by duration of illness and antipsychotic treatment. To minimize these confounds, their levels were compared among never-medicated patients in early illness, medicated patients and control subjects with similar lifestyle and common ethnic background. METHODS: RBC membrane EPUFAs, plasma TBARS, and various dimensions of psychopathology were measured using established procedures in never-medicated (n = 20) and medicated (n= 32) schizophrenia patients and in control subjects (n= 45). RESULTS: Reduced levels of EPUFAs, particularly arachidonic acid (AA) and docosahexaenoic acid (DHA), were found in never-medicated compared with control subjects; however, the reductions in levels of both AA and DHA were much smaller in medicated versus never-medicated patients; AA levels were similar to levels in control subjects. Only DHA levels were significantly reduced in medicated patients. Lower membrane AA levels were associated with increased levels of plasma TBARS in never-medicated patients. Lower levels of membrane EPUFAs and higher levels of plasma TBARS were associated with the severe symptoms in never-medicated versus medicated patients. CONCLUSIONS: Data indicate that reduced EPUFAs and increased TBARS exist in never-medicated patients, and these measures correlate with the severity of psychopathology indicating that the membrane EPUFA status may reflect the outcome of schizophrenia.