An exploratory study on the ability of manganese to supplement rotenone neurotoxicity in rats.

Parkinson's disease (PD) is a complex disorder, primarily of idiopathic origin, with environmental stressors like rotenone and manganese linked to its development. This study explores their potential interaction and resulting neurotoxicity, aiming to understand how environmental factors contribute to PD. In an eight-day experiment, male Wistar rats weighing 280-300 g were subjected to rotenone, manganese, or a combination of both. Various parameters were assessed, including body weight, behavior, serum markers, tissue damage, protein levels (tyrosine hydroxylase, Dopamine- and cAMP-regulated neuronal phosphoprotein -DARPP-32-, and α-synuclein), and mitochondrial function. Manganese heightened rotenone's impact on reducing food intake without causing kidney or liver dysfunction. However, the combined exposure intensified neurotoxicity, which was evident in augmented broken nuclei and decreased tyrosine hydroxylase and DARPP-32 levels in the striatum. While overall mitochondrial function was preserved, co-administration reduced complex IV activity in the midbrain and liver. In conclusion, our findings revealed a parallel toxic effect induced by rotenone and manganese. Notably, while these substances do not target the same dopaminergic regions, a notable escalation in toxicity is evident in the striatum, the brain region where their toxic effects converge. This study highlights the need for further exploration regarding the interaction of environmental factors and their possible impact on the etiology of PD.

Influence of glutathione-related genetic variants on the oxidative stress profile of Mexican patients with psychotic disorders

Objective: The clinical trajectories of patients with psychotic disorders have divergent outcomes, which may result in part from glutathione (GSH)-related high-risk genotypes. We aimed to determine pharmacokinetics of clozapine, GSH levels, GSH peroxidase (GPx) activity, gene variants involved in the synthesis and metabolism of GSH, and their association with psychotic disorders in Mexican patients on clozapine monotherapy and controls. Methods: The sample included 75 patients with psychotic disorders on clozapine therapy and 40 paired healthy controls. Plasma clozapine/N-desmethylclozapine, GSH concentrations, and GPx activity were determined, along with genotyping of GCLC and GSTP1 variants and copy number variations of GSTP1, GSTT1, and GSTM1. Clinical, molecular and biochemical data were analyzed with a logistic regression model. Results: GSH levels were significantly reduced and, conversely, GPx activity was higher among patients than controls. GCLC_GAG-7/9 genotype (OR = 4.3, 95%CI = 1.40-14.31, p = 0.019) and hetero-/homozygous genotypes of GCLC_rs761142 (OR = 6.09, 95%CI = 1.93-22.59, p = 0.003) were found to be risk factors for psychosis. The genetic variants were not related to clozapine/N-desmethylclozapine levels or metabolic ratio. Conclusions: GCLC variants were associated with the oxidative stress profile of patients with psychotic disorders, raising opportunities for intervention to improve their antioxidant defenses. Further studies with larger samples should explore this proposal.

Influence of glutathione-related genetic variants on the oxidative stress profile of Mexican patients with psychotic disorders.

OBJECTIVE: The clinical trajectories of patients with psychotic disorders have divergent outcomes, which may result in part from glutathione (GSH)-related high-risk genotypes. We aimed to determine pharmacokinetics of clozapine, GSH levels, GSH peroxidase (GPx) activity, gene variants involved in the synthesis and metabolism of GSH, and their association with psychotic disorders in Mexican patients on clozapine monotherapy and controls. METHODS: The sample included 75 patients with psychotic disorders on clozapine therapy and 40 paired healthy controls. Plasma clozapine/N-desmethylclozapine, GSH concentrations, and GPx activity were determined, along with genotyping of GCLC and GSTP1 variants and copy number variations of GSTP1, GSTT1, and GSTM1. Clinical, molecular and biochemical data were analyzed with a logistic regression model. RESULTS: GSH levels were significantly reduced and, conversely, GPx activity was higher in PD patients compared to controls. GCLC_GAG-7/9 genotype (OR=4.3, CI95=1.40-14.31, p=0.019) and hetero-/homozygous genotypes of GCLC_rs761142 (OR=6.09, CI95=1.93-22.59, p=0.003) were found as risk factors for psychosis. The genetic variants were not related to clozapine/N-desmethylclozapine levels or to metabolic ratio. CONCLUSIONS: GCLC variants were associated with the oxidative stress profile of PD patients raising opportunities for intervention to improve their antioxidant defenses. Further studies with larger samples should explore this proposal.

Clinical and biological changes under treatment with lithium carbonate and valproic acid in sporadic amyotrophic lateral sclerosis.

The aim of this study was to evaluate the ability of lithium carbonate and valproate cotreatment to modify the survival rate and functional score of patients with definite sporadic amyotrophic lateral sclerosis (ALS). The clinical response of 18 enrolled patients was compared to the evolution of 31 ALS out-patients, carefully paired by age, gender, evolution rate and time of the disease, who never received treatment with lithium and/or valproate. The ALS functional rating scale, revised version (ALSFRS-R), was applied at baseline, 1 month, and every 4 months until the outcome (death or an adverse event). Biochemical markers, such as Cu/Zn superoxide dismutase and glutathione peroxidase activity, and reduced glutathione were assayed in plasma samples obtained at the baseline visit and after 5 and 9 months of treatment. Our results showed that lithium and valproate cotreatment significantly increased survival (p=0.016), and this treatment also exerted neuroprotection in our patients because all three markers reached levels that were not significantly different from the matched samples of healthy donors. The trial stopped after 21 months, when the sample was reduced to under two-thirds, due to the late adverse events of the treatment. The results call for large randomized clinical trials with the dual association, but at low doses to avoid adverse events.

Differential time-course of the increase of antioxidant thiol-defenses in the acute phase after spinal cord injury in rats.

Spinal cord injury (SCI) is a world-wide health problem. After traumatic injury, spinal cord tissue starts a series of self-destructive mechanisms, known as the secondary lesion. The leading mechanisms of damage after SCI are excitotoxicity, free radicals' overproduction, inflammation and apoptosis. Metallothionein (MT) and reduced glutathione (GSH) are low-molecular-weight, cysteine-rich peptides able to scavenge free radicals. MT and GSH participation as neuroprotective molecules after SCI is unknown. The aim of the present study is to describe the changes of MT and GSH contents and GSH peroxidase (GPx) activity in the acute phase after SCI in rats. Female Wistar rats weighing 200-250g were submitted to spinal cord contusion model, by means of a computer-controlled device (NYU impactor). Rats receiving laminectomy were used as a control group. Animals were killed 2, 4, 12 and 24h after surgery. MT was quantified by the silver-saturation method, using atomic absorption spectrophotometry. GSH and GPx were assayed by spectrophotometry. Results indicate an increased MT content by effect of SCI, only at 4 and 24h, as compared to sham group values. Meanwhile, GSH was found decreased at 4, 12 and 24h after SCI. Interestingly, GPx activity was raised at all time points, indicating that this enzymatic defense is activated soon after SCI. Results suggest that thiol-based defenses, MT and GSH, are differentially expressed by spinal cord tissue to cope with the various processes of damage after lesion.

Copper sulfate prevents tyrosine hydroxylase reduced activity and motor deficits in a Parkinson's disease model in mice.

INTRODUCTION: Parkinson's disease (PD) is a neurodegenerative disorder characterized by the presence of motor disturbances, derived from the striatal dopamine depletion. Previously, we reported that CuSO4 pretreatment blocked an oxidative stress marker (lipid peroxidation) and prevented the striatal dopamine depletion induced by the administration of the 1-methyl-4-phenylpiridinium (MPP+), the toxic metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a model of PD. OBJECTIVE: . To determine if tyrosine hydroxylase (TH), the rate-limiting synthetic enzyme of dopamine, is implicated in the neuroprotective effect of CuSO4 pretreatment, and if this neuroprotective effect is able to prevent the hypokinetic state (measured as spontaneous locomotor activity, SLA) induced by the experimental model of PD. MATERIAL AND METHODS: C57 Black/6J mice received a single dose of CuSO4 (2.5 mg/kg, i.p.) either 16 or 24 h before the administration of MPP+ (18 microg/3 microl, i.c.v.). Twenty four hours later, mice SLA was registered and animals sacrificed. Striatal L-DOPA accumulation derived from the administration of a central dopamine descarboxilase inhibitor was evaluated, a strategy considered as a reliable indirect analysis of tyrosine hydroxylase activity (THA). RESULTS: Administration of, MPP+ decreased SLA (-52%; p = 0.003) as compared to control group values, whereas those mice pretreated with CuSO4 16 h before MPP+, increased SLA by 47% as compared with control group (p = 0.015). Mice pretreated with CuSO4 24 h before MPP+, also showed a statistically significant increase in SLA (71%; p = 0.02), when compared with control group. As a consequence of MPP+ administration, THA was also reduced as compared to control group values (32%; p < 0.05). Reduction of THA was blocked when mice were pretreated with CuSO4 16 h before MPP+. Moreover, mice receiving the CuSO4 24 h before MPP+ showed a significant increase (38%; p < 0.05) in THA when compared with control group. CONCLUSION: Results suggest that preservation of THA participates in the neuroprotective effects derived from the copper supplementation, a phenomenon that avoid the hypokinetic state induced by the MPP+ experimental model of PD.

The effect of supplementation with omega-3 polyunsaturated fatty acids on markers of oxidative stress in elderly exposed to PM(2.5).

BACKGROUND: The mechanisms of particulate matter (PM)-induced health effects are believed to involve inflammation and oxidative stress. Increased intake of omega-3 polyunsaturated fatty acids (n-3 PUFA) appears to have anti-inflammatory effects. OBJECTIVE: As part of a trial to evaluate whether n-3 PUFA supplementation could protect against the cardiac alterations linked to PM exposure, we measured biomarkers of response to oxidative stimuli [copper/zinc (Cu/Zn) superoxide dismutase (SOD) activity, lipoperoxidation (LPO) products, and reduced glutathione (GSH)] and evaluated the impact of supplementation on plasma levels. METHODS: We recruited residents from a nursing home in Mexico City chronically exposed to PM < or = 2.5 microm in aerodynamic diameter (PM(2.5)) and followed them from 26 September 2001 to 10 April 2002. We randomly assigned subjects in a double-blind fashion to receive either fish oil (n-3 PUFA) or soy oil. We measured PM(2.5) levels indoors at the nursing home, and measured Cu/Zn SOD activity, LPO products, and GSH at different times during presupplementation and supplementation phases. RESULTS: Supplementation with either fish or soy oil was related to an increase of Cu/Zn SOD activity and an increase in GSH plasma levels, whereas exposure to indoor PM(2.5) levels was related to a decrease in Cu/Zn SOD activity and GSH plasma levels. CONCLUSION: Supplementation with n-3 PUFA appeared to modulate the adverse effects of PM(2.5) on these biomarkers, particularly in the fish oil group. Supplementation with n-3 PUFA could modulate oxidative response to PM(2.5) exposure.

Tissue spinal cord response in rats after implants of polypyrrole and polyethylene glycol obtained by plasma.

Most of the biomaterials used nowadays for the reconstruction of the spinal cord (SC) tissue after an injury, tested in animals, have obtained modest results. This work presents a study about the compatibility of two novel, non-biodegradable, semi-conductive materials, obtained by plasma polymerization: iodine-doped pyrrole (PPy/I) and pyrrole-polyethylene glycol (PPy/PEG). Both polymers, separately, were implanted in the SC tissue of rats after a transection. Prior to implantation, the elemental composition and the physico-chemical properties of polymers were studied by electron scanning microscopy, IR Spectroscopy and thermogravimetric analysis. We used adult female Long Evans rats, subjected to SC transection. Animals were randomized to be allocated in one of the treatment groups and were killed four weeks after the lesion for histology study. Results showed that both implants were integrated to the SC tissue, as inflammatory and gliotic responses, similar to those observed in the control group, and rejection of the implant, were not evident. Moreover, the immediate effect of PPy/I or PPy/PEG in the injured SC prevented secondary tissue destruction, as compared to non-implanted control animals. In conclusion, implants of semi-conductive polymers were well-tolerated and integrated favorably to SC tissue after transection.

Role of manganese accumulation in increased brain glutamine of the cirrhotic rat.

Cirrhosis promotes increases of both manganese and glutamine in brain. Manganese is a modulator and glutamine is the product of glutamine synthetase. This work studies the relationship between manganese and glutamine synthetase in a model of cirrhosis in the rat. We administered manganese (1 g/L) in the drinking water of sham-operated and bile-duct obstructed rats. We evaluated the manganese and glutamine accumulation and the glutamine synthetase activity in frontal cortex, striatum, and pallidum after 2, 4, and 6 weeks of biliary obstruction or sham surgery. Cirrhotic rats receiving manganese increased their brain content of metal about 400%-600% after 4 weeks of treatment (P < .05) and also remarkably accumulated glutamine through time in the three regions studied (P < .05 at week 6). Interestingly, bile-duct obstructed rats treated with manganese showed no effect on glutamine synthetase activity. Results from this study suggest that manganese induces increases of brain glutamine independently of its synthesis.