Camilo Ríos

Quinolinic acid is a potent lipid peroxidant in rat brain homogenates

In this study, we describe the lipoperoxidative effect of quinolinic acid (QUIN) in vitro. The formation of thiobarbituric acid reactive products (TBA-RP), an index of lipid peroxidation, was measured in rat brain homogenates after incubation at 37°C for 30 min in the presence of QUIN and some structurally and metabolically related compounds such as Kynurenine, Kynurenic acid, Glutamate, Aspartate and Kainate. Concentrations of QUIN in the range of 20 to 80 μM increased lipid peroxidation in a concentration-dependent manner from about 15% to about 50%. Kynurenic acid, a compound metabollically related to QUIN that can block its neurotoxic actions in vivo, also inhibited completely the QUIN-induced TBA-RP formation in our system. Lipid fluorescent material, another index of lipid peroxidation was also found increased by 49% after incubation with 40 μM QUIN. It is concluded that lipid peroxidation may be a damaging process involved in the neurotoxicity of QUIN.

Intellectual Function in Mexican Children Living in a Mining Area and Environmentally Exposed to Manganese

Background Excessive exposure to manganese (Mn), an essential trace element, has been shown to be neurotoxic, especially when inhaled. Few studies have examined potential effects of Mn on cognitive functions of environmentally exposed children. Objective This study was intended to estimate environmental exposure to Mn resulting from mining and processing and to explore its association with intellectual function of school-age children. Methods Children between 7 and 11 years of age from the Molango mining district in central Mexico (n = 79) and communities with similar socioeconomic conditions that were outside the mining district (n = 93) participated in the cross-sectional evaluation. The revised version of the Wechsler Intelligence Scale for Children adapted for the Mexican population was applied. Concentrations of Mn in blood (MnB) and hair (MnH) were used as biomarkers of exposure. Results Exposed children had significantly higher median values for MnH (12.6 μg/g) and MnB (9.5 μg/L) than did nonexposed children (0.6 μg/g and 8.0 μg/L, respectively). MnH was inversely associated with Verbal IQ [β = −0.29; 95% confidence interval (CI), −0.51 to −0.08], Performance IQ (β = −0.08; 95% CI, −0.32 to 0.16), and Total Scale IQ (β = −0.20; 95% CI, −0.42 to 0.02). MnB was inversely but nonsignificantly associated with Total and Verbal IQ score. Age and sex significantly modified associations of MnH, with the strongest inverse associations in young girls and little evidence of associations in boys at any age. Associations with MnB did not appear to be modified by sex but appeared to be limited to younger study participants. Conclusions The findings from this study suggest that airborne Mn environmental exposure is inversely associated with intellectual function in young school-age children.

The transition metals copper and iron in neurodegenerative diseases

Neurodegenerative diseases constitute a worldwide health problem. Metals like iron and copper are essential for life, but they are also involved in several neurodegenerative mechanisms such as protein aggregation, free radical generation and oxidative stress. The role of Fe and Cu, their pathogenic mechanisms and possible therapeutic relevance are discussed regarding four of the most common neurodegenerative diseases, Alzheimers, Parkinsons and Huntingtons diseases as well as amyotrophic lateral sclerosis. Metal-mediated oxidation by Fenton chemistry is a common feature for all those disorders and takes part of a self-amplifying damaging mechanism, leading to neurodegeneration. The interaction between metals and proteins in the nervous system seems to be a crucial factor for the development or absence of neurodegeneration. The present review also deals with the therapeutic strategies tested, mainly using metal chelating drugs. Metal accumulation within the nervous system observed in those diseases could be the result of compensatory mechanisms to improve metal availability for physiological processes.

Free Copper, Ferroxidase and SOD1 Activities, Lipid Peroxidation and NO x Content in the CSF. A Different Marker Profile in Four Neurodegenerative Diseases

The understanding of oxidative damage in different neurodegenerative diseases could enhance therapeutic strategies. Our objective was to quantify lipoperoxidation and other oxidative products as well as the activity of antioxidant enzymes and cofactors in cerebrospinal fluid (CSF) samples. We recorded data from all new patients with a diagnosis of either one of the four most frequent neurodegenerative diseases: Parkinson’s disease (PD), Alzheimer’s disease (AD), Huntington’s disease (HD) and lateral amyotrophic sclerosis (ALS). The sum of nitrites and nitrates as end products of nitric oxide (NO) were increased in the four degenerative diseases and fluorescent lipoperoxidation products in three (excepting ALS). A decreased Cu/Zn-dependent superoxide dismutase (SOD) activity characterized the four diseases. A significantly decreased ferroxidase activity was found in PD, HD and AD, agreeing with findings of iron deposition in these entities, while free copper was found to be increased in CSF and appeared to be a good biomarker of PD.

MK-801, an N-methyl-d-aspartate receptor antagonist, blocks quinolinic acid-induced lipid peroxidation in rat corpus striatum

In this study, we evaluate the possible participation of lipid peroxidation (LP) in the neurotoxic events that follow after quinolinic acid (QUIN) microinjection into the rat corpus striatum. Two hours after QUIN (240 nmol/microliters) intrastriatal administration, lipid peroxidation was found increased by 32% vs. control as measured by thiobarbituric acid-reactive substances (TBARS). At the same time tested, the enhancement in LP was of 55% vs. control as measured by lipid fluorescent products (LFP) formation (a second index of lipid peroxidation employed). The increase of QUIN-induced lipid peroxidation was completely abolished by pretreatment of rats with an N-methyl-D-aspartate (NMDA) receptor antagonist, MK-801 (10 mg/kg, i.p.), 60 min before QUIN microinjection. Results suggest an NMDA receptor involvement in the QUIN-induced oxidative processes.

Striatal oxidative damage parallels the expression of a neurological phenotype in mice transgenic for the mutation of Huntington's disease.

We examined the degree of oxidative damage to the brain of mice transgenic for the mutation responsible for Huntingtons disease. We found that there is a progressive increase in striatal lipid peroxidation (LP), that parallels the worsening of the neurological phenotype. We consider that these transgenic mice may provide an interesting system to test treatments aimed at protecting cells from damage induced by free radicals.

Mini reviewCadmium neurotoxicity

The Cd has been recognized as one of the most toxic environmental and industrial pollutants due to its ability to induce disturbances in several organs and tissues following either acute or chronic exposure. This review accounts for the recent evidence on its mechanisms to induce neurotoxicity, the role of the blood-brain barrier, oxidative stress, interference with calcium, and zinc-dependent processes and apoptosis induction as well as the modulatory effect of metallothionein. Discussion about cadmium neurotoxicity is centered on mechanisms of induction of cellular disfunctions. Future investigations must address those neuronal mechanisms in detail in order to understand cadmium-induced neurotoxicity.

Hyperhomocysteinemia, Low Folate and Vitamin B12 Concentrations, and Methylene Tetrahydrofolate Reductase Mutation in Cerebral Venous Thrombosis

Background and Purpose— Elevated plasma levels of homocysteine are associated with an increased risk of deep-vein thrombosis. Through a case–control study, we examined the potential association among homocysteine, folate and vitamin B12 levels, and the common C677→T mutation in the methylene tetrahydrofolate reductase (MTHFR) gene in patients with cerebral venous thrombosis (CVT). Methods— Forty-five patients with CVT and 90 control subjects were studied. Plasma levels of homocysteine (fasting and after methionine load), folate, and vitamin B12 were measured. Genotyping of the MTHFR gene was also performed. The estimated risk of CVT associated with hyperhomocysteinemia, low vitamin levels, and MTHFR mutation were expressed as odds ratio (OR) and its 95% CI (crude and after adjusting by other independent variables). Results— The adjusted OR for CVT associated with high (>90th percentile) fasting levels of homocysteine was 4.6 (1.6 to 12.8). The association between low plasma folate values (<10th percentile) and presence of CVT was 3.5 (1.2 to 10.0) after adjustment for confounding factors. There was a higher frequency of MTHFR mutation in patients with CVT (22% versus 10%), but it was not statistically significant (P = 0.098). Patients with MTHFR mutation and low folate levels presented the highest homocysteine levels. Conclusions— High plasma concentrations of homocysteine and low plasma folate levels were associated with an increased risk of CVT in this population in which low socioeconomic conditions and deficient nutritional status may contribute to its relatively high incidence.

Homocysteine-induced brain lipid peroxidation: Effects of NMDA receptor blockade, antioxidant treatment, and nitric oxide synthase inhibition

The effect of homocysteine (HCY) on lipid peroxidation (LP), a current mechanism of oxidative neurotoxicity, was investigated in rat brain synaptosomes. LP was assessed by measuring the amount of thiobarbituric acid-reactive substances (TBARS) formed from synaptosomal fractions following HCY treatment. Increasing HCY concentrations (5–1000 μM) enhanced the TBARS formation in brain synaptosomes in a concentration-dependent manner. When compared at equimolar concentrations (100 μM), the oxidative potency of HCY was lower than that of the oxidant ferrous sulfate, similar to that produced by glutamate (Glu) and the mitochondrial toxin 3-nitropropionic acid, and higher than that of the Glu agonists, kainate and quinolinate. TheN-methyl-D-aspartate receptor (NMDAr) antagonist dizocilpine (MK-801) completely blocked the HCY-induced LP at concentrations from 5 to 1000 μM, whereas the well-known antioxidantN-acetylcysteine (NAC) was less effective, but still protective against the HCY oxidative toxicity at higher concentrations (400 and 1000 μM). Three nitric oxide synthase (NOS) inhibitors, 7-nitroindazole (7-NI),Nω-nitro-L-arginine (L-NARG) andNω-nitro-L-arginine methyl ester (L-NAME), were also tested on HCY-induced LP at increasing concentrations. Both nonspecific NOS effectively the HCY-induced LP than did the selective neuronal NOS inhibitor, 7-NI. These results show that submillimolar concentrations of HCY can induce oxidative injury to nerve terminals, and this effect involves NMDAr stimulation, NOS activation, and associated free radicals formation.

Enhanced brain regional lipid peroxidation in developing rats exposed to low level lead acetate

Neurotoxicity associated with lead exposure may be the result of a series of small perturbations in brain metabolism, and, in particular, of oxidative stress. Some studies have suggested a lead-induced enhancement on lipid peroxidation as a possible mechanism for some toxic effects of lead. However, there are no reports about the association between lipid peroxidation enhancement and brain lead content. In this study, we determined the concentration of lead and the formation of lipid fluorescence products in the blood, as well as in the parietal cortex, striatum, hippocampus, thalamus, and cerebellum of rats exposed prenatally and postnatally to variable concentrations of lead acetate through drinking water. Pregnant Wistar rats were intoxicated throughout gestation with solutions containing either 320 or 160 ppm of lead. The pups were treated after birth in the same way until 45 days of age. Control animals received deionized water for the same period of time. The developing rats were sacrificed at postnatal day 45 and lead level was assessed biochemically in the blood and different brain regions. Results showed that blood lead levels were increased in a dose-dependent manner. In the brain, lead accumulated preferentially in the parietal cortex, striatum, and thalamus as compared to the control group, while lipid fluorescence products were significantly increased in the striatum, thalamus, and hippocampus of the treated animals. These data suggest that in the brain of rats exposed to lead acetate, lead produces a neurotoxic effect with a complex correlation with both lead regional content and lipid peroxidation.