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1.
PLoS One ; 7(3): e33057, 2012.
Article in English | MEDLINE | ID: mdl-22427945

ABSTRACT

Manganese (Mn) is an essential metal for development and metabolism. However, exposures to high Mn levels may be toxic, especially to the central nervous system (CNS). Neurotoxicity is commonly due to occupational or environmental exposures leading to Mn accumulation in the basal ganglia and a Parkinsonian-like disorder. Younger individuals are more susceptible to Mn toxicity. Moreover, early exposure may represent a risk factor for the development of neurodegenerative diseases later in life. The present study was undertaken to investigate the developmental neurotoxicity in an in vivo model of immature rats exposed to Mn (5, 10 and 20 mg/kg; i.p.) from postnatal day 8 (PN8) to PN12. Neurochemical analysis was carried out on PN14. We focused on striatal alterations in intracellular signaling pathways, oxidative stress and cell death. Moreover, motor alterations as a result of early Mn exposure (PN8-12) were evaluated later in life at 3-, 4- and 5-weeks-of-age. Mn altered in a dose-dependent manner the activity of key cell signaling elements. Specifically, Mn increased the phosphorylation of DARPP-32-Thr-34, ERK1/2 and AKT. Additionally, Mn increased reactive oxygen species (ROS) production and caspase activity, and altered mitochondrial respiratory chain complexes I and II activities. Mn (10 and 20 mg/kg) also impaired motor coordination in the 3(rd), 4(th) and 5(th) week of life. Trolox™, an antioxidant, reversed several of the Mn altered parameters, including the increased ROS production and ERK1/2 phosphorylation. However, Trolox™ failed to reverse the Mn (20 mg/kg)-induced increase in AKT phosphorylation and motor deficits. Additionally, Mn (20 mg/kg) decreased the distance, speed and grooming frequency in an open field test; Trolox™ blocked only the decrease of grooming frequency. Taken together, these results establish that short-term exposure to Mn during a specific developmental window (PN8-12) induces metabolic and neurochemical alterations in the striatum that may modulate later-life behavioral changes. Furthermore, some of the molecular and behavioral events, which are perturbed by early Mn exposure are not directly related to the production of oxidative stress.


Subject(s)
Basal Ganglia/drug effects , Basal Ganglia/metabolism , Environmental Exposure , Gene Expression Regulation, Developmental/drug effects , Manganese/toxicity , Psychomotor Performance/drug effects , Analysis of Variance , Animals , Basal Ganglia/growth & development , Blotting, Western , Caspases/metabolism , Dopamine and cAMP-Regulated Phosphoprotein 32/metabolism , MAP Kinase Signaling System/drug effects , Phosphorylation/drug effects , Proto-Oncogene Proteins c-akt/metabolism , Rats , Reactive Oxygen Species/metabolism , Spectrophotometry, Atomic
2.
Free Radic Res ; 42(8): 707-15, 2008 Aug.
Article in English | MEDLINE | ID: mdl-18661426

ABSTRACT

The present work investigated the in vitro effects of isovaleric acid (IVA) and isovalerylglycine (IVG), which accumulate in isovaleric acidemia (IVAcidemia), on important parameters of oxidative stress in supernatants and mitochondrial preparations from brain of 30-day-old rats. IVG, but not IVA, significantly increased TBA-RS and chemiluminescence values in cortical supernatants. Furthermore, the addition of free radical scavengers fully prevented IVG-induced increase of TBA-RS. IVG also decreased GSH concentrations, whereas IVA did not modify this parameter in brain supernatants. Furthermore, IVG did not alter lipid peroxidation or GSH concentrations in mitochondrial preparations, indicating that the generation of oxidants by IVG was dependent on cytosolic mechanisms. On the other hand, IVA significantly induced carbonyl formation both in supernatants and purified mitochondrial preparations from rat brain, with no effect observed for IVG. Therefore, it is presumed that oxidative damage may be at least in part involved in the pathophysiology of the neuropathology of IVAcidemia.


Subject(s)
Cerebral Cortex/drug effects , Glycine/analogs & derivatives , Metabolism, Inborn Errors/pathology , Oxidative Stress/drug effects , Pentanoic Acids/pharmacology , Animals , Cerebral Cortex/metabolism , Free Radical Scavengers/pharmacology , Glutathione/metabolism , Glycine/pharmacology , Hemiterpenes , Lipid Peroxidation/drug effects , Lipid Peroxidation/physiology , Metabolism, Inborn Errors/metabolism , Mitochondria/drug effects , Mitochondria/metabolism , Protein Carbonylation/drug effects , Rats , Rats, Wistar , Thiobarbituric Acid Reactive Substances/metabolism
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