Neurotoxicity research
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Neurotoxicity research · Apr 2018
Experimental Evidence that In Vivo Intracerebral Administration of L-2-Hydroxyglutaric Acid to Neonatal Rats Provokes Disruption of Redox Status and Histopathological Abnormalities in the Brain.
Tissue accumulation of L-2-hydroxyglutaric acid (L-2-HG) is the biochemical hallmark of L-2-hydroxyglutaric aciduria (L-2-HGA), a rare neurometabolic inherited disease characterized by neurological symptoms and brain white matter abnormalities whose pathogenesis is not yet well established. L-2-HG was intracerebrally administered to rat pups at postnatal day 1 (P1) to induce a rise of L-2-HG levels in the central nervous system (CNS). Thereafter, we investigated whether L-2-HG in vivo administration could disturb redox homeostasis and induce brain histopathological alterations in the cerebral cortex and striatum of neonatal rats. ⋯ Furthermore, L-2-HG-induced lipid peroxidation and GSH decrease in the cerebral cortex were prevented by the antioxidant melatonin and by the classical antagonist of NMDA glutamate receptor MK-801, suggesting the involvement of reactive species and of overstimulation of NMDA receptor in these effects. Finally, L-2-HG provoked significant vacuolation and edema particularly in the cerebral cortex with less intense alterations in the striatum that were possibly associated with the unbalanced redox homeostasis caused by this metabolite. Taken together, it is presumed that these pathomechanisms may underlie the neurological symptoms and brain abnormalities observed in the affected patients.
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Neurotoxicity research · Jan 2018
Creating a Simian Model of Guam ALS/PDC Which Reflects Chamorro Lifetime BMAA Exposures.
The theory that β-N-methylamino-L-alanine (BMAA), a cyanobacterial toxin, contaminates traditional food supplies of the Chamorro people of Guam is supported by the recent finding that chronic dietary exposure to L-BMAA in vervets (Chlorocebus sabaeus) triggers the formation of neurofibrillary tangles (NFT) and β-amyloid plaques in the brain. In the first experiment, we found that all four vervets receiving a 210 mg/kg dose for 140 days developed NFT and sparse amyloid deposits. ⋯ The resultant cumulative lifetime Chamorro exposures ranged from 1 to 41 g/kg and are comparable to the total lifetime vervet exposures in our experiments of 2 and 22 g/kg, respectively. Furthermore, measured protein-bound BMAA concentrations of vervets fed L-BMAA powder are comparable to measured protein-bound BMAA concentrations in postmortem brain tissues of Chamorros who died with ALS/PDC.
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Neurotoxicity research · Nov 2017
Lithium Chloride Facilitates Autophagy Following Spinal Cord Injury via ERK-dependent Pathway.
Spinal cord injury (SCI) is one major cause of death and results in long-term disability even in the most productive periods of human lives with few efficacious drugs. Autophagy is a potential therapeutic target for SCI. In the present study, we examined the role of lithium in functional recovery in the rat model of SCI and explored the related mechanism. ⋯ However, lithium chloride enhanced the level of LC3-II while abrogated the abundance of p62. Furthermore, lithium treatment facilitated ERK activation in vivo, and inhibition of MEK/ERK signaling pathway suppressed lithium-evoked autophagy flux. Taken together, our results illustrated that lithium facilitated functional recovery by enhancing autophagy flux.
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Neurotoxicity research · Oct 2017
Vulnerability to a Metabolic Challenge Following Perinatal Asphyxia Evaluated by Organotypic Cultures: Neonatal Nicotinamide Treatment.
The hypothesis of enhanced vulnerability following perinatal asphyxia was investigated with a protocol combining in vivo and in vitro experiments. Asphyxia-exposed (AS) (by 21 min water immersion of foetuses containing uterine horns) and caesarean-delivered control (CS) rat neonates were used at P2-3 for preparing triple organotypic cultures (substantia nigra, neostriatum and neocortex). At DIV 18, cultures were exposed to different concentrations of H2O2 (0.25-45 mM), added to the culture medium for 18 h. ⋯ The present results demonstrate that perinatal asphyxia induces long-term changes in metabolic pathways related to energy and oxidative stress, priming cell vulnerability with both neuronal and glial phenotype. The observed effects were region dependent, being the substantia nigra particularly prone to cell death. Nicotinamide administration in vivo prevented the deleterious effects observed after perinatal asphyxia in vitro, a suitable pharmacological strategy against the deleterious consequences of perinatal asphyxia.
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Neurotoxicity research · Aug 2017
Neonatal Propofol Anesthesia Changes Expression of Synaptic Plasticity Proteins and Increases Stereotypic and Anxyolitic Behavior in Adult Rats.
Propofol is a general anesthetic commonly used in pediatric clinical practices. Experimental findings demonstrate that anesthetics induce widespread apoptosis and cognitive decline in a developing brain. Although anesthesia-mediated neurotoxicity is the most prominent during intense period of synaptogenesis, the effects of an early anesthesia exposure on the synapses are not well understood. ⋯ GAP-43 and MAP-2 adult and juvenile isoforms are upregulated following anesthesia, suggesting compensatory mechanism in the maintaining of the structural integrity and stabilization of developing axons and dendritic arbors. Neonatal propofol exposure significantly altered spontaneous motor activity (increased stereotypic/repetitive movements) and changed emotional behavior (reduced anxiety-like response) in the adulthood, 6 months later. These findings suggest that propofol anesthesia is synaptotoxic in the developing brain, disturbing synaptic dynamics and producing neuroplastic changes permanently incorporated into existing networks with long-lasting functional consequences.