RESUMO
Astrocytes provide structural, metabolic and trophic support to neurons. They are directly involved in the regulation of neuronal transmission and synaptic activity and respond to the synaptic release and remove neurotransmitters from the extracellular fluid. The dysfunction of astrocytes has been implicated in multiple neurotoxicities, including those associated with drugs of abuse. Methamphetamine (METH) has long-lasting neurotoxic effects, yet little is known about the mechanisms that govern METH-induced neural dysfunction, and especially the astrocytic control over the extracellular milieu. The purpose of this study was to clarify the response of astrocytes and neurons treated with METH and determine their relative sensitivity to this drug of abuse. Confluent rat primary astrocyte and mesencephalic neuron cultures were treated for 24 hrs with 0, 0.1, 0.5 or 1 mM METH, and the initial rate of glutamate and glutamine uptake was measured over a 5 min period. Additional studies examined the effect of METH (24 hr exposure at similar concentrations) on oxidative endpoints, namely glutathione (GSH) levels, lactate dehydrogenase (LDH) release and isoprostane (IsoP) levels, considered to be the most accurate biomarker of lipid peroxidation. There was no effect of METH on the rates of glutamate and glutamine uptake, and these were indistinguishable from controls. However, METH concentration-dependently affected astrocytic and neuronal GSH levels, leading to a significant decrease in redox potential at all of the tested concentrations (p<0.05). METH also significantly enhanced astrocytic LDH release at the 0.5 and 1.0 mM exposures. Consistent with the changes in IsoPs, METH (0.5 and 1.0 mM) also increased the expression of nuclear factor erythroid 2-related factor 2 (Nrf2), a transcription factor with a key role in regulating oxidative stress responses. However, this Nrf2 increased in expression was observed only in astrocytes and no effect was noted in neurons. Taken together, this study establishes that METH affects both astrocyte and neuronal functions, and that oxidative stress is a proximate mechanism for METH's-induced neurotoxicity on both cell types. Furthermore, in response to oxidative stress astrocytes efficiently upregulated Nrf2 nuclear translocation and transcription. These effects were absent in neurons. Combined with their lower content of GSH, these characteristics may account for the greater sensitivity of neurons to METH-induce toxicity.
RESUMO
This study was carried out on rodents, to explore the neurobehavioral effects of acrylonitrile (AN) administered in drinking water. Thirty, male, Sprague-Dawley rats were randomly divided into three groups: two exposure groups (50 and 200 ppm AN), and one control group (tap water without AN). Three tests, including the open field test, rotarod test and spatial water maze, were applied to evaluate locomotor activities, motor co-ordination and learning and memory, respectively, prior to initiation of the treatment, and at Week 4, 8 and 12 postexposure. There were no consistent changes in the open field test, except for locomotion and grooming episodes. In the rotarod test, AN significantly decreased the latencies to fall in a dose and time-dependent manner. In the spatial water maze test, rats exposed to AN for 12 weeks had significantly more training times and longer escape latencies than control animals. These findings indicate that oral exposure to AN induces neurobehavioral alterations in rats.
