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Exposure to environmental contaminants represents an important etiological factor in sporadic Parkinson's disease (PD). It has been reported that PD could arise from events that occur early in development and that lead to delayed adverse consequences in the nigrostriatal dopaminergic system at adult life. We investigated the occurrence of late nigrostriatal dopaminergic neurotoxicity induced by exposures to the pesticides paraquat (PQ) and maneb (MB) during the early postnatal period in mice, as well as whether the exposure to pesticides during development could enhance mice vulnerability to subsequent challenges. Male Swiss mice were exposed to a combination of 0.3 mg/kg PQ and 1.0 mg/kg MB (PQ + MB) from postnatal (PN) day 5 to 19. PN exposure to pesticides neither induced mortally nor modified motor-related parameters. However, PN pesticides exposure decreased the number of tyrosine hydroxylase (TH)– and dopamine transporter (DAT)–positive neurons in the substantia nigra pars compacta (SNpc), as well as reduced TH and DAT immunoreactivity in the striatum. A parallel group of animals developmentally exposed to the pesticides was re-challenged at 3 months of age with 10 mg/kg PQ plus 30 mg/kg MB (twice a week, 6 weeks). Mice exposed to pesticides at both periods (PN + adulthood) presented motor deficits and reductions in the number of TH- and DAT-positive neurons in the SNpc. These findings indicate that the exposure to PQ + MB during the early PN period can cause neurotoxicity in the mouse nigrostriatal dopaminergic system, rendering it more susceptible to a subsequent adult re-challenge with the same pesticides. [ABSTRACT FROM AUTHOR]

Deposition of amyloid-β (Aβ) peptides into specific encephalic structures has been pointed as an important event related to Alzheimer's disease pathogenesis and associated with activation of glial cells, neuroinflammation, oxidative responses, and cognitive deficits. Aβ-induced pro-oxidative damage may regulate the activity of glutamate transporters, leading to reduced glutamate uptake and, as a consequence, excitotoxic events. Herein, we evaluated the effects of the pretreatment of atorvastatin, a HMG-CoA reductase inhibitor, on behavioral and biochemical alterations induced by a single intracerebroventricular (i.c.v.) injection of aggregated Aβ in mice. Atorvastatin (10 mg/kg/day, p.o.) was administered through seven consecutive days before Aβ administration. Aβ caused significant cognitive impairment in the object-place recognition task (2 weeks after the i.c.v. injection) and this phenomenon was abolished by atorvastatin pretreatment. Ex vivo evaluation of glutamate uptake into hippocampal and cerebral cortices slices showed atorvastatin, and Aβ decreased hippocampal and cortical Na-dependent glutamate uptake. However, Aβ increased Na-independent glutamate uptake and it was prevented by atorvastatin in prefrontal cortex slices. Moreover, Aβ treatment significantly increased the cerebrocortical activities of glutathione reductase and glutathione peroxidase and these events were blunted by atorvastatin pretreatment. Reduced or oxidized glutathione levels were not altered by Aβ and/or atorvastatin treatment. These results extend the notion of the protective action of atorvastatin against neuronal toxicity induced by Aβ demonstrating that a pretreatment with atorvastatin prevents the spatial learning and memory deficits induced by Aβ in rodents and promotes changes in glutamatergic and antioxidant systems mainly in prefrontal cortex. [ABSTRACT FROM AUTHOR]

The astrocytic glutamate transporters (GLT-1, GLAST) are critical for removing excess glutamate from synaptic sites, thereby maintaining glutamate homeostasis within the brain. 17β-Estradiol (E2) is one of the most active estrogen hormones possessing neuroprotective effects both in in vivo and in vitro models, and it has been shown to enhance astrocytic glutamate transporter function (Liang et al. in J Neurochem 80:807-814, ; Pawlak et al. in Brain Res Mol Brain Res 138:1-7, ). However, E2 is not clinically optimal for neuroprotection given its peripheral feminizing and proliferative effects; therefore, brain selective estrogen receptor modulators (neuro SERMs) (Zhao et al. in Neuroscience 132:299-311, ) that specifically target estrogenic mechanisms, but lack the systemic estrogen side effects offer more promising therapeutic modality for the treatment of conditions associated with excessive synaptic glutamate levels. This review highlights recent studies from our laboratory showing that E2 and SERMs effectively reverse glutamate transport inhibition in a manganese (Mn)-induced model of glutamatergic deregulation. Specifically, we discuss mechanisms by which E2 restores the expression and activity of glutamate uptake. We advance the hypothesis that E2 and related compounds, such as tamoxifen may offer a potential therapeutic modality in neurodegenerative disorders, which are characterized by altered glutamate homeostasis. [ABSTRACT FROM AUTHOR]