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Physical exercise effects on brain health and cognitive performance have been described. Synaptic remodeling in hippocampus induced by physical exercise has been described in animal models, but the underlying mechanisms remain poorly understood. Changes in astrocytes, the glial cells involved in synaptic remodeling, need more characterization. We investigated the effect of moderate treadmill exercise (20 min/day) for 4 weeks on some parameters of astrocytic activity in rat hippocampal slices, namely, glial fibrillary acidic protein (GFAP), glutamate uptake and glutamine synthetase (GS) activities, glutathione content, and S100B protein content and secretion, as well as brain-derived neurotrophic factor (BDNF) levels and glucose uptake activity in this tissue. Results show that moderate treadmill exercise was able to induce a decrease in GFAP content (evaluated by ELISA and immunohistochemistry) and an increase in GS activity. These changes could be mediated by corticosterone, whose levels were elevated in serum. BDNF, another putative mediator, was not altered in hippocampal tissue. Moreover, treadmill exercise caused a decrease in NO content. Our data indicate specific changes in astrocyte markers induced by physical exercise, the importance of studying astrocytes for understanding brain plasticity, as well as reinforce the relevance of physical exercise as a neuroprotective strategy.

Glutamate is the major excitatory neurotransmitter in the brain and over-stimulation of the glutamate receptors, NMDA, AMPA and kainate (KA), may cause neuronal death in epilepsy, seizures and neurodegenerative diseases. Mitochondria have critical cellular functions that influence neuronal excitability, such as regulation of Ca(2+) homeostasis and ATP production to maintain Na(+)K(+)-ATPase in the central nervous system (CNS). However, mitochondria are also the primary site of reactive oxygen species (ROS) production, and oxidative stress can induce cellular damage. Resveratrol, a polyphenol found in grapes and wines, presents antioxidant and neuroprotective effects on brain pathologies. This study sought to determine the neuroprotective effect of resveratrol against glutamate toxicity in acute hippocampal slices, using specific inhibitors of glutamate channels, and to investigate the targets of glutamate excitotoxicity, such as mitochondrial membrane potential (ΔΨ(m)), Na(+)K(+)-ATPase and glutamine synthetase (GS) activity. Resveratrol decreases intracellular ROS production, most likely by mechanisms involving NMDA, AMPA/KA, intracellular Ca(2+) and the heme oxygenase 1 (HO1) pathway, and prevents mitochondrial dysfunction and impairments in Na(+)K(+)-ATPase and GS activity after glutamate activation. Taken together, these results show that resveratrol may exhibit an important neuroprotective mechanism against neuropsychiatric disorders, focusing on mitochondrial bioenergetics and oxidative stress, as well as inhibitory effects on ionic channels.

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Several molecules have been shown to be involved in glial-neuronal communication, including S100B, an astrocyte-derived neurotrophic cytokine. Extracellular S100B protects hippocampal neurons from excitotoxic damage, whilst toxic levels of glutamate to neurons have been shown to reduce S100B secretion in astrocytes and brain slices, by an unknown mechanism. Here, we investigate which mechanisms are possibly involved in this effect in primary cultures of hippocampal astrocytes using glutamate agonists and glutamate uptake inhibitors. DCG-IV, an agonist of group II metabotropic glutamate receptors, caused a smaller decrease in S100B secretion when compared to 1 mM glutamate. D: -aspartate partially reverted the glutamate effect on S100B release and two other inhibitors, PDC and DIDS, reverted it completely. These findings suggest that S100B secretion is inversely coupled to glutamate uptake. Decrease in S100B secretion may be considered as direct excitotoxic damage, but a beneficial mechanism effect cannot be ruled out, because S100B elevation could cause an additional cell death.

The brain is particularly susceptible to oxidative insults and its antioxidant defense is dependent on its glutathione content. Protein malnutrition (PMN) is an important and very common insult during development and compromises antioxidant defenses in the body, particularly glutathione levels. We investigated whether brain glutathione content and related metabolic pathways, predominantly regulated by astrocytes (particularly glutamate uptake and glutamine synthesis), are altered by pre- and postnatal PMN in rats. Thus, we measured the glutathione content, glutamine synthetase (GS) activity, and glutamate uptake activity in the cerebral cortex (Cx) and hippocampus of rats subjected to pre- and postnatal PMN and in nourished controls. Although malnourished rats exhibited an ontogenetic profile of glutathione levels in both brain regions similar to that of controls, they had lower levels on postnatal d 2 (P2); in Cx this decrease persisted until postnatal d 15. In addition, we found other changes, such as reduced total antioxidant reactivity and glutathione peroxidase activity on P2, and these were not accompanied by alterations in free radical levels or lipoperoxidation in either brain region. Moreover, malnourished rats had elevated GS and reduced glutamate uptake. Taken together, these alterations indicate specific changes in astrocyte metabolism, possibly responsible for the higher vulnerability to excitotoxic/oxidative damage in malnourished rats. The lower antioxidant defense appears to be the main alteration that causes oxidative imbalance, rather than an increase in reactive oxygen species. Moreover, a recovery of altered metabolic variables may occur during adulthood, despite persistent PMN.