Astroglial cells are key modulators of neuropathology events. Resveratrol, a redox-active compound present in grapes and wine, has a wide range of biological effects. The aim of this study was to investigate whether resveratrol is able to prevent hydrogen peroxide (H(2)O(2))-induced oxidative damage in C6 astroglial cells. We found that following a short oxidative insult (Model I-1 mM H(2)O(2)/30 min), resveratrol increased glutamate uptake (60%), glutamine synthetase (GS) (139%), glutathione (GSH) (120%), and S100B secretion (24%); and attenuated DCFH oxidation (34%) as compared to H(2)O(2) values. Under less intense (0.1 mM H(2)O(2)), but lasting (6 h) insult (Model II), resveratrol had an opposite effect, potentiating the H(2)O(2)-induced decrease in glutamate uptake (from 34 to 63%), in GS (from 22 to 50%), in GSH (from 22 to 54%), and also potentiating DCFH oxidation (from 24 to 38%). The transcription factor, NF-kappaB, was activated in both models. Cell morphology alterations were also observed in the presence of H(2)O(2) with process-bearing cells, accompanied by cell body retraction and actin reorganization. This effect was not prevented by resveratrol, but was prevented by lysophosphatidic acid (LPA), a specific upstream positive regulator of Rho A. In summary, these findings showed that resveratrol, a redox-active compound, was able to modulate important neurotrophic function of astroglial cells under different oxidative conditions.

Although inflammation may be a physiological defense process, imbalanced neuroinflammation has been associated with the pathophysiology of brain disorders, including major depression and schizophrenia. Activated glia releases a variety of pro-inflammatory cytokines that contribute to neuronal dysfunction. Elevated levels of S100B, a glia derived protein, have been observed in the serum and CSF of schizophrenic patients suggesting a glial role in the disease. We evaluated whether S100B secretion (in C6 glioma cells and hippocampal slices in Wistar rats) could be directly modulated by the main inflammatory cytokines (IL-1β, TNF-α, IL-6 and IL-8) altered in schizophrenia, as well as the possible involvement of mitogen-activated protein kinase (MAPK) pathways in these responses. We also investigated the effects of typical and atypical antipsychotic drugs on glial cytokine-induced S100B release. Our results suggest that S100B secretion is increased by pro-inflammatory cytokines via MAPK and that oxidative stress may be a component of this modulation. These results reinforce the idea that the S100B protein is involved in the inflammatory response observed in many brain diseases, including schizophrenia. Moreover the antipsychotics, haloperidol and risperidone, were able to inhibit the secretion of S100B following IL-6 stimulation in C6 glioma cells.

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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.