Impact of manganese neurotoxicity on MMP-9 production and superoxide dismutase activity in rat primary astrocytes. Effect of resveratrol and therapeutical implications for the treatment of CNS diseases.

Manganese (Mn) is an environmental contaminant and its overexposure contributes to the pathophysiological processes of numerous disorders of the central nervous system (CNS) in humans with mechanisms of action not completely understood. Activation of astrocytes and the subsequent release of neurotoxic factors has been implicated to contribute to neurodegeneration. Here we assessed the molecular basis of the effects of manganese on modulation of matrix metalloproteinases-2 (MMP-2) and -9 (MMP-9) in rat astrocyte cultures.Primary cultures of rat astrocytes were exposed to different doses of MnCl2. Culture supernatants and cell lysates were used for the detection of MMP-2 and MMP-9 levels and mRNA expression, respectively. The exposure of astrocytes to MnCl2 dose-dependently induced levels and expression of MMP-9. The addition of resveratrol (RSV) inhibited both levels and expression of MMP-9 in astrocytes, whereas N-acetylcysteine (NAC) and quercetin (QRC) were ineffective in inhibiting MMP-9. As a possible mechanism of Mn-induced MMP-9, we determined intracellular redox state in Mn-treated astrocytes by assessing superoxide dismutase (SOD) activity and intracellular reactive oxygen species (ROS) and found a significant increase of ROS and a decrease of SOD activity. RSV, NAC and QRC restored the redox state. The study of the mitogen activated protein kinases (MAPKs) signalling pathway demonstrated that MMP-9 transcription is mainly regulated by extracellular regulated kinase (ERK). Pre-treatment with RSV significantly reduced ERK activation suggesting that its ability to counteract MMP-9 overexpression is due not only to a general redox balance phenomenon, but also to the modulation of ERK signaling pathway.