Effects of microglia-conditioned medium on the inducible antioxidant system in astrocytes

CORREA F., LJUNGGREN E., SANDBERG M

Göteborg - Suecia

Conferencia; 35th FEBS Congress “Molecules of Life”; 2010

Federation of European Biochemical Societies (FEBS)

Gluthation (GSH) is a ubiquitous intracellular peptide with diverse functions that include detoxification, antioxidant defense and maintenance of thiol status and modulation of cell proliferation. Disturbance in the cellular redox balance, due to enhanced ROS production and/or impaired antioxidant defense, eventually leads to oxidative alterations of biological macromolecules, such as proteins, lipids and nucleic acids. These events produce cellular malfunction and eventually cell death. For brain, oxidative stress has been connected with the loss of neurons during the progression of neurological diseases like Parkinson’s disease (PD), Alzheimer’s disease (AD), Huntington’s disease (HS), stroke and both acute and chronic stress. Astrocytes are known to be the main source of GSH for neurons and highly express antioxidant responsive elements (ARE)-driven genes in response to oxidative stress. It has been shown that conditioned medium from activated microglia (MCM) induces the expression of different type II enzymes, suggesting that the modulation of antioxidant enzyme expression in astrocytes by activated microglia is accompanied by a change of the astroglial resistance to oxidative stress. Our main goal is to understand the effects of microglial activation on astrocytes expression of GSH and other type II enzymes as well as the Nrf2/Keap1 system. We exposed astrocytes to MCM and analysed the content of GSH and the activity of glutamate-cystein ligase (GCL), the rate-limiting enzyme in GSH synthesis. We found that MCM-exposed astrocytes exhibited a biphasic expression of GSH and on the GCL activity at 24h post-treatment whereas at 72h post-treatment the intracellular levels of GSH were reduced. Morever, the activation of the Nrf2 inducible system reversed the effects of MCM on GSH levels both at 24h and 72h. Next, we explored the possible molecular mechanisms involved in the differential effects of acute vs chronic exposure to MCM. We found that p38 MAPK is negatively involved in the modulation of Nrf2 and its pharmacological inhibition restores the inducibility of this antioxidant system.