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The Nrf2‐inducible antioxidant defense in astrocytes can be both up‐ and down‐regulated by activated microglia:Involvement of p38 MAPK

The effects of microglia‐conditioned medium (MCM) on the inducible Nrf2 system in astrocyte‐rich cultures were investigated by determination of glutathione (GSH) levels, γglutamylcysteine ligase (γGCL) activity, the protein levels of Nrf2, Keap1, the modulatory subunit of γGCL (γGCL‐M) and activated MAP kinases (ERK1/2, JNK and p38). Microglia were either cultured for 24 h in serum‐free culture medium to achieve microglia‐conditioned medium from non‐activated cells (MCM0), used as control condition, or activated with different concentrations (0.1–1,000 ng mL−1) of lipopolysaccharide (LPS) to produce MCM0.1–1,000. Acute exposure (24 h) to MCM100 increased GSH, γGCL activity, the protein levels of γGCL‐M, Nrf2, and activated JNK and ERK1/2 in astrocyte‐rich cultures. In contrast, treatment with MCM10 for 24 h decreased components of the Nrf2 system in parallel with activation of p38 MAPK. Stimulation of the Nrf2 system by tBHQ was partly intact after 24 h but blocked after 72 h treatment with MCM10 and MCM100. This down‐regulation after 72 h correlated with activation of p38 MAPK and lack of ERK1/2 and JNK activation. The negative effects were partly reversed by an inhibitor of p38 which restored tBHQ mediated protection against oxidative stress. In conclusion, the study showed a negative effect of MCM10 on the inducible anti‐oxidant defense in astrocyte‐rich cultures at both 24 and 72 h that correlated with activation of p38 and was partly reversed by a p38 inhibitor. A transient protective effect of MCM100 on astrocyte‐rich cultures against H2O2 toxicity was observed at 24 h which coincided with activation of JNK and ERK1/2. © 2011 Wiley‐Liss, Inc.