CEFYBO   02669
CENTRO DE ESTUDIOS FARMACOLOGICOS Y BOTANICOS
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
Decreased histone acetylation and impaired Nrf2-induced anti-oxidant defence in astrocytes by activated microglia
Autor/es:
M. SANDBERG, F. CORREA, M. NILSSON, C. MALLARD
Reunión:
Congreso; Neuroscience 2011 (SfN); 2011
Resumen:
Histone deacetylase (HDAC) inhibitors have neuroprotective and
anti-inflammatory properties although the exact mechanisms are not fully
clear. We have earlier (Correa et al., 2011) demonstrated that
lipopolysaccharide (LPS)-activated microglia down-regulate the
astroglial nuclear factor-erythroid 2-related factor 2
(Nrf2)-inducible anti-oxidant defence. Here we have evaluated whether
histone modifications could be involved in these negative effects of
microglia. Microglia were cultured for 24 h in serum-free culture medium
to achieve microglia-conditioned medium from non-activated cells (MCM0) or activated with 10 ng/mL of LPS to produce MCM10. Astrocyte-rich cultures treated with MCM10
showed increased astroglial HDAC activity that correlated with lower
levels of acetylation of histones and decreased levels of the
transcription factor Nrf2 and γglutamyl cysteine ligase modulatory
subunit (γGCL-M) protein levels. The HDAC inhibitors valproic acid (VPA)
and trichostatin-A (TSA) increased the histone acetylation levels,
restored the Nrf2-inducible anti-oxidant defence and conferred
protection from oxidative stress-induced (H2O2) death in astrocyte-rich cultures exposed to MCM10.
Inhibitors of GSK3beta and p38 MAPK signalling pathways restored the
depressed histone acetylation and Nrf2-related transcription whereas an
inhibitor of Akt caused a further decrease in Nrf2-related
transcription. The study shows that inhibitors of HDACs such as VPA and
TSA can restore an inflammatory induced depression in the Nrf2-inducible
antioxidant defence and indicate that the Nrf2-system, at least in
part, can be regulated by epigenetic mechanisms.