The histone deacetylase inhibitor suberoylanilide hydroxamic acid attenuates human astrocyte neurotoxicity induced by interferon-γ.
BACKGROUND
Increasing evidence shows that the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) possesses potent anti-inflammatory and immunomodulatory properties. It is tempting to evaluate the potential of SAHA as a therapeutic agent in various neuroinflammatory and neurodegenerative disorders.


METHODS
We examined the effects of SAHA on interferon (IFN)-γ-induced neurotoxicity of human astrocytes and on IFN-γ-induced phosphorylation of signal transducer and activator of transcription (STAT) 3 in human astrocytes. We also studied the effects of SAHA on the astrocytic production of two representative IFN-γ-inducible inflammatory molecules, namely IFN-γ-inducible T cell α chemoattractant (I-TAC) and intercellular adhesion molecule-1 (ICAM-1).


RESULTS
SAHA significantly attenuated the toxicity of astrocytes activated by IFN-γ towards SH-SY5Y human neuronal cells. In the IFN-γ-activated astrocytes, SAHA reduced the STAT3 phosphorylation. SAHA also inhibited the IFN-γ-induced astrocytic production of I-TAC, but not ICAM-1. These results indicate that SAHA suppresses IFN-γ-induced neurotoxicity of human astrocytes through inhibition of the STAT3 signaling pathway.


CONCLUSIONS
Due to its anti-neurotoxic and anti-inflammatory properties, SAHA appears to have the therapeutic or preventive potential for a wide range of neuroinflammatory disorders associated with activated astrocytes.
Kinsmen Laboratory of Neurological Research, Department of Psychiatry, the University of British Columbia, 2255 Wesbrook Mall, Vancouver, BC, V6T 1Z3, Canada. hashioka@f2.dion.ne.jp
Sadayuki
S
Hashioka
Andis
A
Klegeris
Patrick L
PL
McGeer
D001253:Astrocytes / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology*; D002460:Cell Line; D045744:Cell Line, Tumor; D056572:Histone Deacetylase Inhibitors / Q000633:toxicity*; D006801:Humans; D006877:Hydroxamic Acids / Q000633:toxicity*; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000633:toxicity*; D000077337:Vorinostat
D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D000077337:Vorinostat; D007371:Interferon-gamma