Use of STAT1 Inhibitors in the Treatment of Brain I/R Injury and Neurodegenerative Diseases

F.      H. Ebner; E.      Darra; S.      Mariotto; H.      Suzuki; E.      Cavalieri

Abstract

In the etiology of brain injury associated to ischemia/reperfusion (I/R) and neurodegenerative diseases, a critical involvement of excessive activation of signal transducer and activator of transcription 1 (STAT1) and successive induction of iNOS expression has widely been evidenced. Any compound capable to down-regulate STAT1 activation seems to represent a new, promising anti-inflammatory drug. Among plant compounds, only a few have shown to possess anti-STAT1 activity. Among them, epigallocatechin-3-gallate (EGCG), the main polyphenol present in green tea leaves, efficiently protects heart from I/R injury and this action is strictly correlated to its anti-STAT1 property. Hyperforin, the non-polyphenolic compound present in St. Johns wort, attenuates β-cell death induced by interferon-γ (IFN-γ) by strongly down-regulating STAT1 activation. STAT1, therefore, seems to represent a new molecular target of the protective treatment also against brain injury associated to a number of brain pathologies. Either understanding the molecular mechanism of anti-STAT1 action of these compounds or identification of other anti-STAT1 compounds are urged.

Keywords: STAT1, inhibitor, brain, ischemia, reperfusion, injury, neurodegenerative diseases, nitric oxide (NO), NO synthase (NOS), neuronal NOS, endothelial NOS, inducible NOS, NF-kappaB, JAK/STAT pathway, flavonoids, epigallocatechin-3-gallate, hyperfptin, stroke, microglia, inflammation, pro- and anti-inflammatory cytokines, blood brain barrier, ageing, Arbutus unedo, anti-inflammatory drug