Histone deacetylase inhibition activates transcription factor Nrf2 and protects against cerebral ischemic damage

Interest in histone deacetylase (HDAC)-based therapeutics as a potential treatment for stroke has grown dramatically. The neuroprotection of HDAC inhibition may involve multiple mechanisms, including modulation of transcription factor acetylation independent of histones. The transcription factor Nrf2 has been shown to be protective in stroke as a key regulator of antioxidant-responsive genes. Here, we hypothesized that HDAC inhibition might provide neuroprotection against mouse cerebral ischemia by activating the Nrf2 pathway. We determined that the classic HDAC inhibitor trichostatin A increased neuronal cell viability after oxygen-glucose deprivation (from an OD value of 0.10 ± 0.01 to 0.25 ± 0.08) and reduced infarct volume in wild-type mice with stroke (from 49.1 ± 3.8 to 21.3 ± 4.6%). In vitro studies showed that HDAC inhibition reduced Nrf2 suppressor Keap1 expression, induced Keap1/Nrf2 dissociation, Nrf2 nuclear translocation, and Nrf2 binding to antioxidant response elements in heme oxygenase 1 (HO1), and caused HO1 transcription. Furthermore, we demonstrated that HDAC inhibition upregulated proteins downstream of Nrf2, including HO1, NAD(P)H:quinone oxidoreductase 1, and glutamate-cysteine ligase catalytic subunit in neuron cultures and brain tissue. Finally, unlike wild-type mice, Nrf2-deficient mice were not protected by pharmacologic inhibition of HDAC after cerebral ischemia. Our studies suggest that activation of Nrf2 might be an important mechanism by which HDAC inhibition provides neuroprotection.

Graphical abstractFigure optionsDownload full-size imageDownload high-quality image (176 K)Download as PowerPoint slideHighlights► HDAC inhibition provides neuroprotection from ischemic injury in vitro and in vivo. ► HDAC inhibition reduces Nrf2 suppressor Keap1 expression. ► TSA induces Nrf2 dissociation, nuclear translocation, and ARE-binding activity. ► TSA upregulates proteins downstream of Nrf2, including HO1, NQO1, and GCLC. ► HDAC inhibition does not protect Nrf2 knockout mice against ischemic stroke.