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

Abstract

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.

Epigenetic Mechanisms in Stroke and Epilepsy

“…In pre-clinical studies, four main classes of HDAC are under investigation: the short-chain fatty acids, such as sodium butyrate, phenylbutyrate, and valproic acid, the hyroxamic acids, such as TSA and SAHA, the epoxyketones, such as trapoxin, and the benzamides (Abel and Zukin, 2008). SAHA and TSA promote neuronal survival in animal models of ischemia (Gibson and Murphy, 2010;Baltan et al, 2011b;Wang et al, 2012;Noh et al, 2012) and epilepsy (Huang et al, 2002;Kobow and Blumcke, 2011). Intriguingly, valproic acid, which is commonly prescribed as an anticonvulsant drug, was subsequently discovered to be an HDAC inhibitor (Gottlicher et al, 2001).…”

Novel Protective Effects of Histone Deacetylase Inhibition on Stroke and White Matter Ischemic Injury

“…In vitro analysis demonstrated that the HDAC inhibitor activated Nrf2, in part, by reducing expression of the suppressor Keap1, promoting Keap1/Nrf2 dissociation, and enhancing Nrf2 nuclear translocation [19]. Consistent with these in vitro findings, the addition of TSA to Nrf2-deficient mice did not confer protection from ischemia [19].…”

“…Relevant studies since then have revealed that VPA attenuates stroke-induced blood-brain barrier disruption [18], trichostatin A (TSA) is effective as a stroke neuroprotectant [19], and hints at the specific contributions of HDACs 4 and 5 to stroke injury [20]. Human brain comprises gray matter and WM in equal volumes, which means that injury sustained after a stroke involves both.…”

“…Activation of the Nrf2 pathway has been shown to increase the resistance of neurons to oxidative stress and metabolic insults in culture, and to ischemic stroke in vivo [40]. More recently, a broad-based HDAC inhibitor (TSA) was shown to increase neuron viability after OGD [19]. In vitro analysis demonstrated that the HDAC inhibitor activated Nrf2, in part, by reducing expression of the suppressor Keap1, promoting Keap1/Nrf2 dissociation, and enhancing Nrf2 nuclear translocation [19].…”

Ketone body 3‐hydroxybutyrate mimics calorie restriction via the Nrf2 activator, fumarate, in the retina

“…3HB is an endogenous HDAC inhibitor (Shimazu et al., 2013), and the inhibition of HDAC leads to the activation of the Nrf2 pathway (Wang et al., 2012), promoting protection against neuronal damage. Acetylation levels of histone H3, K9, K14, and K27 in the IF and 3HB groups were similar to those in the AL group (Fig.…”