Activation of Nrf2 and Hypoxic Adaptive Response Contribute to Neuroprotection Elicited by Phenylhydroxamic Acid Selective HDAC6 Inhibitors

Abstract

Activation of HIF-1α and Nrf2 is a primary component of cellular response to oxidative stress, and activation of HIF-1α and Nrf2 provides neuroprotection in models of neurodegenerative disorders, including ischemic stroke, Alzheimer's and Parkinson's diseases. Screening a library of CNS-targeted drugs using novel reporters for HIF-1α and Nrf2 elevation in neuronal cells revealed histone deacetylase (HDAC) inhibitors as potential activators of these pathways. We report the identification of phenylhydroxamates as single agents exhibiting tripartite inhibition of HDAC6, inhibition of HIF-1 prolyl hydroxylase (PHD), and activation of Nrf2. Two superior tripartite agents, ING-6 and ING-66, showed neuroprotection against various cellular insults, associated with stabilization of both Nrf2 and HIF-1, and expression of their respective target genes in vitro and in vivo. Discovery of the innate ability of phenylhydroxamate HDAC inhibitors to activate Nrf2 and HIF provides a novel route to multifunctional neuroprotective agents and cautions against HDAC6 selective inhibitors as chemical probes of specific HDAC isoform function.

Updating a Strategy for Histone Deacetylases and Its Inhibitors in the Potential Treatment of Cerebral Ischemic Stroke

“…On the other hand, HDAC6 inhibits ODG reperfusion-induced tubulin deacetylation and caspase-3 activation and protects Golgi apparatus breakage and apoptosis induced by oxyglucose deprivation reperfusion (OGDR) [ 45 ]. Another research exhibits tripartite inhibition of HDAC6 that showed neuroprotection against various cellular insults [ 46 ]. Pharmacological or gene inhibition experiments on HDAC6 confirmed the block caused by stroke, indicating that the normal function of HDAC6 is necessary for the efficacy of rehabilitation treatment after stroke [ 47 ].…”

The neuroprotective action of 3,3′-diindolylmethane against ischemia involves an inhibition of apoptosis and autophagy that depends on HDAC and AhR/CYP1A1 but not ERα/CYP19A1 signaling

“…It is well known that HDAC inhibitors exert neuroprotective properties in experimental models of stroke and reduce stroke risk after previous ischemic stroke in humans [ 20 – 25 ]. Despite these data, the role of HDAC in stroke is still controversial; there is evidence of HDAC stimulation in response to ischemia but there are also data showing inhibition of HDAC in response to ischemia [ 26 – 30 ]. However, the involvement of HDAC in neuroprotective action of DIM in experimental model of stroke remains unknown.…”

Synthesis of Indoline‐Based Benzhydroxamic Acids as Potential HDAC6 Inhibitors

“…Only compounds 1 a and 1 d have recently been reported in the literature and were shown to exhibit excellent HDAC6 inhibitory activities . To investigate the effect of the structural modifications realized in the other potential inhibitors, all seven compounds were tested for their ability to inhibit HDAC6 on an enzymatic level (Table ).…”

“…For example, it is an essential part of the non‐selective HDAC inhibitor MPT0E028, which shows in vivo anti‐cancer properties . More recently, a series of N ‐(4‐hydroxycarbamoylbenzyl)indolines has been developed as highly active and selective HDAC6 inhibitors . Structural modifications of the ‘cap’‐group, however, were limited to the 3‐, 5‐ and 6‐position, with all compounds possessing HDAC6 IC 50 values between 10 and 50 nM.…”