Potent neuroprotective effects of novel structural derivatives of valproic acid: Potential roles of HDAC inhibition and HSP70 induction

Abstract

Emerging evidence suggests that the neuroprotective effects of valproic acid (VPA) occur via inhibition of histone deacetylases (HDACs) and activation of gene expression. This study assessed the ability of four VPA derivatives to cause histone hyperacetylation and protect against glutamate-induced excitotoxicity in cultured neurons. We found that (S)-2-pentyl-4-pentynoic acid (compound III) and (±)-2-hexyl-4-pentynoic acid (compound V) were far more potent and robust than VPA in inducing histone hyperacetylation and protecting against glutamate excitotoxicity. Thus, the increase in histone acetylation elicited by compounds III and V was significant at 5 µM and reached a maximal increase of 600–700% at 50–100 µM, compared with only a 200% increase by VPA at 100 µM. The neuroprotective effects of compounds III and V were evident at 10–25 µM and reached a complete protection at 50–100 µM, while a significant partial protection by VPA was observed at 100 µM. These two compounds were also more effective than VPA in increasing HSP70-1a and HSP70-1b mRNA levels. At 50 µM, compound V was most robust in increasing HSP-1a mRNA levels, followed by compound III, and then by VPA. HSP-1b mRNA was only significantly upregulated by compounds V and III, but not by VPA or other VPA derivatives under these treatment conditions. Our results suggest that these two VPA derivatives may ultimately be developed into potent neuroprotective drugs in preclinical and clinical studies.

Histone deacetylase inhibition alters histone methylation associated with heat shock protein 70 promoter modifications in astrocytes and neurons

“…Our previous study found that HSP70 is an important target for VPA and other HDAC inhibitors, and is part of the mechanism through which they exert neuroprotective effects against glutamate-induced excitotoxicity in primary neuronal cultures (Marinova et al, 2009; Leng et al, 2010), as well as in a rat model of cerebral ischemia (Ren et al, 2004; Kim et al, 2007a). HSP70 upregulation has been shown to stabilize the NF-κB-IκB complex, thereby preventing the nuclear translocation of the activated NF-κB subunits (Rel A and p50) to elicit inflammatory responses (Zheng et al, 2008).…”

Class-IIa Histone Deacetylase Inhibition Promotes the Growth of Neural Processes and Protects Them Against Neurotoxic Insult

“…Many in vitro and in vivo studies have shown that HDIs protect against a range of toxic insults through the modulation of histones [38], increased the transcription of free radical scavengers [39,40], heat shock proteins [41][42][43] and anti-apoptotic Bcl-2 family members [39,44] as well as decreasing the expression of inflammatory mediators [38,45,46], reducing excitotoxicity [47,48], oxidative stress [49,50] and enhancing neurotrophic factor expression [51]. As many of these events have been implicated in mediating or protecting against dopaminergic cell death in PD, HDIs are appealing candidates for promoting dopaminergic neuronal survival in PD [21,52].…”

Epigenetic mechanisms in the development and maintenance of dopaminergic neurons

“…Moreover, beta-hydroxybutyate, an endogenous and specific inhibitor of class I HDACs (Shimazu et al, 2012), has been reported to protect primary rat mesencephalic neurons from 1-methyl-4-phenylpyridinium [MPP(+)]-induced toxicity (Kashiwaya et al, 2000). Another study reported regulation of heat shock protein 70 (Hsp70) expression through changes to the di-and trimethylation of histone H3 lysine 4 (H3K4me2 and H3K4me3) and p300 (HAT) recruitment (Marinova et al, 2009;Marinova et al, 2011;Leng et al, 2010). As a member of the heat shock protein family, Hsp70 is involved in protein folding, is able to upregulate the apoptotic regulator Bcl2, and is involved in several additional anti-apoptotic mechanisms (Yenari et al, 2005).…”