Sodium Valproate, a Histone Deacetylase Inhibitor, Is Associated With Reduced Stroke Risk After Previous Ischemic Stroke or Transient Ischemic Attack

Abstract

Background and Purpose—A variant in the histone deacetylase 9 (HDAC9) gene is associated with large artery stroke. Therefore, inhibiting HDAC9 might offer a novel secondary preventative treatment for ischemic stroke. The antiepileptic drug sodium valproate (SVA) is a nonspecific inhibitor of HDAC9. We tested whether SVA therapy given after ischemic stroke was associated with reduced recurrent stroke rate.Methods—Data were pooled from 3 prospective studies recruiting patients with previous stroke or transient ischemic attack and long-term follow-up: the South London Stroke Register, The Vitamins to Prevent Stroke Study, and the Oxford Vascular Study. Patients receiving SVA were compared with patients who received antiepileptic drugs other than SVA using survival analysis and Cox Regression.Results—A total of 11 949 patients with confirmed ischemic event were included. Recurrent stroke rate was lower in patient taking SVA (17 of 168) than other antiepileptic drugs (105 of 530; log-rank survival analysis P=0.002). On Cox regression, controlling for potential cofounders, SVA remained associated with reduced stroke (hazard ratio=0.44; 95% confidence interval: 0.3–0.7; P=0.002). A similar result was obtained when patients taking SVA were compared with all cases not taking SVA (Cox regression, hazard ratio=0.47; 95% confidence interval: 0.29–0.77; P=0.003).Conclusions—These results suggest that exposure to SVA, an inhibitor of HDAC, may be associated with a lower recurrent stroke risk although we cannot exclude residual confounding in this study design. This supports the hypothesis that HDAC9 is important in the ischemic stroke pathogenesis and that its inhibition, by SVA or a more specific HDAC9 inhibitor, is worthy of evaluation as a treatment to prevent recurrent ischemic stroke.

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

“…Moreover, there are some data showing that DIM exhibits properties of histone deacetylase (HDAC) inhibitor in prostate and colon cancer cell lines [ 18 , 19 ]. 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 ].…”

Endoplasmic Reticulum Stress-Induced Upregulation of STARD1 Promotes Acetaminophen-Induced Acute Liver Failure

“…13,16 VPA-mediated hepatotoxicity is characterized by necrosis, depletion of endogenous antioxidants, and disruption of mitochondrial b-oxidation of fatty acids, which can contribute to hepatic steatosis. [16][17][18][19][20] Furthermore, VPA has been shown to inhibit HDAC and GSK3 signaling events, 21,22 and although reported to induce endoplasmic reticulum stress (ER stress), 23,24 there are studies showing that VPA protects cells against ER stressmediated apoptosis and atherosclerosis. 25,26 As VPA has been shown to deplete glutathione levels and stimulate steroidogenesis by increasing mitochondrial cholesterol trafficking, 27,28 we hypothesized that VPA can sensitize to APAP-mediated ALF independently of fasting by inducing steroidogenic acute regulatory protein 1 (STARD1), a mitochondrial protein that mediates the transport of cholesterol to the mitochondrial inner membrane, 29 which results in impaired transport of glutathione into mitochondria.…”

Smoking affects gene expression in blood of patients with ischemic stroke

“…LEF1 is a transcriptional repressor which activates HDACs which downregulate expression of many genes important in the pathogenesis of stroke . Indeed, HDAC inhibitors in humans can decrease the risk of stroke after a previous stroke or TIA . Thus, smoking activation of LEF1 would be expected to activate HDACs which could worsen stroke outcomes.…”