Emerging approach to improve functional recovery post-stroke


A large database analysis has reported that histone deacetylase (HDAC) inhibition may be beneficial in the secondary prevention of ischemic stroke (Brookes et al. Stroke 2018;49:54-61).

The study used data from three long-term stroke studies: the South London Stroke Register (SLSR); the Vitamins to Prevent Stroke (VITATOPS) study; and the Oxford Vascular Study (OXVASC) (combined n=11,949). The objective was to determine if the antiepileptic drug sodium valproate, a nonspecific HDAC inhibitor, was associated with a reduced risk of recurrent stroke.

Sodium valproate exposure was associated with a significant 50% reduction in the risk of recurrent stroke compared to no sodium valproate exposure. Recurrent stroke risk was reduced 59% with sodium valproate exposure versus exposure to other antiepileptic drugs. Of particular interest was the effect of sodium valproate in large-artery stroke, but this analysis was limited by the small sample size.

HDAC inhibition has emerged as a potential strategy to reduce stroke risk and promote functional post-stroke recovery (recently reviewed in Kannangara & Vani. J Neurosci 2017;37:12088-12090). Histone deacetylases are a class of enzymes that act epigenetically to regulate gene transcription so that cells can respond to changes in environmental conditions (Robert et al. Nature 2011;471:74-79). Histone deacetylation has been hypothesized to be dysregulated following brain injury.

HDAC inhibition within three hours after an ischemic event has been reported to reduce infarct size and neurological deficits in an animal model (Kim et al. J Pharmacol Exp Ther 2007;321:892-901). Other animal studies have suggested a benefit when an HDAC inhibitor is administered up to seven days post-stroke (Oark & Sohrabji. J Neuroinflammation 2016;13:300).

Genome-wide association studies have identified that variants in the histone deacetylase gene (HDAC9) are associated with an increased risk of ischemic stroke due to large-artery disease (International Stroke Genetics Consortium et al. Nat Gen 2012;44:328-333). A significant association between HDAC9 and large-artery stroke was also found in the METASTROKE meta-analysis (Traylor et al. Lancet Neurol 2012;11:951-962). A population-based analysis found that one HDAC9 polymorphism (rs2107595) was associated with carotid intima-media thickness and with the presence of carotid plaques (Markus et al. Stroke 2013;44:1220-1225). A pilot study subsequently reported that this same polymorphism was associated with upregulation of pathways associated with IL-6 signalling, cholesterol efflux and platelet aggregation (Shroff et al. Transl Stroke Res 2018; epublished April 13, 2018).

Several studies have now investigated the association between HDAC inhibition and stroke risk by examining populations exposed to the HDAC inhibitor sodium valproate. A Danish national cohort study found that sodium valproate exposure was associated with a lower risk of stroke and myocardial infarction (Olesen et al. Pharmacoepidemiol Drug Saf 2011;20:964-971). A UK study found an association between sodium valproate exposure and MI risk, but not for risk of ischemic stroke (Dregan et al. Pharmacoepidemiol Drug Saf 2014;23:759-767). However, there was a relationship between duration of sodium valproate exposure and ischemic stroke risk: the risk was significantly higher (odds ratio 1.62) for lowest versus highest quartile of exposure duration.

These results suggest that HDAC inhibition may have a role in primary and secondary stroke prevention, However, the precise target has not been fully elucidated. There are 18 HDACs in humans grouped into class I (HDAC 1,2,3,8); class IIA (HDAC 4,5,7,9); class IIB (HDAC 6,10); and class IV (HDAC 11,17). To date, class IIA inhibition with the nonspecific agent sodium valproate has been most studied, and there may be a greater benefit with HDAC9-specific agents. However, class I-specific agents have also been reported to reduce ischemic injury and promote functional recovery of axons (Baltan S. J Neurochem 2012;123(Suppl 2):108-115). In addition, that study found that HDAC expression may change with aging, suggesting that neuroprotective mechanisms following brain injury may be a moving target.

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