Abstract
Suberoylanilide hydroxamic acid (SAHA) is an inhibitor of histone deacetylases (HDACs) used for the treatment of cutaneous T cell lymphoma (CTCL) and under consideration for other indications. In vivo studies suggest reducing HDAC function can enhance synaptic function and memory, raising the possibility that SAHA treatment could have neurological benefits. We first examined the impacts of SAHA on synaptic function in vitro using rat organotypic hippocampal brain slices. Following several days of SAHA treatment, basal excitatory but not inhibitory synaptic function was enhanced. Presynaptic release probability and intrinsic neuronal excitability were unaffected suggesting SAHA treatment selectively enhanced postsynaptic excitatory function. In addition, long-term potentiation (LTP) of excitatory synapses was augmented, while long-term depression (LTD) was impaired in SAHA treated slices. Despite the in vitro synaptic enhancements, in vivo SAHA treatment did not rescue memory deficits in the Tg2576 mouse model of Alzheimer’s disease (AD). Along with the lack of behavioral impact, pharmacokinetic analysis indicated poor brain availability of SAHA. Broader assessment of in vivo SAHA treatment using high-content phenotypic characterization of C57Bl6 mice failed to demonstrate significant behavioral effects of up to 150 mg/kg SAHA following either acute or chronic injections. Potentially explaining the low brain exposure and lack of behavioral impacts, SAHA was found to be a substrate of the blood brain barrier (BBB) efflux transporters Pgp and Bcrp1. Thus while our in vitro data show that HDAC inhibition can enhance excitatory synaptic strength and potentiation, our in vivo data suggests limited brain availability may contribute to the lack of behavioral impact of SAHA following peripheral delivery. These results do not predict CNS effects of SAHA during clinical use and also emphasize the importance of analyzing brain drug levels when interpreting preclinical behavioral pharmacology.
Highlights
Histone deacetylases (HDACs) mediate epigenetic changes by decreasing histone acetylation, leading to condensed chromatin structure and decreased transcription [1,2]
At the same time we did not detect changes to inhibitory synaptic transmission, which suggests Suberoylanilide hydroxamic acid (SAHA) treatment leads to an overall shift in the balance between excitation and inhibition in the neural network
These results are consistent with studies of HDAC2 KO mice that show increased spine density in CA1 pyramidal neurons, which has been interpreted as reflecting increased excitation and attributed to HDAC2 regulation of genes involved in synapse formation and plasticity [13]
Summary
Histone deacetylases (HDACs) mediate epigenetic changes by decreasing histone acetylation, leading to condensed chromatin structure and decreased transcription [1,2]. While transgenic HDAC2 over-expression impairs cognitive functions, HDAC2 knockout mice exhibit enhanced synaptic plasticity and memory function [13] In another example, reducing HDAC6 function has been shown to protect against neurodegeneration induced by oxidative stress and promote axon outgrowth [14]. As SAHA can block numerous HDACs including HDAC2 and HDAC6, these observations raise the possibility that patients taking SAHA could experience neurological impacts Such impacts could potentially be beneficial to improve brain function in AD patients. To address this possibility, we explored the impacts of SAHA treatment on neuronal function in vitro and on fear memory in AD model mice and general behavioral activity in wild type mice using the SmartCubeH System [15,16,17]. Consistent with a lack of neurobehavioral activity, SAHA exhibited poor brain penetration and was found to be a substrate of brain efflux transporters
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