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What doesn’t kill you makes you smarter: apoptosis and cognitive enhancement by HDAC inhibitors.

Histone deacetylase (HDAC) inhibition has been a recurring topic at the leading edge of preclinical drug design.  Beyond approved utility for cancer treatment – inducing death in cancer cells - HDAC inhibitor drugs may be useful in therapeutic development for addiction, mood-related disorders and cognitive deficits.  

HDACs are a family of enzymes that function in part to control the acetylation modification of histone proteins which organize DNA packaging within the nucleus of a cell.  Dysfunction in HDAC enzyme expression or activity is thought to be an important facet of a number of brain diseases.  Blocking the function of HDACs with small molecule inhibitors may help treat these diseases – potentially by correcting aberrant gene expression.   

For new drugs that might alter brain circuitry, a lot depends on the target tissue exposure (how much drug gets in the brain?) and residence time (how long does it stick around?)

Until recently, these basic questions were largely addressed in literature on HDAC inhibitors.

The two major classes of HDAC inhibitors, hydroxamates and benzamides, feature differences in the number of HDAC family members they inhibit, but differ moreso in their BINDING KINETICS.  Hydroxamates bind their targets very quickly (on the time scale of minutes) and benzamides are s-l-o-w…only maximally binding HDAC targets after a few hours time. 

Binding HDACs over time: Lauffer et al. JBC, 2013

How do these differences impact histone acetylation, gene expression and biology?  Using a cancer cell model, Lauffer and collegues - J.Biol.Chem.  ‘Histone deacetylase inhibitor kinetic rate constants correlate with histone acetylation but not transcription and cell viability’ July, 2013 -  recently outlined the time-dependent effects of hydroxamate and benzamide exposure on histone acetylation.  Logically, the fast-binding hydroxamates induced histone acetylation quickly, whereas benzamides took time.  This histone acetylation was also long lasting for benzamides, in line with slow dissociation kinetics & long residence times of compounds in this class.

Interestingly, for both hydroxamates and benzamides, gene expression profiling experiments and monitoring of cell death indicated that a refined set of genes were altered by both drug classes and that drug exposure time was linked to a large number of the changes. The authors suggest that genes sensitive to the onset kinetics of either hydroxamates or benzamides leading to downstream changes in gene expression and, over extended exposure, inducing cell death.

We understand from Lauffer’s work that differential outcomes (intermediate gene expression changes vs. cell death) can result from HDAC inhibitor residence times.   To understand the biology induced by HDAC inhibition, it is insufficient to focus on histone acetylation and we should instead focus on biological changes in the brain, including behavior as the net output of these changes.

Impacting the HDACs in brain: Hanson et al. PlosOne 2013.

Cognitive deficits associated with neurodegenerative disease and normal aging have been reported to be alleviated in animal models by HDAC inhibitor treatment, including by the well-known hydroxamate, SAHA.   In a report nearly parallel to Lauffer’s work, Hanson et al (Plos One, July 2013, Vol.8 (7)) demonstrated that the hydroxamate HDAC inhibitor, SAHA, indeed suppress HDAC activity and neural activity, consistent with its role as a potential cognitive enhancer.  However, in experiments in mice, almost NO SAHA could be detected in brain, even when very high doses were given.  This was explained in part by the identification that SAHA is actively pumped OUT of the brain by specialized proteins.  However, Hanson’s work underscores the importance of identifying HDAC inhibitors with good brain exposure in order to best understand the biology of behavioral and neurochemical changes.

Advice to consider:

  1. Don’t use histone acetylation as a metric for biological / behavioral change.
  2. Do design experiments to understand dynamic impact of HDAC inhibition in your system.
  3. Don’t use behavioral change as an indicator of drug presence in brain.
  4. Do investigate brain exposure and residence times early in evaluating novel inhibitors.

-Al Schroeder

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