Tolerance of chronic HDACi treatment for neurological, visceral and lung Niemann-Pick Type C disease in mice

Scientific Reports
Md Suhail AlamKasturi Haldar

Abstract

Histone deacetylase (HDAC) inhibitors are of significant interest as drugs. However, their use to treat neurological disorders has raised concern because HDACs are required for brain function. We have previously shown that a triple combination formulation (TCF) of the pan HDACi vorinostat (Vo), 2-hydroxypropyl-beta-cyclodextrin (HPBCD) and polyethylene glycol (PEG) 400 improves pharmacokinetic exposure and entry of Vo into the brain. TCF treatment significantly delayed both neurodegeneration and death in the Npc1 nmf164 murine model of Niemann-Pick Type C (NPC) disease. The TCF induces no metabolic toxicity, but its risk to normal brain functions and potential utility in treating lung disease, a major NPC clinical complication, remain unknown. Here we report that TCF administered in healthy mice for 8-10 months was not detrimental to the brain or neuromuscular functions based on quantitative analyses of Purkinje neurons, neuroinflammation, neurocognitive/muscular disease symptom progression, cerebellar/hippocampal nerve fiber-staining, and Hdac gene-expression. The TCF also improved delivery of Vo to lungs and reduced accumulation of foamy macrophages in Npc1 nmf164 mice, with no injury. Together, these data support feasibility...Continue Reading

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Citations

Oct 15, 2019·Journal of Neurochemistry·Simon Wheeler, Dan J Sillence
May 6, 2019·Biochimica Et Biophysica Acta. Molecular and Cell Biology of Lipids·Jessica DavidsonDaniel S Ory
May 12, 2020·Biochimica Et Biophysica Acta. Biomembranes·Marjan Huizing, William A Gahl

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Methods Mentioned

BETA
acetylation
histone acetylation
PCR
electrophoresis

Software Mentioned

ImageJ
softWoRx
Elements
NIS
DeltaVision
Nikon

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