title: Histone deacetylase inhibitors are neuroprotective and preserve NGF-mediated cell survival following traumatic brain injury.
abstract: Acute traumatic brain injury (TBI) is associated with long-term cognitive and behavioral dysfunction. In vivo studies have shown histone deacetylase inhibitors (HDACis) to be neuroprotective following TBI in rodent models. HDACis are intriguing candidates because they are capable of provoking widespread genetic changes and modulation of protein function. By using known HDACis and a unique small-molecule pan-HDACi (LB-205), we investigated the effects and mechanisms associated with HDACi-induced neuroprotection following CNS injury in an astrocyte scratch assay in vitro and a rat TBI model in vivo. We demonstrate the preservation of sufficient expression of nerve growth factor (NGF) and activation of the neurotrophic tyrosine kinase receptor type 1 (TrkA) pathway following HDACi treatment to be crucial in stimulating the survival of CNS cells after TBI. HDACi treatment up-regulated the expression of NGF, phospho-TrkA, phospho-protein kinase B (p-AKT), NF-κB, and B-cell lymphoma 2 (Bcl-2) cell survival factors while down-regulating the expression of p75 neurotrophin receptor (NTR), phospho-JNK, and Bcl-2-associated X protein apoptosis factors. HDACi treatment also increased the expression of the stem cell biomarker nestin, and decreased the expression of reactive astrocyte biomarker GFAP within damaged tissue following TBI. These findings provide further insight into the mechanisms by which HDACi treatment after TBI is neuroprotective and support the continued study of HDACis following acute TBI.
authors.affiliation: Laboratory of Molecular Imaging and Nanomedicine, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Lu
authors.forename: Jason M
authors.initials: JM
authors.lastname: Frerich
authors.forename: L Christine
authors.initials: LC
authors.lastname: Turtzo
authors.forename: Siqi
authors.initials: S
authors.lastname: Li
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Chiang
authors.forename: Chunzhang
authors.initials: C
authors.lastname: Yang
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Wang
authors.forename: Chao
authors.initials: C
authors.lastname: Zhang
authors.forename: Chenxi
authors.initials: C
authors.lastname: Wu
authors.forename: Zhongchan
authors.initials: Z
authors.lastname: Sun
authors.forename: Gang
authors.initials: G
authors.lastname: Niu
authors.forename: Zhengping
authors.initials: Z
authors.lastname: Zhuang
authors.forename: Roscoe O
authors.initials: RO
authors.lastname: Brady
authors.forename: Xiaoyuan
authors.initials: X
authors.lastname: Chen
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001930:Brain Injuries / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D056572:Histone Deacetylase Inhibitors / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D009414:Nerve Growth Factors / Q000378:metabolism / Q000502:physiology*; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D056572:Histone Deacetylase Inhibitors; D009414:Nerve Growth Factors; D018696:Neuroprotective Agents