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.A cute traumatic brain injury (TBI) is a leading cause of disability and death, and results in reduced quality of life for surviving patients and prolonged economic effects on society (1). Primary injury occurs at the moment of trauma and is the direct result of shearing, tearing, and stretching of the brain parenchyma affecting neural tissue and blood vessels, and causing immediate contusion, hemorrhage, diffuse axonal injury, and ischemia (2, 3). TBI brings about cognitive and behavioral dysfunction through a complex sequence of secondary pathologic changes following injury. The mechanisms evolve over time and include excessive neurotransmitter release, mitochondrial dysfunction, increased bloodbrain barrier (BBB) permeability, cerebral edema, inflammation, and seizures, causing cell death and clinical morbidity (4).Clinical trials designed to test therapeutic agents aimed at improving residual cerebral function after TBI have not been successful because of the multifactorial nature of the disorder (2, 5-7). No pharmacological agent is currently approved for the treatment of acute TBI. The present standard of care consists of maintaining physiologic function by preserving adequate cerebral perfusion and normal intracranial pressure. Histone deacetylase inhibitors (HDACis) are potential candidates for the treatment of TBI. They are capable of inducing widespread alterations in cellular function and protein expression through posttranslational modification of histones, transcriptional factors, and heat shock chaperones (8-...

Celastrol increases glucocerebrosidase activity in Gaucher disease by modulating molecular chaperones

“…For example, clinically available HDACi, Hsp inhibitors, and celastrol itself are associated with significant toxicities (42)(43)(44)(45)(46)(47). Our results demonstrate that HDACi and celastrol could have undesirable "off-target" effects that should be identified before clinical trials in GD are pursued (48). Further work is required to determine whether route of administration, dose, molecular structure, or other aspects of these compounds can be selected to maximize therapeutic effect and minimize toxicity.…”

Neuroprotection after Traumatic Brain Injury in Heat-Acclimated Mice Involves Induced Neurogenesis and Activation of Angiotensin Receptor Type 2 Signaling

“…28 NGF expression may be necessary to promote neuron survival and function post TBI during repair. 29 Similarly, the neuroprotective effects of BDNF have also been demonstrated in animal models of ischemia 30,31 and TBI. 32 BDNF also has a pivotal role in learning and memory.…”

The efficacy of erythropoietin in treating experimental traumatic brain injury: a systematic review of controlled trials in animal models

“…17,23 Erythropoietin (EPO), a secreted 30-kD glycoprotein, is a multifunctional tissue-protecting agent that exerts antiapoptotic, antiinflammatory, antioxidative, angiogenic, and neurotrophic effects. 7,38 Recently, several investigations have shown that EPO and its analogs provide substantial benefits to rodents after TBI.…”