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Histone deacetylase (HDAC) inhibitors are currently in human clinical trials as antitumor drugs because of their ability to induce cell dysfunction and death in cancer cells. The toxic effects of HDAC inhibitors are also apparent in cortical neurons in vitro, despite the ability of these agents to induce significant protection in the cells they do not kill. Here we demonstrate that pulse exposure of cortical neurons (2 h) in an in vitro model of oxidative stress results in durable neuroprotection without toxicity. Protection was associated with transcriptional upregulation of the cell cycle inhibitor, p21waf1/cip1, both in this model and in an in vivo model of permanent ischemia. Transgenic overexpression of p21waf1/cip1 in neurons can mimic the protective effect of HDAC inhibitors against oxidative stress-induced toxicity, including death induced by glutathione depletion or peroxide addition. The protective effect of p21waf1/cip1 in the context of oxidative stress appears to be unrelated to its ability to act in the nucleus to inhibit cell cycle progression. However, although p21waf1/cip1 is sufficient for neuroprotection, it is not necessary for HDAC inhibitor neuroprotection, because these agents can completely protect neurons cultured from p21waf1/cip1-null mice. Together these findings demonstrate (1) that pulse inhibition of HDACs in cortical neurons can induce neuroprotection without apparent toxicity; (2) that p21waf1/cip1 is sufficient but not necessary to mimic the protective effects of HDAC inhibition; and (3) that oxidative stress in this model induces neuronal cell death via cell cycle-independent pathways that can be inhibited by a cytosolic, noncanonical action of p21waf1/cip1. [ABSTRACT FROM AUTHOR]

Inhibition of histone deacetylase 6 (HDAC6) was shown to support axon growth on the nonpermissive substrates myelinassociated glycoprotein (MAG) and chondroitin sulfate proteoglycans (CSPGs). Though HDAC6 deacetylates a-tubulin, we find that another HDAC6 substrate contributes to this axon growth failure. HDAC6 is known to impact transport of mitochondria, and we show that mitochondria accumulate in distal axons after HDAC6 inhibition. Miro and Milton proteins link mitochondria to motor proteins for axon transport. Exposing neurons to MAG and CSPGs decreases acetylation of Miro1 on Lysine 105 (K105) and decreases axonal mitochondrial transport. HDAC6 inhibition increases acetylated Miro1 in axons, and acetyl-mimetic Miro1 K105Q prevents CSPG-dependent decreases in mitochondrial transport and axon growth. MAG- and CSPG-dependent deacetylation of Miro1 requires RhoA/ROCK activation and downstream intracellular Ca2+ increase, and Miro1 K105Q prevents the decrease in axonal mitochondria seen with activated RhoA and elevated Ca2+. These data point to HDAC6-dependent deacetylation of Miro1 as a mediator of axon growth inhibition through decreased mitochondrial transport. [ABSTRACT FROM AUTHOR]

Abstract: Most olfactory bulb (OB) interneurons are derived from neural stem cells in the subventricular zone (SVZ) and migrate to the OB via the rostral migratory stream (RMS). Mature dopaminergic interneurons in the OB glomerular layer are readily identified by their synaptic activity-dependent expression of tyrosine hydroxylase (TH). Paradoxically, TH is not expressed in neural progenitors migrating in the RMS, even though ambient GABA and glutamate depolarize these progenitors. In forebrain slice cultures prepared from transgenic mice containing a GFP reporter gene under the control of the Th 9kb upstream regulatory region, treatment with histone deacetylase (HDAC) inhibitors (either sodium butyrate, Trichostatin A or Scriptaid) induced Th-GFP expression specifically in the RMS independently of depolarizing conditions in the culture media. Th-GFP expression in the glomerular layer was also increased in slices treated with Trichostatin A, but this increased expression was dependent on depolarizing concentrations of KCl in the culture media. Th-GFP expression was also induced in the RMS in vivo by intra-peritoneal injections with either sodium butyrate or valproic acid. Quantitative RT-PCR analysis of neurosphere cultures confirmed that HDAC inhibitors de-repressed Th expression in SVZ-derived neural progenitors. Together, these findings suggest that HDAC function is critical for regulating Th expression levels in both neural progenitors and mature OB dopaminergic neurons. However, the differential responses to the combinatorial exposure of HDAC inhibitors and depolarizing culture conditions indicate that Th expression in mature OB neurons and neural progenitors in the RMS are regulated by distinct HDAC-mediated mechanisms. [Copyright &y& Elsevier]

Abstract: We demonstrate that the histone deacetylase (HDAC) inhibitor drug trichostatin A (TSA) reduces spinal cord inflammation, demyelination, neuronal and axonal loss and ameliorates disability in the relapsing phase of experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis (MS). TSA up-regulates antioxidant, anti-excitotoxicity and pro-neuronal growth and differentiation mRNAs. TSA also inhibits caspase activation and down-regulates gene targets of the pro-apoptotic E2F transcription factor pathway. In splenocytes, TSA reduces chemotactic, pro-Th1 and pro-proliferative mRNAs. A transcriptional imbalance in MS may contribute to immune dysregulation and neurodegeneration, and we identify HDAC inhibition as a transcriptional intervention to ameliorate this imbalance. [Copyright &y& Elsevier]

Charcot-Marie-Tooth type 2A (CMT2A) peripheral neuropathy, the most common axonal form of CMT, is caused by dominantly inherited point mutations in the Mitofusin 2 (Mfn2) gene. It is characterized by progressive length-dependent degeneration of motor and sensory nerves with corresponding clinical features of motor and sensory impairment. There is no cure for CMT, and therapeutic approaches are limited to physical therapy, orthopedic devices, surgery, and analgesics. In this study we focus on histone deacetylase 6 (HDAC6) as a therapeutic target in a mouse model of mutant MFN2 (MFN2R94Q)-induced CMT2A. We report that these mice display progressive motor and sensory dysfunction as well as a significant decrease in α-tubulin acetylation in distal segments of long peripheral nerves. Treatment with a new, highly selective HDAC6 inhibitor, SW-100, was able to restore α-tubulin acetylation and ameliorate motor and sensory dysfunction when given either prior to or after the onset of symptoms. To confirm HDAC6 is the target for ameliorating the CMT2A phenotype, we show that genetic deletion of Hdac6 in CMT2A mice prevents the development of motor and sensory dysfunction. Our findings suggest α-tubulin acetylation defects in distal parts of nerves as a pathogenic mechanism and HDAC6 as a therapeutic target for CMT2A. • CMT2AR94Q mice show early-onset of neuropathic pain and progressive motor performance defects • CMT2AR94Q mice exhibit a progressive decrease of α-tubulin acetylation in distal sciatic nerves • Treatment of CMT2AR94Q mice with an HDAC6 inhibitor, SW-100, rescues distal sciatic nerves α-tubulin acetylation • SW-100 ameliorates CMT2AR94Q mouse motor and sensory defects when given prior to or after the onset of symptoms • HDAC6 genetic deletion in CMT2AR94Q mice prevents their development of motor performance defects and neuropathic pain • HDAC6 is a promising therapeutic target for CMT2A [ABSTRACT FROM AUTHOR]