Parkinson’s Disease

Parkinson’s Disease / 2015 / Article

Review Article | Open Access

Volume 2015 |Article ID 303294 |

Sorabh Sharma, Rajeev Taliyan, "Targeting Histone Deacetylases: A Novel Approach in Parkinson’s Disease", Parkinson’s Disease, vol. 2015, Article ID 303294, 11 pages, 2015.

Targeting Histone Deacetylases: A Novel Approach in Parkinson’s Disease

Academic Editor: Hélio Teive
Received30 Sep 2014
Accepted03 Jan 2015
Published28 Jan 2015


The worldwide prevalence of movement disorders is increasing day by day. Parkinson’s disease (PD) is the most common movement disorder. In general, the clinical manifestations of PD result from dysfunction of the basal ganglia. Although the exact underlying mechanisms leading to neural cell death in this disease remains unknown, the genetic causes are often established. Indeed, it is becoming increasingly evident that chromatin acetylation status can be impaired during the neurological disease conditions. The acetylation and deacetylation of histone proteins are carried out by opposing actions of histone acetyltransferases (HATs) and histone deacetylases (HDACs), respectively. In the recent past, studies with HDAC inhibitors result in beneficial effects in both in vivo and in vitro models of PD. Various clinical trials have also been initiated to investigate the possible therapeutic potential of HDAC inhibitors in patients suffering from PD. The possible mechanisms assigned for these neuroprotective actions of HDAC inhibitors involve transcriptional activation of neuronal survival genes and maintenance of histone acetylation homeostasis, both of which have been shown to be dysregulated in PD. In this review, the authors have discussed the putative role of HDAC inhibitors in PD and associated abnormalities and suggest new directions for future research in PD.

1. Introduction

Movement disorders are a group of nervous system disorders that primarily affect the basal ganglia and result in abnormal voluntary or involuntary movements. They are generally categorized as a group of neurological symptoms, signs, or diseases that manifest as either slowness or paucity of movement (hypokinesias; typically seen in Parkinson’s disease (PD) and other parkinsonian disorders) or by excessive, abnormal involuntary movements (hyperkinesias) typically seen in Huntington’s disease (HD), tremors, dystonia hemi-facial spasm, and akathisia [1, 2].

Among all the movement disorders, PD affects approximately 2% of the population over the age of 65 and is characterized by behavioral motor deficits including tremor, rigidity, bradykinesia, and postural instability. Selective dopaminergic neuronal degeneration in substantia nigra pars compacta (SNpc) is the prominent feature of PD pathology [2, 3]. Levodopa (L-DOPA) is a substitutive pharmacological agent that restores the physiological concentration of dopamine in the brain, particularly in the striatum. However, long term use of L-DOPA results in complications such as movement behaviour fluctuations and dyskinesia in most patients with PD. Thus, there is an unmet medical need to identify and explore new therapeutic options for PD, which should be effective and safe.

The past decade has produced an exponential increase in research examining the genetic and environmental factors that contribute to the etiology of PD [4]. The gene expression regulated by the chromatin, a densely packed complex structure containing DNA and histone proteins, has been found to be altered in patients of PD. There are five major families of histones: H1/H5, H2A, H2B, H3, and H4. Histones H2A, H2B, H3, and H4 are known as the core histones, while histones H1 and H5 are known as the linker histones [5]. These core histone proteins are subjected to posttranslational modifications on their N-terminal tails. These posttranslational modifications of histones are often dynamic and reversible and are mediated by two antagonistic sets of enzymatic complexes that attach or remove the corresponding chemical groups in a site-specific manner. Various posttranslational modifications include acetylation, phosphorylation, ubiquitination, SUMOylation, and ADP-ribosylation, all of which are capable of influencing the rate of gene transcription. One of the most thoroughly studied modification of histone tails is the acetylation at lysine residues [5].

Recent investigations suggest that gene expression modulated by histone acetylation might be associated with neurodegenerative processes [6, 7]. Histone deacetylases (HDACs) along with histone acetyltransferases (HATs) are the enzymes that regulate the homeostasis of histone acetylation. Inhibitors of HDACs, which were initially characterized as anticancer drugs, are recently suggested to act as neuroprotective agents that act by enhancing synaptic plasticity, neuronal survival, learning, and memory in a wide range of neurodegenerative disorders, including Alzheimer’s disease (AD), PD, and HD [610]. Moreover, we have explored the neuroprotective role of HDAC inhibitors in high fat diet induced cognitive deficits in mice and also in intracerebroventricular streptozotocin induced AD in rats [11, 12]. In this review we have discussed the putative role of HDACs in PD and the potential of specific HDAC inhibitors as new pharmacological strategies for the treatment of PD.

2. Mechanism of Histone Acetylation

Histone acetylation is a chromatin modification that modulates histone-DNA interactions via two different classes of enzymes: HATs and HDACs (Figure 1). HATs are the enzymes that acetylate the lysine residues on N-terminal tails of core histones using acetyl-coenzyme A as an acetyl group donor. The addition of acetyl group neutralises the positive charge of the lysine residue, thus reducing the electrostatic interaction between the lysine in the histone tail and the negatively charged phosphate group on DNA. This causes a relaxation of chromatin, known as euchromatin and thus turns on the gene transcription, whereas on the other hand, deacetylation carried out by HDACs results in removal of the acetyl groups from lysine in the histone tail and thus restoring the positive charge and causing a condensation of chromatin, known as heterochromatin, thus turning off the gene transcription [13]. However, it is important to remember that it cannot be generalized that an increase in acetylation will induce an increase in transcription.

In mammals the HDACs are divided into 4 classes based on their function and structural homologies to yeast HDACs. The classification of HDACs along with their pan inhibitors is provided in Figure 2 [1416]. HDACs modulate both histone and nonhistone proteins. The nonhistone protein targets are transcription factors (e.g., p53, STAT1, or STAT3), cytoskeleton proteins (e.g., α-tubulin), and other cellular proteins (e.g., heat shock protein 90 (HSP 90) or KU70). Till date, more than 50 nonhistone proteins have been identified as substrates for HDACs. The structure and activity of these nonhistone proteins may be altered by acetylation/deacetylation with consequent effects on various cell functions including gene expression, cell cycle progression, and cell death pathways. Classes I, II, and III of HDACs regulate lysine acetylation of these nonhistone proteins that exert neuroprotective effects [17, 18] adding some complexity to the interpretation of therapeutic potentials of currently available broad spectrum or even class specific HDAC inhibitors for neurodegenerative diseases. For detailed study of these nonhistone targets refer to [19, 20]. HDACs are expressed in multiple tissues, including the brain and spinal cord. Although some HDAC family members have limited tissue specificity and central nervous system (CNS) distribution, individual neurons frequently express multiple HDAC (Table 1) [2134]. Rouaux and colleagues were the first to identify alterations of histone acetylation levels in neurodegeneration, by demonstrating that histone acetylation levels were decreased globally in neurons [35]. Since then, the linkage between histone hypoacetylation and neurodegeneration has been well established in numerous cognitive and movement disorders, including AD, PD, and HD [36, 37].

HDAC classIsoforms expressed in brainLocalizationSpeciesReferences

Class 1 (Zn2+ dependent)HDAC 1Cortex, caudate/putamen,
hippocampus, amygdala
SNpc, SNpr, locus coeruleus,
corpus callosum, gray matter,
white matter
HDAC 2Cortex, caudate/putamen hippocampus, amygdala SNpc, SNpr, locus coeruleus, gray matter, white matter, corpus callosumMouse,
HDAC 3Cortex, caudate/putamen hippocampus, amygdala SNpc, SNpr, locus coeruleus, globus pallidusMouse,
HDAC 8Hippocampus, amygdala SNpc, locus coeruleusHuman,
[21, 22, 25]

Class IIa (Zn2+ dependent)HDAC 4Cortex, caudate/putamen, hippocampus, amygdala SNpc, SNpr, locus coeruleus, globus pallidusHuman,
[21, 22, 24, 26, 27]
HDAC 5Cortex, caudate/putamen, hippocampus, amygdala SNpc, SNpr, locus coeruleus, globus pallidusRat,
[21, 22, 28]
HDAC 7Cortex, caudate/putamen, hippocampus, amygdala SNpc, locus coeruleus, striatum, cerebellumRat,
[21, 22, 29]
HDAC 9Cortex, SNpc, hippocampus, amygdalaHuman,
[21, 22, 30, 31]

Class IIb (Zn2+ dependent)HDAC 6Cortex, caudate/putamen Hippocampus, amygdala, SNpc, locus coeruleus, cerebellumHuman,
[21, 22, 32]
HDAC 10Cortex, amygdala, hippocampusHuman,
[21, 22, 33]

Class IV (Zn2+ dependent)HDAC11Cortex, hippocampus, brain stem, cerebellum, diencephalonHuman,
[21, 22, 34]

SNpc: substantia nigra pars compacta, SNpr: substantia nigra pars reticulata, and HDAC: histone deacetylase.

3. Historical Aspects of HDACs and HDAC Inhibitors

The isolation, purification, and identification processes of various HDAC isoforms begin right after the discovery of histone acetylation phenomenon. Thereafter, various HDAC inhibitors have been synthesized and studied which helps to explore the pharmacological actions of HDACs. A timeline figure regarding the historical aspects of HDACs has been provided (Figure 3) [25, 26, 3857].

4. HDAC Inhibitors and Parkinson’s Disease

4.1. HDAC Inhibitors in Animal Models of Parkinson’s Disease
4.1.1. MPTP (1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine)

Initially, MPTP was identified as a strong neurotoxin when heroin addicts accidentally self-administered MPTP and developed an acute form of Parkinsonism that was indistinguishable from idiopathic PD [58]. MPTP has been widely used as an animal model to replicate human PD symptoms in nonhuman primates and in rodents. MPTP is a highly lipophilic agent that following systemic injection (usually i.p or s.c) rapidly crosses the blood-brain barrier. Once inside the brain, MPTP is converted by MAO-B (monoamine oxidase) into a neurotoxin precursor, MPP+ (1-methyl-4-phenylpyridinium), which causes selective destruction of dopaminergic neurons in the SNpc (substantia nigra pars compacta). MPP+ induces neurotoxicity primarily by inhibiting complex I of the mitochondrial electron transport chain, resulting in ATP depletion and increased oxidative stress [3, 59]. The therapeutic potential of HDAC inhibitors has been evaluated in MPTP induced neuronal toxicity in rodent models. Generally, HDAC inhibition in the brain has been associated with the increased transcription of free radical scavengers, heat-shock proteins, and antiapoptotic bcl-2 family members that may contribute to the protection of dopaminergic neurons following MPTP exposure [60].

Phenylbutyrate was among the very first HDAC inhibitors to be tested in MPTP model. Pretreatment of MPTP intoxicated mice with phenylbutyrate significantly attenuated the loss of dopamine and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the striatum. Moreover, phenylbutyrate also protects tyrosine hydroxylase (TH+) neurons from MPTP induced toxicity, which is basically a rate limiting enzyme in dopamine biosynthesis [54].

Neuroinflammation and oxidative stress have been well reported to play a key role in the pathophysiology of PD [61, 62]. Increased levels of inflammatory and oxidative stress markers along with decreased endogenous antioxidants level have been observed in both animal models and PD patients [5963]. Recently, oral administration of sodium phenylbutyrate in MPTP treated mice has been reported to suppress the expression of proinflammatory markers, nuclear factor-kB (NF-kB), and reactive oxygen species in activated glial cells. Activation of small G proteins and has been linked with generation of neuroinflammation and oxidative stress after MPTP intoxication. The authors suggested that phenylbutyrate results in reduced nigral activation of and G proteins and hence results in dopaminergic neuronal protection along with improved motor functions in MPTP-intoxicated mice [64]. Along with oxidative stress and neuroinflammation, excitotoxicity has also been reported to play pathogenic role in development of PD [65]. Glutamate, a well-known excitatory amino acid has been found to be elevated in PD patients [65]. The therapeutic potential of HDAC inhibitors has been evaluated against glutamate induced toxicity and it was reported that TSA, a HDAC inhibitor, prevents glutamate induced toxicity in the medium of MPP+ treated primary cultured astrocytes [66]. The authors suggested that TSA alleviates MPP+-induced impairment of astrocytic glutamate uptake, which might be a novel mechanism contributing to neuroprotection by HDAC inhibitors.

Olfactory and cognitive deficits have been reported very frequently in PD. A study shows that valproate pretreatment in rats infused with a single intranasal administration of MPTP was able to prevent olfactory discrimination and short-term memory impairments as evaluated in the social recognition and step-down inhibitory avoidance tasks. Moreover, valproate alone or in combination with lithium prevented dopamine depletion in the olfactory bulb and striatum of MPTP-infused rats [59]. In another study, valproate pretreatment has been found to protect midbrain dopaminergic neurons from MPP+-induced neurotoxicity [67] and upregulate the expression of neurotrophic factors, including glial cell line-derived neurotrophic factor (GDNF), and brain derived neurotrophic factor (BDNF) from astrocytes. The expression of these neurotrophins has been reported to be decreased in animal models as well as in postmortem brains of PD patients [68, 69]. Other HDAC inhibitors such as vorinostat, TSA, and sodium butyrate have also been reported to mimic the neuroprotective and survival promoting effects of valproate on dopaminergic neurons in neuron-glia cultures [56, 70, 71]. All these HDAC inhibitors were demonstrated to increase the expression of GDNF and BDNF in astrocytes along with marked increase in histone H3 acetylation. Taken together, these studies highlight that HDAC inhibitors upregulate GDNF and BDNF expression in astrocytes and protect dopaminergic neurons, at least in part, through HDAC inhibition and consequential H3 acetylation.

As discussed earlier, MPP+ the toxic metabolite of MPTP acts by selectively inhibiting complex I of mitochondria. In a recent study, mitochondrial fragmentation was found to be an early event during apoptosis caused by MPP+ in SH-SY5Y cells. TSA selectively rescues mitochondrial fragmentation and cell death induced by lower doses of MPP+. The mitochondrial fragmentation occurring as a result of MPP+ treatment could possibly be mediated through downregulation of Mfn2. However, TSA administration results in complete reversal of Mfn2 expression. Further investigation suggests that TSA prevents MPP+-induced Mfn2 downregulation via inhibiting HDAC over Mfn2 promoter and alleviating its transcriptional dysfunction [72]. This study implicates that mitochondrial fragmentation, an early event during neuronal apoptosis in PD, may be a result of alteration in the acetylase/deacetylase balance and also indicates that HDAC inhibitors might be a potential early treatment for PD.

In their later study, Kidd and Schneider found the neuroprotective effects of valproate in MPTP intoxicated FVBn mice. Valproate partially prevents striatal dopamine depletion and almost completely protects dopaminergic cell loss in SNpc. These neuroprotective effects of valproate were attributed to its HDAC activity as increased acetylation of histone 3 lysine 9 was observed in SNpc of FVBn mice [73]. In another study, the therapeutic potential of valproate, sodium butyrate, and vorinostat was tested against MPP+-mediated cytotoxicity in human derived SK-N-SH and rat derived MES 23.5 cells. These HDAC inhibitors partially prevented MPP+-mediated apoptotic cell death. The protective effects of these drugs coincided with significant increases in histone acetylation [74].

The majority of PD cases are sporadic; that is, only about 10% of patients report a positive family history [2, 75]. Out of the various genes unequivocally linked to monogenic PD, mutations in PARK 2, 6, and 7 are responsible for autosomal-recessive PD. The DJ-1 protein has been repeatedly associated with early-onset, autosomal recessive Parkinson disease (PARK7). As low levels of this protein increase the risk for PD [30], it is obvious to find a therapeutic strategy which could results in increased expression of DJ-1. Recently, the HDAC inhibitor, phenylbutyrate, has been demonstrated to increase DJ-1 expression by 300% in the N27 dopamine cell line and rescues cells from oxidative stress and mutant alpha-synuclein (α-syn) toxicity. α-syn forms abnormal protein deposits in dopamine neurons and is believed to cause the death of brain cells, leading to PD. Moreover, in mice intoxicated with MPTP, phenylbutyrate treatment results in protection of dopaminergic neurons as well as increasing DJ-1 levels in brain. In addition, long-term administration of phenylbutyrate reduces α-syn aggregation in brain and prevents age-related deterioration in motor and cognitive function in a transgenic mouse model of diffuse Lewy body disease [30].

The major complication in PD treatment with chronic L-DOPA is the occurrence of L-DOPA induced dyskinesias (LIDs). Various therapeutic strategies have been adopted to delay the use of L-DOPA as much as possible or by finding a suitable treatment option to reduce the dose of L-DOPA. However, none of these options fully serves the purpose and rendering LIDs, a major hurdle in PD treatment. However, recently, HDAC inhibitor, RGFP109, has been demonstrated to attenuate LIDs in the MPTP-lesioned marmoset [76]. RGFP109 has been well reported to penetrate into brain and have an oral bioavailability of 35% as reported in dogs [76]. Importantly, the authors demonstrate that antidyskinetic effects of RGFP109 were obtained without compromising peak antiparkinsonian efficacy or duration of L- benefit, which suggests that abnormal HDAC activity is a consequence of LID and not L-DOPA therapy per se.

4.1.2. 6-Orthohydroxydopamine (6-OHDA)

The neurotoxin 6-hydroxydopamine (6-OHDA) continues to constitute a valuable tool used in modelling PD in rodents. To target specific neurons and to bypass the blood-brain barrier, 6-OHDA is typically injected stereotactically into the brain region of interest. The classical method of intracerebral infusion of 6-OHDA involves a massive destruction of nigrostriatal dopaminergic neurons. Once it enters the brain, 6-OHDA accumulates in the cytosol where it is readily oxidized leading to the generation of reactive oxygen species and ultimately oxidative stress-related cytotoxicity. To date, 6-OHDA is widely used to lesion the nigrostriatal dopaminergic system as a model of PD [7779]. Multiple intrastriatal injections of this neurotoxin result in rapid loss of dopaminergic terminals in the striatum itself followed by slower (3-4 weeks) and partial retrograde degeneration of dopaminergic neurons in the SNpc [77, 78]. 6-OHDA administration into the striatum leads to shrinkage of this area along with loss of TH+ neurons in rats. The HDAC inhibitor, valproate, has been reported to attenuate 6-OHDA induced toxicity in rats and results in sparing of TH+-immunoreactivity and elevation of TH+ content in SNpc as well as striatum. Also, valproate treatment increased the expression of α-syn in SNpc and striatum as compared to 6-OHDA treated rats [78]. These results are in agreement with the previous study of same authors in which they confirmed the prosurvival role of α-syn in this model [77]. This prosurvival role of α-syn seems awkward and is still debateable. While its aggregation is usually considered linked to neuropathology of PD, its normal function may be related to fundamental processes of synaptic transmission and plasticity. The authors demonstrate that α-syn silencing in cultured cerebellar granule cells results in widespread death of these neurons. In contrast, treatment with HDAC inhibitor, valproate, results in increased expression of α-syn and preventing its monoubiquitination and nuclear translocation in cerebellar granule cells exposed to 6-OHDA [77].

As mentioned earlier, PD patients often experience cognitive impairment during the disease progression. Recently, Rane and colleagues studied the effect of sodium butyrate in 6-OHDA induced cognitive deficit in premotor stage of PD and they found sodium butyrate to be highly effective in attenuating cognitive deficits in 6-OHDA administered rats [79]. We have also demonstrated the neuroprotective effects of HDAC inhibitors, vorinostat, and TSA in 6-OHDA induced hemiparkinsonism in rats in our laboratory and we found that HDAC inhibition results in improved motor activity as assessed by narrow beam walk and wire suspension tasks. Moreover, the rats treated with HDAC inhibitors results in significant increase in histone H3 acetylation as compared with 6-OHDA treated rats (unpublished data). Thus, these reports suggest that HDAC inhibition could be of therapeutic importance in restoring motor and cognitive disabilities associated with PD.

4.1.3. Rotenone

Rotenone is a strong inhibitor of mitochondrial complex I, which is located at the inner mitochondrial membrane and protrudes into the matrix. It has been demonstrated that the chronic systemic exposure to rotenone develops many features of PD, including nigrostriatal dopaminergic degeneration [80]. Rotenone administration in rats results in activation of various pathogenic pathways including oxidative stress, α-syn phosphorylation and aggregation and lewy body pathology and so forth [80] and also reproduces all the behavioral features seen in the typical form of human PD [62]. Recently, chronic administration of valproate significantly protects nigrostriatal dopaminergic neurons and counteracts the drop in striatal dopamine levels caused by rotenone administration in rats. Further, valproate treatment prevents alterations in α-syn and attenuates loss of TH+ in SNpc and striatum of rotenone treated rats [81]. Valproate treatment has also been reported to attenuate apoptosis in neuroblastoma cells, SHSY5Y, a human dopaminergic cell line often used for study of PD [82]. The authors revealed that neuroprotective effects of valproate occurred as a result of cytochrome-c (cyt-c) inhibition along with decreased production of caspase-9 and caspase-3. Valproate treatment also results in increased expression of HSP70 protein and this activation of HSP70 could be a consequence of HDAC inhibition [83]. Another HDAC inhibitor, Phenylbutyrate has been demonstrated to attenuate motor deficits and reduced α-Syn accumulation induced by repeated rotenone administration in C57BL/6 mice [84]. Recently, sodium butyrate has also been demonstrated to reduce degeneration of dopaminergic neurons in a mutant α-syn drosophila transgenic model of familial PD. Chronic exposure to rotenone causes locomotor impairment and early mortality in drosophila. However, treatment with 10 mM sodium butyrate-supplemented food rescued the rotenone-induced locomotor impairment and early mortality in flies [57]. In addition, it was found that flies with the genetic knockdown of HDAC activity were resistant to rotenone-induced locomotor impairment and early mortality. This is one of the very few studies which indicate the beneficial effect of HDAC gene knockout in animal models. Moreover, the authors showed increased dopamine levels in brains of flies after sodium butyrate treatment as compared to alone rotenone treated flies. Thus, the above studies highlight the importance of HDAC inhibitors in attenuating rotenone induced toxicity in animals and cell culture models and support the notion that HDAC inhibitors result in increased transcription of neuronal survival genes and hence provide neuroprotection [85].

4.1.4. Lipopolysaccharide (LPS)

Neuroinflammation triggered by activated microglial cells results in deleterious events, that is, oxidative stress and cytokine-receptor-mediated apoptosis, which might eventually lead to dopaminergic cell death and PD progression [61]. Lipopolysaccharide (LPS), an endotoxin from Gram-negative bacteria, acts as a potent stimulator of microglia and has been used to study the inflammatory process in the pathogenesis of PD. Various studies have highlighted the neuroprotective role of HDAC inhibitors in LPS-treated neuroglia cultures through the inhibition of release of proinflammatory cytokines and chemokines from microglia [86, 87]. These authors suggest that this reduced neuroinflammation could be achieved as a result of microglial apoptosis and treatment with HDAC inhibitors, TSA and sodium butyrate and valproate, has been found to reduce the number of microglial cells [86]. In line with these studies, TSA administration has also been reported to reduce the expression of numerous cytokines and chemokines in primary human fetal microglial cultures activated by LPS [88]. Further, HDAC inhibitors have been demonstrated to increase neurite formation, interneuronal networks, and number of TH+ neurons in LPS-pretreated cultures along with increased expression of BDNF and GDNF from astrocytes [56, 70]. These reports suggest that, along with increased expression of neurotrophic factors, the HDAC inhibitors also have significant impact on inflammatory conditions. Based upon these results, it is highly conceivable that neuroinflammation, which is mostly mediated by activated microglial and peripheral immune cells, can be controlled with the use of HDAC inhibitors.

4.2. α-Synuclein Toxicity

As discussed above, α-syn is a neuronal protein implicated genetically in PD and whose exact role is still controversial. However, it has been demonstrated in drosophila model that a nuclear localization of α-syn promoted its toxicity through increased binding of α-syn to histones which ultimately results in reduced levels of acetylated histone H3, moderates HAT activity, and inhibits HAT-mediated acetyltransferase activity [36]. In contrast, treatment with HDAC inhibitors, sodium butyrate and vorinostat, in SH-SY5Y cells or transgenic flies, rescued α-syn-induced toxicity and decreased neuronal cell death, suggesting that HDAC inhibitors may represent a promising therapeutic strategy to mitigate the progressive neurodegeneration linked to PD [36]. In another study, it has been demonstrated that inhibition of SIRT2, a Class III HDAC, by a potent inhibitor results in reducing the α-syn toxicity and modified inclusion morphology in a cellular model of PD. Moreover, SIRT2 inhibitors result in neuroprotection against dopaminergic cell death in both in vitro and a drosophila model of PD [89]. From these studies, it can be concluded that increased levels of nuclear α-syn in PD lead to decreased histone acetylation and neurotoxicity. Thus, the treatments that raise the levels of neuronal acetylation (i.e., HDAC inhibitors) may be attractive therapeutic strategies in PD. However, most of these beneficial effects observed in animal studies were obtained from pretreatment with HDAC inhibitors.

4.3. HDAC Inhibitors in PD Patients and Clinical Trials

Although initial trials with valproate did not significantly alter Parkinson features in PD patients [90], however, in a double-blind crossover trial with 12 PD patients, sodium valproate administration at 1200 mg daily results in slight to moderate improvement in LIDs. Moreover, excess salivation was found to be improved in four subjects with sodium valproate treatment [91]. Recently, a nonrandomized Open Label Phase I clinical trial (NCT02046434) of the FDA approved drug phenylbutyrate was started to observe the therapeutic potential of this drug in enhancing the removal of α-syn from the brain into the bloodstream ( identifier: NCT02046434). However, as such no results in PD patients are still available.

5. Future Directions and Conclusions

HDAC inhibition is a validated approach in cancer therapy, as evidenced by the FDA approval of vorinostat and romidepsin followed by encouraging clinical data from other HDAC inhibitors. Recent evidences reveal that HDAC inhibitors could play an important role in various brain diseases. Chronic dysregulation of the acetylation/deacetylation activities can ultimately lead to neuronal cell death as manifested in neurodegenerative diseases. Thus, more research is required to fully understand the precise mechanism(s) by which this system impacts neuronal survival. This study has summarised and described the most prevalent movement disorder, that is, PD that involve alterations in histone modifications which can be reversed, at least in part, by treatment with HDAC inhibitors. HDAC inhibitors have specific effects on gene expression, upregulating a selective set of target genes and reducing expression of others. The neuroprotective effects of various HDAC inhibitors are accomplished either through increased histone acetylation or through the increased transcription of genes encoding neurotropic factors (BDNF, GDNF), HSPs or reduction in the accumulation of neurotoxic proteins (α-syn), and so forth (Figure 4). Although there are some reports indicating the beneficial effects of HDAC inhibitors in human subjects suffering from LIDs and some HDAC inhibitors have recently entered clinical trials for PD, still there are much awaited results. Moreover, some of the clinical studies have reported no improvement in PD symptoms when treated with HDAC inhibitors. It might be because of the multiple target approach of these HDAC inhibitors. Nevertheless, these data provide support for the continued study of the role of epigenetic modifications in PD and associated abnormalities and the potential of HDAC inhibition as a treatment for motor complications of in PD.


AD:Alzheimer’s disease
GSK 3β:Glycogen synthase kinase 3β
HDAC:Histone deacetylase
HAT:Histone acetyl transferases
HSP 70:Heat shock protein 70
HD:Huntington’s disease
PD:Parkinson’s disease.

Conflict of Interests

The authors declare that there is no conflict of interests regarding the publication of this paper.


The authors are thankful to University Grants Commission—New Delhi, BITS—Pilani, and DST—New Delhi, for providing necessary facilities during the literature search for paper.


  1. S. Fahn and J. Jankovic, Principles and Practice of Movement Disorders, Churchill Livingstone, Elsevier, Philadelphia, Pa, USA, 2007.
  2. S. Sharma, K. Kumar, R. Deshmukh, and P. L. Sharma, “Phosphodiesterases: regulators of cyclic nucleotide signals and novel molecular target for movement disorders,” European Journal of Pharmacology, vol. 714, no. 1–3, pp. 486–497, 2013. View at: Publisher Site | Google Scholar
  3. S. Sharma and R. Deshmukh, “Vinpocetine attenuates MPTP-induced motor deficit and biochemical abnormalities in Wistar rats,” Neuroscience C, vol. 286, pp. 393–403, 2014. View at: Google Scholar
  4. T. T. Warner and A. H. V. Schapira, “Genetic and environmental factors in the cause of Parkinson's disease,” Annals of Neurology, vol. 53, no. 3, pp. S16–S25, 2003. View at: Publisher Site | Google Scholar
  5. Z. Konsoula and F. A. Barile, “Epigenetic histone acetylation and deacetylation mechanisms in experimental models of neurodegenerative disorders,” Journal of Pharmacological and Toxicological Methods, vol. 66, no. 3, pp. 215–220, 2012. View at: Publisher Site | Google Scholar
  6. G. Sadri-Vakili and J.-H. J. Cha, “Histone deacetylase inhibitors: a novel therapeutic approach to huntington's disease (complex mechanism of neuronal death),” Current Alzheimer Research, vol. 3, no. 4, pp. 403–408, 2006. View at: Publisher Site | Google Scholar
  7. I. F. Harrison and D. T. Dexter, “Epigenetic targeting of histone deacetylase: therapeutic potential in Parkinson's disease?” Pharmacology & Therapeutics, vol. 140, no. 1, pp. 34–52, 2013. View at: Publisher Site | Google Scholar
  8. A. Giralt, M. Puigdellívol, O. Carretón et al., “Long-term memory deficits in Huntington's disease are associated with reduced CBP histone acetylase activity,” Human Molecular Genetics, vol. 21, no. 6, pp. 1203–1216, 2012. View at: Publisher Site | Google Scholar
  9. H. Jia, R. J. Kast, J. S. Steffan, and E. A. Thomas, “Selective histone deacetylase (HDAC) inhibition imparts beneficial effects in Huntington's disease mice: implications for the ubiquitin-proteasomal and autophagy systems,” Human Molecular Genetics, vol. 21, no. 24, pp. 5280–5293, 2012. View at: Publisher Site | Google Scholar
  10. K. Xu, X.-L. Dai, H.-C. Huang, and Z.-F. Jiang, “Targeting HDACs: a promising therapy for Alzheimer's disease,” Oxidative Medicine and Cellular Longevity, vol. 2011, Article ID 143269, 5 pages, 2011. View at: Publisher Site | Google Scholar
  11. S. Sharma, R. Taliyan, and S. Ramagiri, “Histone deacetylase inhibitor, trichostatin A, improves learning and memory in high-fat diet-induced cognitive deficits in mice,” Journal of Molecular Neuroscience, 2014. View at: Publisher Site | Google Scholar
  12. S. Sharma and R. Taliyan, “Synergistic effects of GSK-3β and HDAC inhibitors in intracerebroventricular streptozotocin-induced cognitive deficits in rats,” Naunyn-Schmiedeberg's Archives of Pharmacology, 2014. View at: Publisher Site | Google Scholar
  13. J. P. Lopez-Atalaya, S. Ito, L. M. Valor, E. Benito, and A. Barco, “Genomic targets, and histone acetylation and gene expression profiling of neural HDAC inhibition,” Nucleic Acids Research, vol. 41, no. 17, pp. 8072–8084, 2013. View at: Publisher Site | Google Scholar
  14. G. P. Delcuve, D. H. Khan, and J. R. Davie, “Roles of histone deacetylases in epigenetic regulation: emerging paradigms from studies with inhibitors,” Clinical Epigenetics, vol. 4, no. 1, article 5, 2012. View at: Publisher Site | Google Scholar
  15. E. Verdin, F. Dequiedt, and H. G. Kasler, “Class II histone deacetylases: versatile regulators,” Trends in Genetics, vol. 19, no. 5, pp. 286–293, 2003. View at: Publisher Site | Google Scholar
  16. X. J. Yang and E. Seto, “The Rpd3/Hda1 family of lysine deacetylases: from bacteria and yeast to mice and men,” Nature Reviews Molecular Cell Biology, vol. 9, no. 3, pp. 206–218, 2008. View at: Publisher Site | Google Scholar
  17. M. Dokmanovic and P. A. Marks, “Prospects: histone deacetylase inhibitors,” Journal of Cellular Biochemistry, vol. 96, no. 2, pp. 293–304, 2005. View at: Publisher Site | Google Scholar
  18. W. Zhao, J.-P. Kruse, Y. Tang, S. Y. Jung, J. Qin, and W. Gu, “Negative regulation of the deacetylase SIRT1 by DBC1,” Nature, vol. 451, no. 7178, pp. 587–590, 2008. View at: Publisher Site | Google Scholar
  19. M. A. Glozak, N. Sengupta, X. Zhang, and E. Seto, “Acetylation and deacetylation of non-histone proteins,” Gene, vol. 363, no. 1-2, pp. 15–23, 2005. View at: Publisher Site | Google Scholar
  20. S. Spange, T. Wagner, T. Heinzel, and O. H. Krämer, “Acetylation of non-histone proteins modulates cellular signalling at multiple levels,” International Journal of Biochemistry and Cell Biology, vol. 41, no. 1, pp. 185–198, 2009. View at: Publisher Site | Google Scholar
  21. R. S. Broide, J. M. Redwine, N. Aftahi, W. Young, F. E. Bloom, and C. J. Winrow, “Distribution of histone deacetylases 1-11 in the rat brain,” Journal of Molecular Neuroscience, vol. 31, no. 1, pp. 47–58, 2007. View at: Publisher Site | Google Scholar
  22. A. K. B. Lucio-Eterovic, M. A. A. Cortez, E. T. Valera et al., “Differential expression of 12 histone deacetylase (HDAC) genes in astrocytomas and normal brain tissue: class II and IV are hypoexpressed in glioblastomas,” BMC Cancer, vol. 8, article 243, 2008. View at: Publisher Site | Google Scholar
  23. S. Baltan, A. Bachleda, R. S. Morrison, and S. P. Murphy, “Expression of histone deacetylases in cellular compartments of the mouse brain and the effects of ischemia,” Translational Stroke Research, vol. 2, no. 3, pp. 411–423, 2011. View at: Publisher Site | Google Scholar
  24. C. Janssen, S. Schmalbach, S. Boeselt, A. Sarlette, R. Dengler, and S. Petri, “Differential histone deacetylase mRNA expression patterns in amyotrophic lateral sclerosis,” Journal of Neuropathology and Experimental Neurology, vol. 69, no. 6, pp. 573–581, 2010. View at: Publisher Site | Google Scholar
  25. E. Hu, Z. Chen, T. Fredrickson et al., “Cloning and characterization of a novel human class I histone deacetylase that functions as a transcription repressor,” Journal of Biological Chemistry, vol. 275, no. 20, pp. 15254–15264, 2000. View at: Publisher Site | Google Scholar
  26. C. M. Grozinger, C. A. Hassig, and S. L. Schreiber, “Three proteins define a class of human histone deacetylases related to yeast Hda1p,” Proceedings of the National Academy of Sciences of the United States of America, vol. 96, no. 9, pp. 4868–4873, 1999. View at: Publisher Site | Google Scholar
  27. T. A. Bolger and T.-P. Yao, “Intracellular trafficking of histone deacetylase 4 regulates neuronal cell death,” Journal of Neuroscience, vol. 25, no. 41, pp. 9544–9553, 2005. View at: Publisher Site | Google Scholar
  28. N. M. Tsankova, O. Berton, W. Renthal, A. Kumar, R. L. Neve, and E. J. Nestler, “Sustained hippocampal chromatin regulation in a mouse model of depression and antidepressant action,” Nature Neuroscience, vol. 9, no. 4, pp. 519–525, 2006. View at: Publisher Site | Google Scholar
  29. C. L. Benn, R. Butler, L. Mariner et al., “Genetic knock-down of HDAC7 does not ameliorate disease pathogenesis in the R6/2 mouse model of Huntington's disease,” PLoS ONE, vol. 4, no. 6, Article ID e5747, 2009. View at: Publisher Site | Google Scholar
  30. W. Zhou, K. Bercury, J. Cummiskey, N. Luong, J. Lebin, and C. R. Freed, “Phenylbutyrate up-regulates the DJ-1 protein and protects neurons in cell culture and in animal models of Parkinson disease,” Journal of Biological Chemistry, vol. 286, no. 17, pp. 14941–14951, 2011. View at: Publisher Site | Google Scholar
  31. B. Lang, T. M. Alrahbeni, D. S. Clair, D. H. Blackwood, C. D. McCaig, and S. Shen, “HDAC9 is implicated in schizophrenia and expressed specifically in post-mitotic neurons but not in adult neural stem cells,” American Journal of Stem Cells, vol. 1, no. 1, pp. 31–41, 2011. View at: Google Scholar
  32. C. M. Southwood, M. Peppi, S. Dryden, M. A. Tainsky, and A. Gow, “Microtubule deacetylases, SirT2 and HDAC6, in the nervous system,” Neurochemical Research, vol. 32, no. 2, pp. 187–195, 2007. View at: Publisher Site | Google Scholar
  33. H. Y. Kao, C. H. Lee, A. Komarov, C. C. Han, and R. M. Evans, “Isolation and characterization of mammalian HDAC10, a novel histone deacetylase,” The Journal of Biological Chemistry, vol. 277, no. 1, pp. 187–193, 2002. View at: Publisher Site | Google Scholar
  34. L. Gao, M. A. Cueto, F. Asselbergs, and P. Atadja, “Cloning and functional characterization of HDAC11, a novel member of the human histone deacetylase family,” Journal of Biological Chemistry, vol. 277, no. 28, pp. 25748–25755, 2002. View at: Publisher Site | Google Scholar
  35. C. Rouaux, N. Jokic, C. Mbebi, S. Boutillier, J. P. Loeffler, and A. L. Boutillier, “Critical loss of CBP/p300 histone acetylase activity by caspase-6 during neurodegeneration,” The EMBO Journal, vol. 22, no. 24, pp. 6537–6549, 2003. View at: Publisher Site | Google Scholar
  36. G. Sadri-Vakili, B. Bouzou, C. L. Benn et al., “Histones associated with downregulated genes are hypo-acetylated in Huntington's disease models,” Human Molecular Genetics, vol. 16, no. 11, pp. 1293–1306, 2007. View at: Publisher Site | Google Scholar
  37. E. Kontopoulos, J. D. Parvin, and M. B. Feany, “α-synuclein acts in the nucleus to inhibit histone acetylation and promote neurotoxicity,” Human Molecular Genetics, vol. 15, no. 20, pp. 3012–3023, 2006. View at: Publisher Site | Google Scholar
  38. V. Allfrey, “Acetylation and methylation of histones and their possible role in the regulation of RNA synthesis,” Proceedings of the National Academy of Sciences of the United States of America, vol. 51, pp. 786–794, 1964. View at: Google Scholar
  39. M. G. Riggs, R. G. Whittaker, J. R. Neumann, and V. M. Ingram, “n-Butyrate causes histone modification in HeLa and Friend erythroleukaemia cells,” Nature, vol. 268, no. 5619, pp. 462–464, 1977. View at: Publisher Site | Google Scholar
  40. M. Yoshida, M. Kijima, M. Akita, and T. Beppu, “Potent and specific inhibition of mammalian histone deacetylase both in vivo and in vitro by trichostatin A,” The Journal of Biological Chemistry, vol. 265, no. 28, pp. 17174–17179, 1990. View at: Google Scholar
  41. J. Taunton, C. A. Hassig, and S. L. Schreiber, “A mammalian histone deacetylase related to the yeast transcriptional regulator Rpd3p,” Science, vol. 272, no. 5260, pp. 408–411, 1996. View at: Publisher Site | Google Scholar
  42. W.-M. Yang, C. Inouye, Y. Zeng, D. Bearss, and E. Seto, “Transcriptional repression by YY1 is mediated by interaction with a mammalian homolog of the yeast global regulator RPD3,” Proceedings of the National Academy of Sciences of the United States of America, vol. 93, no. 23, pp. 12845–12850, 1996. View at: Publisher Site | Google Scholar
  43. S. Emiliani, W. Fischle, C. Van Lint, Y. Al-Abed, and E. Verdin, “Characterization of a human RPD3 ortholog, HDAC3,” Proceedings of the National Academy of Sciences of the United States of America, vol. 95, no. 6, pp. 2795–2800, 1998. View at: Publisher Site | Google Scholar
  44. R. A. Frye, “Characterization of five human cDNAs with homology to the yeast SIR2 gene: Sir2-like proteins (Sirtuins) metabolize NAD and may have protein ADP-ribosyltransferase activity,” Biochemical and Biophysical Research Communications, vol. 260, no. 1, pp. 273–279, 1999. View at: Publisher Site | Google Scholar
  45. H.-Y. Kao, M. Downes, P. Ordentlich, and R. M. Evans, “Isolation of a novel histone deacetylase reveals that class I and class II deacetylases promote SMRT-mediated repression,” Genes and Development, vol. 14, no. 1, pp. 55–66, 2000. View at: Google Scholar
  46. J. J. Buggy, M. L. Sideris, P. Mak, D. D. Lorimer, B. McIntosh, and J. M. Clark, “Cloning and characterization of a novel human histone deacetylase, HDAC8,” Biochemical Journal, vol. 350, no. 1, pp. 199–205, 2000. View at: Publisher Site | Google Scholar
  47. I. Van Den Wyngaert, W. De Vries, A. Kremer et al., “Cloning and characterization of human histone deacetylase 8,” FEBS Letters, vol. 478, no. 1-2, pp. 77–83, 2000. View at: Publisher Site | Google Scholar
  48. X. Zhou, P. A. Marks, R. A. Rifkind, and V. M. Richon, “Cloning and characterization of a histone deacetylase, HDAC9,” Proceedings of the National Academy of Sciences of the United States of America, vol. 98, no. 19, pp. 10572–10577, 2001. View at: Publisher Site | Google Scholar
  49. A. R. Guardiola and T. P. Yao, “Molecular cloning and characterization of a novel histone deacetylase HDAC10,” The Journal of Biological Chemistry, vol. 277, no. 5, pp. 3350–3356, 2002. View at: Publisher Site | Google Scholar
  50. J. J. Tong, J. Liu, N. R. Bertos, and X.-J. Yang, “Identification of HDAC10, a novel class II human histone deacetylase containing a leucine-rich domain,” Nucleic Acids Research, vol. 30, no. 5, pp. 1114–1123, 2002. View at: Publisher Site | Google Scholar
  51. D. D. Fischer, R. Cai, U. Bhatia et al., “Isolation and characterization of a novel class II histone deacetylase, HDAC10,” The Journal of Biological Chemistry, vol. 277, no. 8, pp. 6656–6666, 2002. View at: Publisher Site | Google Scholar
  52. P. A. Marks and R. Breslow, “Dimethyl sulfoxide to vorinostat: development of this histone deacetylase inhibitor as an anticancer drug,” Nature Biotechnology, vol. 25, no. 1, pp. 84–90, 2007. View at: Publisher Site | Google Scholar
  53. J. M. Wagner, B. Hackanson, M. Lübbert, and M. Jung, “Histone deacetylase (HDAC) inhibitors in recent clinical trials for cancer therapy,” Clinical Epigenetics, vol. 1, no. 3-4, pp. 117–136, 2010. View at: Publisher Site | Google Scholar
  54. G. Gardian, L. Yang, C. Cleren, N. Y. Calingasan, P. Klivenyi, and M. F. Beal, “Neuroprotective effects of phenylbutyrate against MPTP neurotoxicity,” NeuroMolecular Medicine, vol. 5, no. 3, pp. 235–241, 2004. View at: Publisher Site | Google Scholar
  55. G. Gardian, S. E. Browne, D. K. Choi et al., “Neuroprotective effects of phenylbutyrate in the N171-82Q transgenic mouse model of Huntington's disease,” The Journal of Biological Chemistry, vol. 280, no. 1, pp. 556–563, 2005. View at: Publisher Site | Google Scholar
  56. M. Zhu, W.-W. Li, and C.-Z. Lu, “Histone decacetylase inhibitors prevent mitochondrial fragmentation and elicit early neuroprotection against MPP+,” CNS Neuroscience & Therapeutics, vol. 20, no. 4, pp. 308–316, 2014. View at: Publisher Site | Google Scholar
  57. R. St. Laurent, L. M. O'Brien, and S. T. Ahmad, “Sodium butyrate improves locomotor impairment and early mortality in a rotenone-induced Drosophila model of Parkinson's disease,” Neuroscience, vol. 246, pp. 382–390, 2013. View at: Publisher Site | Google Scholar
  58. J. W. Langston, P. Ballard, J. W. Tetrud, and I. Irwin, “Chronic parkinsonism in humans due to a product of meperidine-analog synthesis,” Science, vol. 219, no. 4587, pp. 979–980, 1983. View at: Publisher Site | Google Scholar
  59. A. A. Castro, K. Ghisoni, A. Latini, J. Quevedo, C. I. Tasca, and R. D. S. Prediger, “Lithium and valproate prevent olfactory discrimination and short-term memory impairments in the intranasal 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) rat model of Parkinson's disease,” Behavioural Brain Research, vol. 229, no. 1, pp. 208–215, 2012. View at: Publisher Site | Google Scholar
  60. G. Faraco, T. Pancani, L. Formentini et al., “Pharmacological inhibition of histone deacetylases by suberoylanilide hydroxamic acid specifically alters gene expression and reduces ischemic injury in the mouse brain,” Molecular Pharmacology, vol. 70, no. 6, pp. 1876–1884, 2006. View at: Publisher Site | Google Scholar
  61. E. C. Hirsch and S. Hunot, “Neuroinflammation in Parkinson's disease: a target for neuroprotection?” The Lancet Neurology, vol. 8, no. 4, pp. 382–397, 2009. View at: Publisher Site | Google Scholar
  62. S. A. Zaitone, D. M. Abo-Elmatty, and S. M. Elshazly, “Piracetam and vinpocetine ameliorate rotenone-induced Parkinsonism in rats,” Indian Journal of Pharmacology, vol. 44, no. 6, pp. 774–779, 2012. View at: Publisher Site | Google Scholar
  63. H. L. Martin and P. Teismann, “Glutathione—a review on its role and significance in Parkinson's disease,” The FASEB Journal, vol. 23, no. 10, pp. 3263–3272, 2009. View at: Publisher Site | Google Scholar
  64. A. Roy, A. Ghosh, A. Jana et al., “Sodium phenylbutyrate controls neuroinflammatory and antioxidant activities and protects dopaminergic neurons in mouse models of Parkinson's disease,” PLoS ONE, vol. 7, no. 6, Article ID e38113, 2012. View at: Publisher Site | Google Scholar
  65. A. Mehta, M. Prabhakar, P. Kumar, R. Deshmukh, and P. L. Sharma, “Excitotoxicity: bridge to various triggers in neurodegenerative disorders,” European Journal of Pharmacology, vol. 698, no. 1–3, pp. 6–18, 2013. View at: Publisher Site | Google Scholar
  66. J.-Y. Wu, F.-N. Niu, R. Huang, and Y. Xu, “Enhancement of glutamate uptake in 1-methyl-4-phenylpyridinium-treated astrocytes by trichostatin A,” NeuroReport, vol. 19, no. 12, pp. 1209–1212, 2008. View at: Publisher Site | Google Scholar
  67. P.-S. Chen, G.-S. Peng, G. Li et al., “Valproate protects dopaminergic neurons in midbrain neuron/glia cultures by stimulating the release of neurotrophic factors from astrocytes,” Molecular Psychiatry, vol. 11, no. 12, pp. 1116–1125, 2006. View at: Publisher Site | Google Scholar
  68. N. B. Chauhan, G. J. Siegel, and J. M. Lee, “Depletion of glial cell line-derived neurotrophic factor in substantia nigra neurons of Parkinson's disease brain,” Journal of Chemical Neuroanatomy, vol. 21, no. 4, pp. 277–288, 2001. View at: Publisher Site | Google Scholar
  69. D. W. Howells, M. J. Porritt, J. Y. F. Wong et al., “Reduced BDNF mRNA expression in the Parkinson's disease substantia nigra,” Experimental Neurology, vol. 166, no. 1, pp. 127–135, 2000. View at: Publisher Site | Google Scholar
  70. X. Wu, P. S. Chen, S. Dallas et al., “Histone deacetylase inhibitors up-regulate astrocyte GDNF and BDNF gene transcription and protect dopaminergic neurons,” International Journal of Neuropsychopharmacology, vol. 11, no. 8, pp. 1123–1134, 2008. View at: Publisher Site | Google Scholar
  71. S. Yasuda, M. H. Liang, Z. Marinova, A. Yahyavi, and D. M. Chuang, “The mood stabilizers lithium and valproate selectively activate the promoter IV of brain-derived neurotrophic factor in neurons,” Molecular Psychiatry, vol. 14, no. 1, pp. 51–59, 2009. View at: Publisher Site | Google Scholar
  72. S. K. Kidd and J. S. Schneider, “Protection of dopaminergic cells from MPP+-mediated toxicity by histone deacetylase inhibition,” Brain Research, vol. 1354, pp. 172–178, 2010. View at: Publisher Site | Google Scholar
  73. S. K. Kidd and J. S. Schneider, “Protective effects of valproic acid on the nigrostriatal dopamine system in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson's disease,” Neuroscience, vol. 194, pp. 189–194, 2011. View at: Publisher Site | Google Scholar
  74. S. H. Chen, H. M. Wu, B. Ossola et al., “Suberoylanilide hydroxamic acid, a histone deacetylase inhibitor, protects dopaminergic neurons from neurotoxin-induced damage,” British Journal of Pharmacology, vol. 165, no. 2, pp. 494–505, 2012. View at: Publisher Site | Google Scholar
  75. A. Samii, J. G. Nutt, and B. R. Ransom, “Parkinson's disease,” The Lancet, vol. 363, no. 9423, pp. 1783–1793, 2004. View at: Publisher Site | Google Scholar
  76. T. H. Johnston, P. Huot, S. Damude et al., “RGFP109, a histone deacetylase inhibitor attenuates l-DOPA-induced dyskinesia in the MPTP-lesioned marmoset: a proof-of-concept study,” Parkinsonism and Related Disorders, vol. 19, no. 2, pp. 260–264, 2013. View at: Publisher Site | Google Scholar
  77. B. Monti, E. Polazzi, L. Batti, C. Crochemore, M. Virgili, and A. Contestabile, “Alpha-synuclein protects cerebellar granule neurons against 6-hydroxydopamine-induced death,” Journal of Neurochemistry, vol. 103, no. 2, pp. 518–530, 2007. View at: Publisher Site | Google Scholar
  78. B. Monti, D. Mercatelli, and A. Contestabile, “Valproic acid neuroprotection in 6-OHDA lesioned rat, a model for parkinson's disease,” HOAJ Biology, vol. 1, no. 1, pp. 1–4, 2012. View at: Publisher Site | Google Scholar
  79. P. Rane, J. Shields, M. Heffernan, Y. Guo, S. Akbarian, and J. A. King, “The histone deacetylase inhibitor, sodium butyrate, alleviates cognitive deficits in pre-motor stage PD,” Neuropharmacology, vol. 62, no. 7, pp. 2409–2412, 2012. View at: Publisher Site | Google Scholar
  80. R. Betarbet, R. M. Canet-Aviles, T. B. Sherer et al., “Intersecting pathways to neurodegeneration in Parkinson's disease: effects of the pesticide rotenone on DJ-1, alpha-synuclein, and the ubiquitin-proteasome system,” Neurobiology of Disease, vol. 22, no. 2, pp. 404–420, 2006. View at: Publisher Site | Google Scholar
  81. B. Monti, V. Gatta, F. Piretti, S. S. Raffaelli, M. Virgili, and A. Contestabile, “Valproic acid is neuroprotective in the rotenone rat model of Parkinson's disease: involvement of α-synuclein,” Neurotoxicity Research, vol. 17, no. 2, pp. 130–141, 2010. View at: Publisher Site | Google Scholar
  82. X. Wang, Z.-H. Qin, Y. Leng et al., “Prostaglandin A1 inhibits rotenone-induced apoptosis in SH-SY5Y cells,” Journal of Neurochemistry, vol. 83, no. 5, pp. 1094–1102, 2002. View at: Publisher Site | Google Scholar
  83. T. Pan, X. Li, W. Xie, J. Jankovic, and W. Le, “Valproic acid-mediated Hsp70 induction and anti-apoptotic neuroprotection in SH-SY5Y cells,” FEBS Letters, vol. 579, no. 30, pp. 6716–6720, 2005. View at: Publisher Site | Google Scholar
  84. M. Inden, Y. Kitamura, H. Takeuchi et al., “Neurodegeneration of mouse nigrostriatal dopaminergic system induced by repeated oral administration of rotenone is prevented by 4-phenylbutyrate, a chemical chaperone,” Journal of Neurochemistry, vol. 101, no. 6, pp. 1491–1504, 2007. View at: Publisher Site | Google Scholar
  85. B. H. Meurers, C. Zhu, P. O. Fernagut et al., “Low dose rotenone treatment causes selective transcriptional activation of cell death related pathways in dopaminergic neurons in vivo,” Neurobiology of Disease, vol. 33, no. 2, pp. 182–192, 2009. View at: Publisher Site | Google Scholar
  86. G. S. Peng, G. Li, N. S. Tzeng et al., “Valproate pretreatment protects dopaminergic neurons from LPS-induced neurotoxicity in rat primary midbrain cultures: role of microglia,” Molecular Brain Research, vol. 134, no. 1, pp. 162–169, 2005. View at: Publisher Site | Google Scholar
  87. P. S. Chen, C.-C. Wang, C. D. Bortner et al., “Valproic acid and other histone deacetylase inhibitors induce microglial apoptosis and attenuate lipopolysaccharide-induced dopaminergic neurotoxicity,” Neuroscience, vol. 149, no. 1, pp. 203–212, 2007. View at: Publisher Site | Google Scholar
  88. H.-S. Suh, S. Choi, P. Khattar, N. Choi, and S. C. Lee, “Histone deacetylase inhibitors suppress the expression of inflammatory and innate immune response genes in human microglia and astrocytes,” Journal of Neuroimmune Pharmacology, vol. 5, no. 4, pp. 521–532, 2010. View at: Publisher Site | Google Scholar
  89. T. F. Outeiro, E. Kontopoulos, S. M. Altmann et al., “Sirtuin 2 inhibitors rescue α-synuclein-mediated toxicity in models of Parkinson's disease,” Science, vol. 317, no. 5837, pp. 516–519, 2007. View at: Publisher Site | Google Scholar
  90. J. Nutt, A. Williams, C. Plotkin, N. Eng, M. Ziegler, and D. B. Calne, “Treatment of Parkinson's disease with sodium valproate: clinical, pharmacological, and biochemical observations,” Canadian Journal of Neurological Sciences, vol. 6, no. 3, pp. 337–343, 1979. View at: Google Scholar
  91. P. A. Price, J. D. Parkes, and C. D. Marsden, “Sodium valproate in the treatment of levodopa-induced dyskinesia,” Journal of Neurology Neurosurgery and Psychiatry, vol. 41, no. 8, pp. 702–706, 1978. View at: Publisher Site | Google Scholar

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