Editorial of the Special Issue "Neurobiological Mechanisms Implicated in Stress-Related Psychiatric Disorders".

Mental disorders may seriously impair the quality of life of affected individuals and cause a significant public health burden [...].

Anti-N-methyl-d-aspartate receptor encephalitis in an older patient presenting with a rapid onset of delusions and amnesia.

We present the case of a 77-year-old patient with a rapid onset of delusions, amnesia, agitation, insomnia and no previous psychiatric history, who was diagnosed with anti-N-methyl-d-aspartate receptor encephalitis. This case report highlights the importance of including autoimmune encephalitis in the differential diagnosis of older patients presenting with rapid onset psychiatric episodes.

Effects of oxytocin and arginine vasopressin on the proliferation and differentiation of a serotonergic cell line.

The neuropeptides oxytocin and arginine vasopressin (AVP) are involved in the regulation of social behavior and cognition. The current study analyzed the effect of oxytocin and AVP on proliferation and differentiation of serotonergic neurons (RN46A cells). Oxytocin did not affect, while 5-10 µM AVP decreased RN46A proliferation. Oxytocin did not significantly alter, while 10 µM AVP decreased the number of cells extending neurites. We found divergent effects of oxytocin and AVP in serotonergic neurons, underscoring their functional differences.

Combining genetic and epigenetic parameters of the serotonin transporter gene in obsessive-compulsive disorder.

While genetic variants have been reported to be associated with obsessive-compulsive disorder (OCD), the small effect sizes suggest that epigenetic mechanisms such as DNA methylation may also be relevant. The serotonin transporter (SLC6A4) gene has been extensively investigated in relation to OCD, since serotonin reuptake inhibitors are the pharmacological treatment of choice for the disorder. The current study set three questions: Firstly, whether the high expressing loci of the SLC6A4 polymorphisms, 5-HTTLPR + rs25531, rs25532 and rs16965628 are associated with family-based (n = 164 trios) and case-control OCD (n = 186, 152, respectively). This was also examined by a meta-analysis. Secondly, whether DNA methylation and RNA levels of the SLC6A4 differ in saliva and blood of a subset of samples from pediatric and adult OCD patients and matched controls. And lastly, whether morning awakening cortisol levels correlate with the above. A meta-analysis confirmed the association of the LA-allele with OCD (OR = 1.21, p = 0.00018), maintaining significance in the early-onset OCD subgroup (OR = 1.21, p = 0.022). There was no association between rs25532 or rs16965628 and OCD. Our preliminary data showed that SLC6A4 DNA methylation levels in an amplicon located at the beginning of the first intron were significantly higher in the saliva of pediatric OCD patients compared to controls and adult patients with OCD, but no alterations in RNA levels or in polymorphism interactions were observed. Morning awakening salivary cortisol levels positively correlated with methylation levels, and negatively correlated with RNA levels. This study further supports the involvement of the SLC6A4 gene in OCD through both genetic and epigenetic mechanisms. This finding needs to be explored further in an independent large sample.

A pilot investigation on DNA methylation modifications associated with complex posttraumatic symptoms in elderly traumatized in childhood.

OBJECTIVE: Complex posttraumatic stress disorder (CPTSD) is a newly proposed diagnosis in the International Classification of Diseases-version 11, which is currently intensively investigated. Childhood trauma is regarded as main source of CPTSD symptoms, even in later life. Induction of DNA methylation changes by childhood trauma may contribute to its long-lasting adverse health consequences. The current study analyzed the correlation of genome-wide DNA methylation profiles with complex posttraumatic sequelae in buccal epithelial cells from 31 elderly former indentured child laborers (Verdingkinder) using the Infinium Illumina 450k Human DNA methylation chip. RESULTS: DNA methylation modifications indicated experiment-wide significant associations with the following complex posttraumatic symptom domains: dissociation, tension reduction behavior and dysfunctional sexual behavior. Differentially methylated CpG sites were mapped to the genes huntington associated protein 1 (HAP1), RAN binding protein 2 (RANBP2) and proteasome subunit alpha 4 (PSMA4), respectively. In addition, the methylation of cg07225277 located in carnosine synthase 1 (CARNS1) correlated with trauma symptom complexity. Our pilot data suggest correlation of DNA methylation modifications with complex posttraumatic symptoms in elderly individuals subjected to prolonged and complex childhood trauma. More comprehensive and elaborated studies should be carried out to analyze epigenetic modifications associated with CPTSD.

Differential DNA Methylation in Monozygotic Twins Discordant for Female Sexual Functioning.

BACKGROUND: Research has repeatedly suggested genetic and environmental factors in the etiology underlying female sexual dysfunction (FSD). Because sexual functioning is a highly variable trait, epigenetics could provide a promising approach to tackle the origins of FSD and consequently offer a step-change in our understanding of these problems. AIM: To identify differentially methylated CpG positions for sexual functioning in a sample of monozygotic twin pairs discordant for sexual functioning. METHODS: The sample consisted of 33 trait-discordant monozygotic twin pairs (mean age = 54.1 years, SD = 9.05) from the Twins UK Registry. Phenotypic data on sexual desire, arousal, lubrication, orgasm, satisfaction, and pain were collected using the Female Sexual Function Index-Lifelong (FSFI-LL). The Illumina Infinium HumanMethylation 450 DNA BeadChip was used for epigenome-wide analyses of DNA methylation in whole-blood samples. OUTCOMES: Comparison of DNA methylation patterns associated with the FSFI-LL total score and its six subdomains. RESULTS: Two differentially methylated CpG positions (cg09580409 and cg14734994) reaching experiment-wide statistical significance were found for overall sexual functioning, mapping to MGC45800 and the threonine synthase-like 2 gene (THNSL2), respectively. Furthermore, potential biologically relevant candidates for sexual desire (CUB and zona pellucida-like domains 1, CUZD1) and satisfaction (solute carrier family 6 member 19, SLC6A19) were identified. CLINICAL TRANSLATION: THNSL2 and SLC6A19, which have been linked to weight and adiposity, might represent novel candidates for sexual problems in women. STRENGTHS AND LIMITATIONS: This is the first study to investigate epigenetic mechanisms underlying FSD. The study used a relative small sample of monozygotic female twins. The cutoff to determine discordance in sexual problems was chosen based on a 10% FSFI score difference. Therefore, the results have to be interpreted with caution and need replication in larger clinical samples. CONCLUSION: Understanding how genes and environment interact to influence our sexuality might inform clinical practice and lead to new treatments for women experiencing FSD. Burri A, Leupin M, Spector T, Marinova Z. Differential DNA Methylation in Monozygotic Twins Discordant for Female Sexual Functioning. J Sex Med 2017;14:1357-1364.

Expression of D-Amino Acid Oxidase (DAO/DAAO) and D-Amino Acid Oxidase Activator (DAOA/G72) during Development and Aging in the Human Post-mortem Brain.

In the brain, D-amino acid oxidase (DAO/DAAO) mainly oxidizes D-serine, a co-agonist of the N-methyl-D-aspartate (NMDA) receptors. Thus, DAO can regulate the function of NMDA receptors via D-serine breakdown. Furthermore, DAO activator (DAOA)/G72 has been reported as both DAOA and repressor. The co-expression of DAO and DAOA genes and proteins in the human brain is not yet elucidated. The aim of this study was to understand the regional and age span distribution of DAO and DAOA (mRNA and protein) in a concomitant manner. We determined DAO and DAOA mRNA and protein expression across six brain regions in normal human post-mortem brain samples (16 weeks of gestation to 91 years) using quantitative real-time reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay. We found higher expression of DAO mRNA in the cerebellum, whereas lower expression of DAO protein in the cerebellum compared to the other brain regions studied, which suggests post-transcriptional regulation. We detected DAOA protein but not DAOA mRNA in all brain regions studied, suggesting a tightly regulated expression. To understand this regulation at the transcriptional level, we analyzed DNA methylation levels at DAO and DAOA CpG sites in the cerebellum and frontal cortex of control human post-mortem brain obtained from Gene Expression Omnibus datasets. Indeed, DAO and DAOA CpG sites in the cerebellum were significantly more methylated than those in the frontal cortex. While investigating lifespan effects, we found that DAO mRNA levels were positively correlated with age <2 years in the cerebellum and amygdala. We also detected a significant positive correlation (controlled for age) between DAO and DAOA protein in all of the brain regions studied except for the frontal cortex. In summary, DAO and DAOA expression in the human brain are both age and brain region dependent.

DNA methylation profiles of elderly individuals subjected to indentured childhood labor and trauma.

BACKGROUND: Childhood trauma is associated with increased vulnerability to mental and somatic disorders later in life. Epigenetic modifications such as DNA methylation are one potential mechanism through which such long-lasting impairments/consequences can be explained. The aim of the present study was to investigate whether childhood trauma is associated with long-term DNA methylation alterations in old age. METHODS: We assessed genome-wide DNA methylation profiles in a cohort of former indentured child laborers ("Verdingkinder") who suffered severe childhood adversities (N = 30; M age = 75.9 years), and compared them to control group with similar demographic characteristics (N = 15, M age = 72.8 years). DNA was isolated from epithelial buccal cells and hybridized to the Illumina Infinium 450 k DNA methylation array, which provides coverage of 485,000 methylation sites. RESULTS: After accounting for batch effects, age, gender and multiple testing, 71 differentially methylated CpG positions were identified between the two groups. They were annotated among others to genes involved in neuronal projections and neuronal development. Some of the identified genes with differential methylation (DLG associated protein 2, mechanistic target of rapamycin) have previously been associated with traumatic stress. CONCLUSIONS: The results indicate specific epigenetic alterations in elderly individuals who were subjected to childhood adversities. Psychiatric and somatic comorbidities as well as differences in buccal epithelial cells proportion may contribute to the observed epigenetic differences.

The hallucinogen 2,5-dimethoxy-4-iodoamphetamine hydrochloride activates neurotrophin receptors in a neuronal cell line and promotes neurites extension.

Decreased neurotrophic factors expression and neurotrophin receptors signalling have repeatedly been reported in association with stress, depression, and neurodegenerative disorders. We have previously identified the hallucinogen 2,5-dimethoxy-4-iodoamphetamine hydrochloride (DOI) as protective against trophic deprivation-induced cytotoxicity in human neuroblastoma SK-N-SH cells and established the dependence of this effect on the 5-HT2A receptor, tyrosine kinases activity, and the extracellular signal-regulated kinase pathway. In the current study, we investigated the effect of DOI on tropomyosin-related kinase receptor A (TrkA) phosphorylation. Treatment with DOI increased TrkA tyrosine phosphorylation in SK-N-SH cells, determined by immunoprecipitation with TrkA antibody and immunoblotting with anti-phosphotyrosine- and TrkA-antibodies. Analysis of DOI's effect on individual TrkA residues in SK-N-SH cells showed that it increases TrkA Tyr490 phosphorylation (177 ± 23% after 5 µM DOI for 30 min compared to vehicle). Furthermore, DOI treatment increased the percentage of SK-N-SH cells extending neurites in a TrkA-dependent manner (17.2 ± 2.2% after 5 µM DOI treatment for 6 days compared to 5.6 ± 1.7% after vehicle). In a different cell model-lymphoblastoid cell lines-DOI treatment increased tropomyosin-related kinase receptor B (TrkB) phosphorylation, determined by immunoprecipitation with TrkB antibody and immunoblotting with anti-phosphotyrosine antibody and total Trk antibody. Our results identify the Trk receptors as a downstream target of the hallucinogen DOI. In light of the known involvement of Trk receptors in mental diseases, their participation in DOI-mediated effects warrants further investigation.

Glutamate-Modulating Drugs as a Potential Therapeutic Strategy in Obsessive-Compulsive Disorder.

OBJECTIVE: Obsessive-compulsive disorder (OCD) is a mental disease commonly associated with severe distress and impairment of social functioning. Serotonin reuptake inhibitors and/or cognitive behavioural therapy are the therapy of choice, however up to 40% of patients do not respond to treatment. Glutamatergic signalling has also been implicated in OCD. The aim of the current study was to review the clinical evidence for therapeutic utility of glutamate-modulating drugs as an augmentation or monotherapy in OCD patients. METHODS: We conducted a search of the MEDLINE database for clinical studies evaluating the effect of glutamate-modulating drugs in OCD. RESULTS: Memantine is the compound most consistently showing a positive effect as an augmentation therapy in OCD. Anti-convulsant drugs (lamotrigine, topiramate) and riluzole may also provide therapeutic benefit to some OCD patients. Finally, ketamine may be of interest due to its potential for a rapid onset of action. CONCLUSION: Further randomized placebo-controlled trials in larger study populations are necessary in order to draw definitive conclusions on the utility of glutamate-modulating drugs in OCD. Furthermore, genetic and epigenetic factors, clinical symptoms and subtypes predicting treatment response to glutamate-modulating drugs need to be investigated systematically.

Are Epigenetic Factors Implicated in Chronic Widespread Pain?

BACKGROUND: Chronic widespread musculoskeletal pain (CWP) is the cardinal symptom of fibromyalgia and affects about 12% of the general population. Familial aggregation of CWP has been repeatedly demonstrated with estimated heritabilities of around 50%, indicating a genetic susceptibility. The objective of the study was to explore genome-wide disease-differentially methylated positions (DMPs) for chronic widespread pain (CWP) in a sample of unrelated individuals and a subsample of discordant monozygotic (MZ) twins. METHODOLOGY/PRINCIPLE FINDINGS: A total of N = 281 twin individuals from the TwinsUK registry, including N = 33 MZ twins discordant for self-reported CWP, were part of the discovery sample. The replication sample included 729 men and 756 women from a subsample of the KORA S4 survey-an independent population-based cohort from Southern Germany. Epigenome-wide analysis of DNA methylation was conducted using the Illumina Infinium HumanMethylation 450 DNA BeadChip in both the discovery and replication sample. Of our 40 main loci that were carried forward for replication, three CPGs reached significant p-values in the replication sample, including malate dehydrogenase 2 (MDH2; p-value 0.017), tetranectin (CLEC3B; p-value 0.039), and heat shock protein beta-6 (HSPB6; p-value 0.016). The associations between the collagen type I, alpha 2 chain (COL1A2) and monoamine oxidase B (MAOB) observed in the discovery sample-both of which have been previously reported to be biological candidates for pain-could not be replicated. CONCLUSION/SIGNIFICANCE: Our results may serve as a starting point to encourage further investigation in large and independent population-based cohorts of DNA methylation and other epigenetic changes as possible disease mechanisms in CWP. Ultimately, understanding the key mechanisms underlying CWP may lead to new treatments and inform clinical practice.

Biological correlates of complex posttraumatic stress disorder-state of research and future directions.

Complex posttraumatic stress disorder (PTSD) presents with clinical features of full or partial PTSD (re-experiencing a traumatic event, avoiding reminders of the event, and a state of hyperarousal) together with symptoms from three additional clusters (problems in emotional regulation, negative self-concept, and problems in interpersonal relations). Complex PTSD is proposed as a new diagnostic entity in ICD-11 and typically occurs after prolonged and complex trauma. Here we shortly review current knowledge regarding the biological correlates of complex PTSD and compare it to the relevant findings in PTSD. Recent studies provide support to the validity of complex PTSD as a separate diagnostic entity; however, data regarding the biological basis of the disorder are still very limited at this time. Further studies focused on complex PTSD biological correlates and replication of the initial findings are needed, including neuroimaging, neurobiochemical, genetic, and epigenetic investigations. Identification of altered biological pathways in complex PTSD may be critical to further understand the pathophysiology and optimize treatment strategies.

Region-specific regulation of the serotonin 2A receptor expression in development and ageing in post mortem human brain.

AIMS: The serotonin 2A receptor (HTR2A) is widely expressed in the brain and involved in the modulation of fear, mood, anxiety and other symptoms. HTR2A and HTR2A gene variations are implicated in depression, schizophrenia, anxiety and obsessive-compulsive disorder. To understand HTR2A signalling changes in psychiatric or neurodegenerative disorders, its normal pattern of brain expression and region specificity during development and ageing needs to be clarified. The aim of the present study was to assess HTR2A expression through developmental and ageing stages in six brain regions in post mortem human brain samples from individuals with no clinical or neuropathological evidence of neuropsychiatric disorders and to investigate the interaction with the rs6311 HTR2A promoter polymorphism. METHODS: DNA, RNA and protein were isolated from post mortem brain samples including six regions (frontal cortex, striatum, amygdala, thalamus, brain stem and cerebellum) from 55 individuals. HTR2A mRNA levels were assessed using quantitative real-time RT-PCR and HTR2A protein levels - with Western blot. The rs6311 HTR2A polymorphism was analysed with genotyping. RESULTS: We found that HTR2A mRNA and protein levels are differentially regulated with age in different brain regions studied, but are not affected by gender. Significant changes in HTR2A expression with age were found in frontal cortex, amygdala, thalamus, brain stem and cerebellum. CONCLUSIONS: Our results show plasticity and region specificity of HTR2A expression regulation in human brain with age, which may be important for the interaction with other neurotransmitter systems and for the occurrence of developmental periods with increased vulnerability to neuropsychiatric or neurodegenerative disorders.

Trio study and meta-analysis support the association of genetic variation at the serotonin transporter with early-onset obsessive-compulsive disorder.

Despite compelling evidence for major genetic contributions to the etiology of obsessive-compulsive disorder (OCD), few genetic variants have been consistently associated with this debilitating illness. Molecular genetic studies in children and adolescents with OCD are of particular interest, since early onset of the disease has been observed to be associated with increased familiality. We replicate here for the first time in early-onset OCD patients, a previously reported association of OCD with the common gain-of-function LA allele at the serotonin transporter linked polymorphic region known as 5-HTTLPR in a collection of parent-offspring trios. The present meta-analysis of this recently refined serotonin transporter gene variant revealed further support for the LA allele conferring increased genetic susceptibility to OCD. We conclude that the 5-HTTLPR is currently the single best supported risk variant for OCD, in regards of early-onset OCD, albeit of modest effect size and the possibility that the conferred risk might not be specific to OCD.

Real-time impedance-based cell analyzer as a tool to delineate molecular pathways involved in neurotoxicity and neuroprotection in a neuronal cell line.

Many brain-related disorders have neuronal cell death involved in their pathophysiology. Improved in vitro models to study neuroprotective or neurotoxic effects of drugs and downstream pathways involved would help gain insight into the molecular mechanisms of neuroprotection/neurotoxicity and could potentially facilitate drug development. However, many existing in vitro toxicity assays have major limitations - most assess neurotoxicity and neuroprotection at a single time point, not allowing to observe the time-course and kinetics of the effect. Furthermore, the opportunity to collect information about downstream signaling pathways involved in neuroprotection in real-time would be of great importance. In the current protocol we describe the use of a real-time impedance-based cell analyzer to determine neuroprotective effects of serotonin 2A (5-HT2A) receptor agonists in a neuronal cell line under label-free and real-time conditions using impedance measurements. Furthermore, we demonstrate that inhibitors of second messenger pathways can be used to delineate downstream molecules involved in the neuroprotective effect. We also describe the utility of this technique to determine whether an effect on cell proliferation contributes to an observed neuroprotective effect. The system utilizes special microelectronic plates referred to as E-Plates which contain alternating gold microelectrode arrays on the bottom surface of the wells, serving as cell sensors. The impedance readout is modified by the number of adherent cells, cell viability, morphology, and adhesion. A dimensionless parameter called Cell Index is derived from the electrical impedance measurements and is used to represent the cell status. Overall, the real-time impedance-based cell analyzer allows for real-time, label-free assessment of neuroprotection and neurotoxicity, and the evaluation of second messenger pathways involvement, contributing to more detailed and high-throughput assessment of potential neuroprotective compounds in vitro, for selecting therapeutic candidates.

5-HT2A serotonin receptor agonist DOI alleviates cytotoxicity in neuroblastoma cells: role of the ERK pathway.

Disturbances of serotonergic signaling, including the serotonin 2A (5-HT2A) receptor, have been implicated in neuropsychiatric and neurodegenerative disorders. The aim of the present study was to characterize the effect of a 5-HT2A receptor agonist on cytotoxicity in a neuronal cell line and address the involved mechanism. HTR2A mRNA and protein expression in human neuroblastoma SK-N-SH cells was confirmed. Cells were subjected to serum deprivation and cell viability was monitored continuously with xCELLigence. In a dose-response study the 5-HT2A agonist (±)-2,5-dimethoxy-4-iodoamphetamine hydrochloride (DOI) (25 nM to 5 µM) protected against serum deprivation cytotoxicity. The selective 5-HT2A receptor antagonist MDL 11,939, the general protein tyrosine kinase inhibitor genistein, and the extracellular signal-regulated kinase (ERK) pathway MEK inhibitor U0126, all attenuated DOI's protective effect. An antibody array suggested that 1 µM DOI affected phosphorylation of several tyrosine kinases. Western blot further confirmed that DOI transiently increased ERK phosphorylation, indicating its activation. Finally, protective concentrations of DOI increased cellular mitochondrial mass, an effect prevented by pretreatment with U0126. In conclusion, our results suggest that DOI protects SK-N-SH cells against serum deprivation through ERK pathway activation. They imply 5-HT2A receptor modulation as a potential target for neuroprotection.

In vitro study methodologies to investigate genetic aspects and effects of drugs used in attention-deficit hyperactivity disorder.

Attention-deficit/hyperactivity disorder (ADHD) is one of the most common psychiatric disorders in children and adolescents, with up to 5 % affected worldwide. Twin and family studies on ADHD show its high familiality with heritability estimated around 70 %, but, to date, no specific polymorphism or gene was found to be specifically affected. Psychostimulants (amphetamine, methylphenidate) and non-psychostimulants (atomoxetine) are used successfully in ADHD therapy, but many of their mechanisms of action and their adverse effects are not yet fully understood. Therefore, both genetic findings and therapeutic interventions should be further investigated. One easy platform for such studies is in vitro analyses, which encompass neuronal cell culture studies, transfections of genetic constructs, binding and electrophysiology analyses. In this review, different methods will be referred in particular to ADHD findings, and new techniques will be mentioned for future studies of drug or genetic effects in vitro.

Histone deacetylase inhibition alters histone methylation associated with heat shock protein 70 promoter modifications in astrocytes and neurons.

The mood-stabilizing and anticonvulsant drug valproic acid (VPA) inhibits histone deacetylases (HDACs). The aim of the present study was to determine the effect of HDAC inhibition on overall and target gene promoter-associated histone methylation in rat cortical neurons and astrocytes. We found that VPA and other HDAC inhibitors, including sodium butyrate (SB), trichostatin A (TSA), and the Class I HDAC inhibitors MS-275 and apicidin all increased levels of histone 3 lysine 4 dimethylation and trimethylation (H3K4Me2 and H3K4Me3); these processes are linked to transcriptional activation in rat cortical neurons and astrocytes. VPA, SB, TSA, MS-275, and apicidin also upregulated levels of the neuroprotective heat shock protein 70 (HSP70) in rat astrocytes. Moreover, Class I HDAC inhibition by VPA and MS-275 increased H3K4Me2 levels at the HSP70 promoter in astrocytes and neurons. We also found that VPA treatment facilitated the recruitment of acetyltransferase p300 to the HSP70 promoter and that p300 interacted with the transcription factor NF-Y in astrocytes. Taken together, the results suggest that Class I HDAC inhibition is key to upregulating overall and gene-specific H3K4 methylation in primary neuronal and astrocyte cultures. In addition, VPA-induced activation of the HSP70 promoter in astrocytes appears to involve an increase in H3K4Me2 levels and recruitment of p300. This article is part of a Special Issue entitled 'Trends in neuropharmacology: in memory of Erminio Costa'.

Potent neuroprotective effects of novel structural derivatives of valproic acid: potential roles of HDAC inhibition and HSP70 induction.

Emerging evidence suggests that the neuroprotective effects of valproic acid (VPA) occur via inhibition of histone deacetylases (HDACs) and activation of gene expression. This study assessed the ability of four VPA derivatives to cause histone hyperacetylation and protect against glutamate-induced excitotoxicity in cultured neurons. We found that (S)-2-pentyl-4-pentynoic acid (compound III) and (+/-)-2-hexyl-4-pentynoic acid (compound V) were far more potent and robust than VPA in inducing histone hyperacetylation and protecting against glutamate excitotoxicity. Thus, the increase in histone acetylation elicited by compounds III and V was significant at 5microM and reached a maximal increase of 600-700% at 50-100microM, compared with only a 200% increase by VPA at 100microM. The neuroprotective effects of compounds III and V were evident at 10-25microM and reached a complete protection at 50-100microM, while a significant partial protection by VPA was observed at 100microM. These two compounds were also more effective than VPA in increasing HSP70-1a and HSP70-1b mRNA levels. At 50microM, compound V was most robust in increasing HSP-1a mRNA levels, followed by compound III, and then by VPA. HSP-1b mRNA was only significantly upregulated by compounds V and III, but not by VPA or other VPA derivatives under these treatment conditions. Our results suggest that these two VPA derivatives may ultimately be developed into potent neuroprotective drugs in preclinical and clinical studies.

Multiple roles of HDAC inhibition in neurodegenerative conditions.

Histone deacetylases (HDACs) play a key role in homeostasis of protein acetylation in histones and other proteins and in regulating fundamental cellular activities such as transcription. A wide range of brain disorders are associated with imbalances in protein acetylation levels and transcriptional dysfunctions. Treatment with various HDAC inhibitors can correct these deficiencies and has emerged as a promising new strategy for therapeutic intervention in neurodegenerative disease. Here, we review and discuss intriguing recent developments in the use of HDAC inhibitors to combat neurodegenerative conditions in cellular and disease models. HDAC inhibitors have neuroprotective, neurotrophic and anti-inflammatory properties; improvements in neurological performance, learning/memory and other disease phenotypes are frequently seen in these models. We discuss the targets and mechanisms underlying these effects of HDAC inhibition and comment on the potential for some HDAC inhibitors to prove clinically effective in the treatment of neurodegenerative disorders.