Sorabh Sharma

Histone deacetylase inhibitors: Future therapeutics for insulin resistance and type 2 diabetes.

Insulin resistance is a common feature of obesity and predisposes the affected individuals to a variety of pathologies, including type 2 diabetes mellitus (T2DM), dyslipidemias, hypertension, cardiovascular disease etc. Insulin resistance is the primary cause of T2DM and it occurs many years before the disease onset. Although Thiazolidinediones (TZDs) such as rosiglitazone and pioglitazone are outstanding insulin sensitizers and are in clinical use since 1990s, however, their serious side effects such as heart attack and bladder cancer have limited their utilization. Thus, there is an unmet need to identify a new class of drugs with insulin sensitizing activity and minimal side effects. In the recent years, Histone deacetylase (HDAC) has emerged as a new molecular target in the control of insulin resistance and T2DM. The level of histone acetylation/deacetylation has been found to be altered during insulin resistance and T2DM conditions. HDAC inhibitors have been found to effectively manage insulin resistance and T2DM in various preclinical models and clinical trials. In this review we will focus on various aspects related to regulation of insulin signalling by HDACs and the future scope of HDAC inhibitors as therapeutics for insulin resistance.

Targeting histone deacetylases: a novel approach in Parkinson's disease.

The worldwide prevalence of movement disorders is increasing day by day. Parkinsons 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.

Beneficial effects of sodium butyrate in 6-OHDA induced neurotoxicity and behavioral abnormalities: Modulation of histone deacetylase activity

Parkinsons disease (PD) is the second most common neurodegenerative disorder. Recent studies have investigated the involvement of epigenetic modifications in PD. Histone deacetylase (HDAC) inhibitors have been reported to be beneficial in cognitive and motor deficit states. The present study was designed to investigate the effect of sodium butyrate, a HDAC inhibitor in 6-hydroxydopamine (6-OHDA) - induced experimental PD like symptoms in rats. To produce motor deficit, 6-OHDA was administered unilaterally in the right medial forebrain bundle. Three weeks after 6-OHDA administration, the rats were challenged with apomorphine. Following this, the animals were treated with sodium butyrate (150 and 300 mg/kg i.p.) once daily for 14 days. Movement abnormalities were assessed by battery of behavioral tests. Biochemically, oxidative stress markers, neuroinflammation and dopamine were measured in striatal brain homogenate. Further, to explore the molecular mechanism(s), we measured the level of global H3 histone acetylation and brain derived neurotrophic factor (BDNF). 6-OHDA administration results in significant motor deficit along with reduction in striatal dopamine level. 6-OHDA treated rats showed elevated oxidative stress and neuroinflammatory markers. Treatment with sodium butyrate results in significant attenuation of motor deficits and increased striatal dopamine level. Moreover, sodium butyrate treatment attenuated the oxidative stress and neuroinflammatory markers. These effects occur concurrently with increased global H3 histone acetylation and BDNF levels. Thus, the observed results of the present study are indicative for the therapeutic potential of HDAC inhibitors in PD.

Transcriptional dysregulation in Huntington’s disease: The role of histone deacetylases

Huntingtons disease (HD) is a progressive neurological disorder for which there are no disease-modifying treatments. Although, the exact underlying mechanism(s) leading to the neural cell death in HD still remains elusive, the transcriptional dysregulation is a major molecular feature. Recently, the transcriptional activation and repression regulated by chromatin acetylation has been found to be impaired in HD pathology. The acetylation and deacetylation of histone proteins is carried out by opposing actions of histone acetyl-transferases and histone deacetylases (HDACs), respectively. Studies carried out in cell culture, yeast, Drosophila and rodent model(s) have indicated that HDAC inhibitors (HDACIs) might provide useful class of therapeutic agents for HD. Clinical trials have also reported the beneficial effects of HDACIs in patients suffering from HD. Therefore, the development of HDACIs as therapeutics for HD has been vigorously pursued. In this review, we highlight and summarize the putative role of HDACs in HD like pathology and further discuss the potential of HDACIs as new therapeutic avenues for the treatment of HD.

The malleable brain: plasticity of neural circuits and behavior - a review from students to students

One of the most intriguing features of the brain is its ability to be malleable, allowing it to adapt continually to changes in the environment. Specific neuronal activity patterns drive long‐lasting increases or decreases in the strength of synaptic connections, referred to as long‐term potentiation and long‐term depression, respectively. Such phenomena have been described in a variety of model organisms, which are used to study molecular, structural, and functional aspects of synaptic plasticity. This review originated from the first International Society for Neurochemistry (ISN) and Journal of Neurochemistry (JNC) Flagship School held in Alpbach, Austria (Sep 2016), and will use its curriculum and discussions as a framework to review some of the current knowledge in the field of synaptic plasticity. First, we describe the role of plasticity during development and the persistent changes of neural circuitry occurring when sensory input is altered during critical developmental stages. We then outline the signaling cascades resulting in the synthesis of new plasticity‐related proteins, which ultimately enable sustained changes in synaptic strength. Going beyond the traditional understanding of synaptic plasticity conceptualized by long‐term potentiation and long‐term depression, we discuss system‐wide modifications and recently unveiled homeostatic mechanisms, such as synaptic scaling. Finally, we describe the neural circuits and synaptic plasticity mechanisms driving associative memory and motor learning. Evidence summarized in this review provides a current view of synaptic plasticity in its various forms, offers new insights into the underlying mechanisms and behavioral relevance, and provides directions for future research in the field of synaptic plasticity.

Epigenetics in neurodegenerative diseases: the role of histone deacetylases

BACKGROUND & OBJECTIVE Imbalance in histone acetylation levels and consequently the dysfunction in transcription are associated with a wide variety of neurodegenerative diseases. Histone proteins acetylation and deacetylation is carried out by two opposite acting enzymes, histone acetyltransferases and histone deacetylases (HDACs), respectively. In-vitro and in-vivo animal models of neurodegenerative diseases and post mortem brains of patients have been reported overexpressed level of HDACs. In recent past numerous studies have indicated that HDAC inhibitors (HDACIs) might be a promising class of therapeutic agents for treating these devastating diseases. HDACs being a part of repressive complexes, the outcome of their inhibition has been attributed to enhanced gene expression due to heightened histone acetylation. Beneficial effects of HDACIs has been explored both in preclinical and clinical studies of these diseases. Thus, their screening as future therapeutics for neurodegenerative diseases has been widely explored. CONCLUSION In this review, we focus on the putative role of HDACs in neurodegeneration and further discuss their potential as a new therapeutic avenue for treating neurodegenerative diseases.

High fat diet feeding induced insulin resistance exacerbates 6-OHDA mediated neurotoxicity and behavioral abnormalities in rats

ABSTRACT Some of the clinical reports suggest that insulin resistance could be a risk factor for Parkinsons disease (PD) development, however experimental data is scarce. Our previous work has suggested that insulin resistance could be an important factor that leads to diabetes associated neurodegeneration. In the present study, we evaluated whether insulin resistance is linked to PD pathology or not. For this purpose, we first standardized an animal model which could mimic the co‐morbid insulin resistance and PD condition. For development of insulin resistance, we fed the male Wistar rats with high fat diet (HFD) for eight weeks, followed by 6‐hydroxydopamine (6‐OHDA) administration, a toxin widely used for PD induction, in medial forebrain bundle (MFB) of rats. The 6‐OHDA treatment resulted in neuronal damage and loss of striatal dopamine level. This dopamine loss was correlated with impaired performance in behavioral tasks such as rotarod, narrow beam walk test and locomotor activity. Interestingly, we found that exposure to HFD exacerbated the effects of 6‐OHDA on striatal dopamine loss and behavioral parameters in rats, indicating that HFD‐induced insulin resistance is associated with a diminished capacity of dopaminergic neurons to cope with 6‐OHDA mediated neurotoxicity. Based upon these findings, it can be suggested that HFD feeding induced insulin resistance exacerbates the PD pathology. HIGHLIGHTSThe relationship of insulin resistance and PD pathology was studied.Insulin resistance may be an important modifiable risk factor for PD.HFD exacerbated the effects of 6‐OHDA on striatal dopamine loss and behavioral observations in rats.

AR-A014418, A GSK-3β INHIBITOR, ATTENUATES ALZHEIMER'S- LIKE PATHOLOGY IN HIGH FAT DIET-INDUCED COGNITIVE DEFICIT IN MICE

the underlying mechanisms involved. Results:Our ChIP analysis and luciferase reporter assays show that palmitate-induced SREBP1 activation directly regulates BACE1 expression at the transcriptional level. Knocking-down or ectopic expression of the dominant negative SREBP1 mutant significantly mitigated the palmitate-induced BACE1 expression and subsequent Ab genesis. Conclusions: Our study elucidates a novel signaling pathway and SREBP1 as a unique downstream effector of palmitate-induced up-regulation in BACE1 expression and subsequent Ab genesis.