Rajeev Taliyan

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.

Possible involvement of α1-adrenergic receptor and KATP channels in cardioprotective effect of remote aortic preconditioning in isolated rat heart

Background: Remote preconditioning is a phenomenon in which brief episodes of ischemia and reperfusion to remote organs protect the target organ against sustained ischemia/reperfusion (I/R)-induced injury. Protective effects of remote aortic preconditioning (RAPC) are well established in the heart, but their mechanisms still remain to be elucidated. Objective: This study has been designed to investigate the possible involvement of α-1-adrenergic receptor (AR) and KATP channels in cardio-protective effect of RAPC in isolated rat heart. Materials and Methods: Four episodes of ischemia and reperfusion, each comprising of 5 min occlusion and 5 min reperfusion, were used to produce RAPC. Isolated perfused rat heart was subjected to global ischemia for 30 min followed by reperfusion for 120 min. Coronary effluent was analyzed for LDH and CK-MB release to assess the degree of cardiac injury. Myocardial infarct size was estimated macroscopically using TTC staining. Results: Phenylephrine (20 μ/kg i.p.), as α-1-AR agonist, was noted to produce RAPC-like cardio-protection. However, administration of glibenclamide concomitantly or prior to phenylephrine abolished cardioprotection. Moreover, prazocin (1 mg/kg. i.p), as α-1-AR antagonist and glibenclamide (1 mg/kg i.p), a KATP channel blocker, abolished the cardioprotective effect of RAPC. Conclusion: These data provide the evidence that α-1-AR activation involved in cardioprotective effect of RAPC-mediated trough opening of KATP channels.

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.

Protective effect and mechanism of Ginkgo biloba extract-EGb 761 on STZ-induced diabetic cardiomyopathy in rats

Diabetes mellitus (DM) is a complex metabolic disorder which leads to development of various long-term complications including cardiomyopathy. Oxidative stress due to hyperglycemia plays a key role in the development and progression of diabetic cardiomyopathy (DC). Oxidative stress causes the opening of mitochondrial permeability transition pore (mPTP) eventually leading to myocardium dysfunction. The Ginkgo biloba extract (EGb 761) has antioxidant and mitochondrial membrane potential stabilizing property. Therefore, this study was designed to evaluate the effect of EGb 761 and its possible mechanism of action in DC. Materials and Methods: DM was induced by single injection of Streptozotocin (STZ) (50 mg/kg, i.p.) and cardiac dysfunction was developed on 8th weeks after STZ injection. Cardiac dysfunction was assessed by measuring left ventricle weight/body weight (LVW/BW) ratio, left ventricle (LV) collagen content, LV protein content, serum lactate dehydrogenase (LDH) level. Results: EGb 761 treatment (started after 7th week of STZ injection and continued for 3 weeks) attenuated cardiac dysfunction in diabetic rats as evidenced by a decrease in LV collagen content, protein content, LVW/BW ratio, serum LDH level. Moreover, EGb 761 attenuated the oxido-nitrosative stress (thiobarbituric acid reactive substances, superoxide anion generation, myocardium nitrite) and concomitantly improved the antioxidant enzyme (reduced glutathione) level as compared to untreated diabetic rats. However, protective effect of EGb 761 was inhibited by atractyloside (mPTP opener) that was given for 3 weeks, 30 min before the EGb 761 treatment. These results indicate that EGb 761 corrects diabetic cardiac dysfunction probably by its direct radical scavenging activity and its ability to inhibit the opening of mPTP channel since the cardioprotective effect of EGb 761 was completely abolished by atractyloside.

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.

Neuroprotective effect of hydroxy safflor yellow A against cerebral ischemia-reperfusion injury in rats: putative role of mPTP.

Abstract Background: Hydroxy safflor yellow A (HSYA) has been translated clinically for cardiovascular diseases. HSYA is also greatly acknowledged for its protective effects against cerebral ischemic-reperfusion (I/R) injury. Although the precise mechanism of cerebral I/R injury is not fully understood, oxygen-derived free radicals and mitochondrial permeability transition pore (mPTP) opening during I/R injury are widely recognized as an important contributor to neuronal injury. Thus, we speculated that the neuroprotective effects of HSYA against cerebral I/R injury may be associated with mPTP modulation. Methods: Induction of I/R injury was achieved by 60 min of middle cerebral artery occlusion, followed by reperfusion for 24 h. For behavior and cognitive assessment, neurological scoring (NSS), rotarod, and Y-maze task were performed. Oxidative damage was measured in terms of markers such as malondialdehyde, reduced glutathione, and catalase levels and cerebral infarct volumes were quantified using 2,3,5-triphenyl tetrazolinium chloride staining. I/R injury-induced inflammation was determined using tumor necrosis factor-α (TNF-α) levels. Results: Animals exposed to I/R injury showed neurological severity, functional and cognitive disability, elevated oxidative markers, and TNF-α levels along with large infarct volumes. HSYA treatment during onset of reperfusion ameliorated performance in NSS, rotarod and Y-maze attenuated oxidative damage, TNF-α levels, and infarction rate. However, treatment with carboxyatractyloside, an mPTP opener, 20 min before HSYA, attenuated the protective effect of HSYA. Conclusions: Our study confirmed that protective effect of HSYA may be conferred through its free radical scavenger action followed by inhibiting the opening of mPTP during reperfusion and HSYA might act as a promising therapeutic agent against cerebral I/R injury.

Remote limb ischemic post conditioning during early reperfusion alleviates cerebral ischemic reperfusion injury via GSK-3β/CREB/ BDNF pathway

Abstract Remote limb ischemic post conditioning (RIPOC) has been reported to attenuate cerebral ischemic reperfusion (I/R) injury, while the molecular mechanisms remain elusive. Various studies have highlighted the involvement of glycogen synthase kinase (GSK‐3&bgr;) in cerebral I/R injury and cognitive disorders. Hence, the present study was designed to explore the role of GSK‐3&bgr; and its downstream regulators in RIPOC mediated neuroprotection against cerebral I/R injury and associated cognitive impairment. Male Wistar rats are randomly assigned into four groups: Sham, bilateral common carotid arteries occlusion (BCCAO), RIPOC and BCCAO+RIPOC. BCCAO was achieved by transient occlusion of bilateral common carotid arteries for 20 min, followed by reperfusion. Non‐invasive RIPOC was induced by 3 cycles each of 10 min occlusion and reperfusion of both femoral arteries by using tourniquets, during early reperfusion phase. A battery of behavioral and cognitive tests were performed. Biochemical estimation of oxidative markers, anti‐oxidants and pro‐inflammatory markers were estimated. Levels of GSK‐3&bgr;, CREB and BDNF were estimated to confirm the molecular mechanism. Hippocampal structural abnormalities were confirmed by H and E staining. The neurobehavioral analysis revealed that neurological and cognitive deficits caused by BCCAO, were reduced by RIPOC intervention. Meanwhile, the results of biochemical tests suggested that RIPOC attenuates the BCCAO induced oxidative damage, neuroinflammation and hippocampal structural abnormalities. Further, RIPOC prevented the elevation of BCCAO induced GSK‐3&bgr;. RIPOC exerts neuroprotective effect against I/R injury, putatively by attenuating GSK‐3&bgr; expression and upregulating the levels of CREB and BDNF.

Delayed neuroprotection against cerebral ischemia reperfusion injury: putative role of BDNF and GSK-3β.

Abstract Aim: Numerous studies have demonstrated the possible neuroprotective role of lithium treatment against neurological disorders. However, the role of lithium in delayed phase of neuronal death against focal ischemia has not been explored. Therefore, the present study was designed to investigate the effect and molecular mechanisms of post-lithium treatment against cerebral ischemic reperfusion (I/R) injury and associated cognitive deficits in rats. Methods: I/R injury was induced by right middle cerebral artery occlusion and lithium (40 and 60 mg/kg) were given intraperitoneally, 24 h after the insult and continued for 1 week with 24-h interval. Using Lasser Doppler, cerebral blood flow was monitored before, during and after MCAO induction. Besides behavioral, biochemical, and histological evaluation, levels of tumor necrosis factor alpha (TNF-α) and brain-derived neurotrophic factor (BDNF) were also estimated. Results: I/R injury resulted in significant elevation of neurological deficits, oxidative stress, neuroinflammation, and cognitive impairments. We found that lithium injection, 24 h after I/R-injury continued for 1 week, dose dependently prevented behavioral abnormality and cognitive impairments. Moreover, lithium attenuated the levels of oxidative stress and pro-inflammatory-cytokines TNF-α level. Further, lithium treatments significantly reduced neuronal damage and augmented healthy neuronal count and improved neuronal density in hippocampus. These neuroprotective effects of delayed lithium treatment were associated with upregulation of neurotrophic factor BDNF levels. Conclusion: Delayed lithium treatment provides neuroprotection against cerebral I/R injury and associated cognitive deficits by upregulating BDNF expression that opens a new avenue to treat I/R injury even after active cell death.

Evaluation of thyroid hormone induced pharmacological preconditioning on cardiomyocyte protection against ischemic-reperfusion injury

Objectives: Ischemic preconditioning (IPC) has been demonstrated to make myocardium transiently more resistant to deleterious effect of prolonged ischemia. The opening of the mitochondrial permeability transition pore (mPTP) at the time of myocardial reperfusion is a critical determinant of cell death. L-thyroxine pre-treatment increases the tolerance of the heart to ischemia and produces cardioprotection similar to ischemic precondition. This study has been designed to investigate the mechanism involved in L-thyroxine-induced cardiomyocyte protection against ischemia-reperfusion (I/R) injury in rats. Materials and Methods: L-thyroxine (T4) was administered to Wistar rats (n=6) (25 μg/100 g/day s.c.) for two weeks. Hearts from normal and L-thyroxine-treated rats were perfused in Langendorffs mode and subjected to 30 min of ischemia followed by 120 min of reperfusion. Myocardial infarct size was estimated by triphenyltetrazolium chloride (TTC) staining and lactate dehydrogenase (LDH) and creatine kinase-MB (CK-MB) was analyzed in coronary effluent. Results: IPC and pharmacological preconditioning (PPC) significantly decreased (P<0.05) myocardial infarct size, release of LDH and CK-MB in rat heart. Perfusion of atractyloside, an opener of mPTP, significantly (P<0.05) attenuated the cardioprotective effect of IPC and L-thyroxine-induced pharmacological preconditioning (PPC) in normal rat heart. Conclusion: The cardioprotective effect of L-thyroxine-induced preconditioning may be mediated through inhibition of mPTP opening during reperfusion phase.