Ashok Kumar Datusalia

Amelioration of diabetes-induced neurobehavioral and neurochemical changes by melatonin and nicotinamide: Implication of oxidative stress–PARP pathway

Diabetes associated hyperglycemia results in generation of reactive oxygen species which induces oxidative stress and initiate massive DNA damage leading to overactivation of poly (ADP-ribose) polymerase (PARP). In this study, we have elucidated the involvement of oxidative stress-PARP pathway using pharmacological interventions (melatonin, as an anti-oxidant and nicotinamide, as a PARP inhibitor) in diabetes-induced neurobehavioral and neurochemical alterations. Sprague-Dawley rats were rendered diabetic by a single intraperitoneal injection of streptozotocin. Behavioral and cognitive deficits were assessed after 8weeks of diabetes induction using a functional observation battery, passive avoidance and rotarod test. Acetylcholinesterase activity was significantly decreased in hippocampus of diabetic rats as compared to control rats. Diabetic animals showed significant increase in malondialdehyde levels and reduction in NAD levels in hippocampus. Glutamate and GABA levels were also altered in hippocampus of the diabetic animals. Two week treatment with melatonin (3 and 10mg/kg) and nicotinamide (300 and 1000mg/kg) alone and in combination significantly improved the neurobehavioral parameters which were altered in diabetes. Neurotransmitter (glutamate and GABA) levels were improved by these interventions. Our results emphasize that simultaneous inhibition of oxidative stress-PARP overactivation cascade can be beneficial in treatment of diabetes associated CNS changes.

Reversal of neurobehavioral and neurochemical alterations in STZ-induced diabetic rats by FeTMPyP, a peroxynitrite decomposition catalyst and 1,5-Isoquinolinediol a poly(ADP-ribose) polymerase inhibitor

Abstract Objective: In this study, we have evaluated the involvement of nitrosative stress and poly-ADP ribosyl polymerase (PARP) in diabetes induced neurobehavioral and neurochemical changes using pharmacological agents peroxynitrite decomposition catalyst (FeTMPyP) and a PARP inhibitor (1,5-Isoquinolinediol) in diabetic brains. Methods: The extent of neurobehavioral changes was assessed by functional observation battery, motor coordination activity (rota rod performance) and passive avoidance test. Neurochemical changes were assessed by measuring nicotinamide adenine dinucleotide (NAD), malondialdehyde, acetylcholinesterase, neurotransmitters (GABA and glutamate) levels in the hippocampus. GABA and glutamate were measured by high-performance liquid chromatography with electrochemical detection method. Results: Two weeks’ treatment with FeTMPyP (3 mg/kg, i.p.) and 1,5-Isoquinolinediol (3 mg/kg, i.p.) improved the cognitive deficits in diabetic rats as observed in passive avoidance test. Both the agents inhibited lipid peroxidation and improves the acetylcholinesterase level in the hippocampus. 1,5-Isoquinolinediol treatment also improves the NAD, neurotransmitter level in the hippocampus. Discussion: These results suggest that peroxynitrite decomposition catalyst and PARP inhibitor have beneficial effects in neurobehavioral alterations induced by diabetes. Improvement in neurobehavioral alteration may be attributed to reversal of neurotransmitter homeostasis deficits.

Reversal of diabetes-induced behavioral and neurochemical deficits by cinnamaldehyde

BACKGROUND Chronic hyperglycemia during diabetes is associated with altered cognitive function. Cinnamaldehyde showed to have many pharmacological activities indicating anti-diabetic, cognitive enhancer, antiinflammatory etc. In the present study, we have investigated the effects of cinnamaldehyde (CA) on diabetes-induced cognitive deficits. METHODS Diabetes was induced in Sprague Dawley rats using high fat diet followed by streptozotocin (35mg/kg, i.p.). High fat diet feeding was continued for 18 week after STZ administration. CA was administered daily during the last 3 weeks (week 16-18) at a doses of 10, 20 and 40mg/kg (p.o.). Animals were subjected to behavioral tests during 18th week. Neurotransmitter levels (glutamate and GABA), acetylcholine esterase (AChE) activity and inflammatory markers (TNF-α and IL-6) were assessed in the hippocampus and cortex. RESULTS Vehicle-treated diabetic rats showed impaired behavior in open field, elevated plus maze and water maze test compared to age-matched control rats. Cinnamaldehyde showed significant reduction in blood glucose levels at dose of 20 and 40mg/kg. Three weeks treatments of cinnamaldehyde showed significant amelioration of behavioral deficits in diabetic rats. Chronic treatment with cinnamaldehyde showed improvement in brain ChE activity, neurotransmitter levels and reduction in IL-6 and TNF-α levels. CONCLUSION The present study demonstrates that treatment with cinnamaldehyde reverse neuroinflammation and changes in neurotransmitter levels, and consequently improves behavioral deficits in diabetic rats.

NF-κB Inhibition Resolves Cognitive Deficits in Experimental Type 2 Diabetes Mellitus through CREB and Glutamate/GABA Neurotransmitters Pathway.

Diabetes is associated with deficits in memory and cognitive functions and sustained inflammation. Recently, involvement of NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) has been postulated in many cognitive functions, immune system and inflammation. Despite of role of NF-κB in inflammation, a large gap remains in understanding of the mechanisms and consequences of NF-κB activation in the central nervous system.In this study, we have evaluated the effects of NF-κB activation inhibitor on memory function, neurotransmitter levels changes and brain inflammatory cytokines in type-2 diabetic rats. BAY 11-7082 (BAY) was used as a pharmacological inhibitor of IκBα (inhibitor of kappa B alpha) phosphorylation to block NF-κB activation. Type-2 diabetic rats showed significant memory impairment at 15(th) week. Three weeks BAY treatment produced significant increase in Morris water maze test learning and memory performance. Diabetic animals also showed improved performance in passive avoidance and Y-maze test paradigm following treatment with NF-κB inhibitor BAY. BAY treatment did not show any significant effect on blood glucose and insulin levels. NF-κB inhibition significantly reduced neuroinflammation as evidenced by decrease in IL-6 and TNF-α levels. BAY treatment in diabetic rats also increased the phosphorylation of CREB which indicates that the NF-κB activation inhibitor engage a CREB regulated mechanism in-vivo. Moreover, BAY also reversed the alterations in brain glutamate and GABA levels in diabetic rats. These findings corroborate that NF-κB inhibition may be an effective treatment strategy in diabetes associated cognitive deficits.

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.

Refolded Recombinant Human Paraoxonase 1 Variant Exhibits Prophylactic Activity Against Organophosphate Poisoning

Organophosphate (OP) compounds are neurotoxic chemicals, and current treatments available for OP-poisoning are considered as unsatisfactory and inadequate. There is an urgent need for the development of more effective treatment(s) for OP-poisoning. Human paraoxonase 1 (h-PON1) is known to hydrolyze a variety of OP-compounds and is a leading candidate for the development of prophylactic and therapeutic agent against OP-poisoning in humans. Non-availability of effective system(s) for the production of recombinant h-PON1 (rh-PON1) makes it hard to produce improved variant(s) of this enzyme and analyze their in vivo efficacy in animal models. Production of recombinant h-PON1 (rh-PON1) using an Escherichia coli expression system is a key to develop variant(s) of h-PON1. Recently, we have developed a procedure to produce active rh-PON1 enzymes by using E. coli expression system. In this study, we have characterized the OP-hydrolyzing properties of refolded rh-PON1(wt) and rh-PON1(H115W;R192K) variant. Our results show that refolded rh-PON1(H115W;R192K) variant exhibit enhanced OP-hydrolyzing activity in in vitro and ex vivo assays and exhibited prophylactic activity in mouse model of OP-poisoning, suggesting that refolded rh-PON1 can be developed as a therapeutic candidate.

Combined and individual strategy of exercise generated preconditioning and low dose copper nanoparticles serve as superlative approach to ameliorate ISO-induced myocardial infarction in rats

BACKGROUND Myocardial infarction (MI) is a solitary fatal condition with towering prevalence of mortality worldwide. Our previous study reports that low-dose copper nanoparticles (CuNP) can halt the progression of diabetes-induced cardiotoxicity as copper has anti-inflammatory, anti-proliferative and anti-oxidant potential. In addition, exercise training has also been considered a hallmark for cardiac health. METHOD Cardioprotective potential of CuNP (1mg/kg/day, po, 4 weeks) and exercise (swimming, 90min, 5days/4 weeks) either alone or in combination was estimated by measuring the surge in serum nitrite/nitrate concentration and reduction in creatine kinase MB (CKMB), lactate dehydrogenase (LDH), cardiac troponin I (cTnI), lipid profile, oxidative stress, structural abnormalities against isproterenol (ISO)-induced MI. RESULTS ISO significantly increased CKMB, LDH, cTnI, lipid alteration, oxidative stress, structural abnormalities and decrease nitrite/nitrate concentration in serum. Quantitative estimation of total and phosphorylated Akt(SER-473)/GSK-3b(SER-9) indicated the significant reduction in pAkt and pGSK-3b in ISO treated animal. Individual and combined treatment of CuNP and exercise significantly reduce ISO -induced CKMB, cTnI, LDH, and improve nitrite/nitrate concentration and lipid profile. Attenuation of myocardial oxidative stress and serum TBARS revealed the associated preconditioning effect of exercise and CuNP against oxidative stress. Exercise and CuNP also showed the protective potential against structural abnormalities. However, the cardioprotective effect of individual and combined strategy of exercise and CuNP was vanished by wortmannin and also avoid the downregulation of pGSK-3b. CONCLUSION Low-dose CuNP and exercise training significantly prevents ISO-induced MI through preconditioning and GSK-3b inhibition. Ability to upsurge the NO level, lipid profile and reduced oxidative stress improve the potency of combined strategy.

Exercise preconditioning and low dose copper nanoparticles exhibits cardioprotection through targeting GSK-3β phosphorylation in ischemia/reperfusion induced myocardial infarction

BACKGROUND Drinking water from copper vessels and aerobic exercise have been the known facts for cardioprotection. Our previous report explored the significant cardioprotective potential of copper and exercise training by increasing phosphorylation of GSK-3β and anti-oxidant potential. OBJECTIVE Present study focuses the therapeutic potential of CuNP and exercise training through their molecular interaction with GSK-3β, inflammatory cytokinin, oxidative stress and necrosis. METHODS The Myocardial damage was assessed by estimating the serum nitrite/nitrate concentration, increased CKMB, LDH, cTnI level, oxidative stress, inflammatory cytokinin and structural abnormalities in I/R insulted rats. Expression of Akt/pAkt and GSK-3β/pGSK-3β was measured by western blotting. RESULT Treatment with CuNP (1 mg/kg/day, p.o., 4 weeks) and exercise training (swimming, 90 min/4 weeks) either alone or in combination markedly reduced I/R induced myocardial damage by attenuating biochemical and structural alteration. A significant reduction in oxidative stress and inflammatory mediators were observed in CuNP and exercise training treatment against I/R insulted rats. Moreover, improved serum NO bioavailability was observed in CuNP and exercise treated rats. Wortmannin associated blockage of cardioprotection induced by CuNP and exercise training and up-regulation of pAkt and pGSK-3β in I/R insulted heart confirmed the GSK-3β phosphorylation potential of CuNP and exercise training and -associated cardioprotection. CONCLUSION Treatment with CuNP and exercise training either alone or in combination favourably phosphorylate GSK-3β kinase pathways and further diminish oxidative stress, inflammatory cytokines, apoptosis and increase serum bioavailability of NO in the I/R insulted rats which tends to protect myocardial damage.

Hyper-insulinemia increases the glutamate-excitotoxicity in cortical neurons: A mechanistic study

Abstract Insulin resistance in type‐2 diabetic condition increases the risk of stroke and cognitive deficits in which involvement of glutamate has been postulated. It has been hypothesized that hyper‐insulinemia in cortical neurons increases the vulnerability towards glutamate‐induced excitotoxicity. To mimic insulin resistance, cortical neurons were incubated with high insulin (1 &mgr;M) and high glucose (50 mM final concentration) in in‐vitro condition for 24 h. Pre‐treatment of cortical neurons with high insulin blocked acute insulin‐induced activation of Akt and GSK‐3&bgr; but not in the case of high glucose. Our results demonstrate that chronic high insulin exposure increases glutamate‐induced excitotoxity, which was blocked by insulin receptor antagonist (S961) and GSK‐3&bgr; inhibitor (SB216763). These inhibitors also ameliorated pAkt (Ser473) and pGSK‐3&bgr;(Ser9) levels after chronic insulin exposure. Increase in glutamate‐excitotoxicity in insulin‐resistant cortical neurons was found to be associated with increased expression of PICK1. However, GluR2 did not get altered in hyper‐insulinemia condition. This study demonstrates that hyper‐insulinemia increases glutamate excitotoxicity which could be attributed to activation of GSK‐3&bgr; and increased expression of PICK1.

A Retrospect Study on Thiazole Derivatives as the Potential Antidiabetic Agents in Drug Discovery and Developments

BACKGROUND Heterocycles containing thiazole, a moiety with sulfur and nitrogen is a core structure which is found in a number of biologically active compounds. The thiazole ring is notable as a component of the certain natural products, such as vitamin B1 (thiamine) and penicillins. Thiazole is also known as wonder nucleus and has uses in different biological fields. A number of new compounds contain heterocycle thiazole moieties, thus it is one of the important areas of research. METHODS We searched the scientific database using relevant keywords. Among the searched literature only peer-reviewed papers were collected which addresses our questions. The retrieved quality research articles were screened and analyzed critically. The key findings of these studies were included along with their importance. RESULTS The quality research articles included in this review were selected for the lifethreatening diseases i.e. diabetes, which is one of the serious issues all over the globe with an estimated worldwide prevalence in 2016 of 422 million people, which is expected to rise double to by 2030. Since 1995, there has been an explosion of the introduction of new classes of pharmacological agents having thiazole moieties. However, most of the drugs can cause noncompliance, hypoglycemia, and obesity. Thus, new antidiabetic drugs with thiazole moieties came up with improved compliance and reduced side effects such as pioglitazone (Actos), rosiglitazone (Avandia), netoglitazone, DRF-2189, PHT46, PMT13, DRF-2519. With such a great importance, research in thiazole is part of many academic and industrial laboratories worldwide. CONCLUSION The present review describes the importance of thiazole nucleus and its derivatives as antidiabetic agents with an emphasis on the past as well as recent developments.