Central Drug Research Institute CDRI

Lucknow, India

Central Drug Research Institute CDRI

Lucknow, India
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Shegokar R.,Free University of Berlin | Shaal L.A.L.,Free University of Berlin | Mishra P.R.,Central Drug Research Institute CDRI
Pharmazie | Year: 2011

Gene silencing by RNA interference is a rapidly growing therapeutic area for managing diseases. Despite research advances in this direction, the poor cellular uptake of synthetic small interfering RNAs is a major impediment to their clinical applications. Polymer and lipid-based systems are attractive carrier systems for delivery of siRNA and provide options for desirable engineering of carrier particles. In this review, there is a detailed discussion of RNAi delivery systems and recent advances in the field.

Dubey P.K.,Strides Arcolab Ltd | Singodia D.,Central Drug Research Institute CDRI | Vyas S.P.,Dr Hari Singh Gour University
Journal of Drug Targeting | Year: 2010

YIGSR peptide anchored sterically stabilized liposomes (YIGSR-SL) were investigated for selective and preferential presentation of carrier contents at angiogenic endothelial cells overexpressing laminin receptors on and around tumor tissue and thus for assessing their targetabilty. In vitro endothelial cell binding of liposomes exhibited 7-fold higher binding of YIGSR-SL to HUVEC in comparison to the nontargeted sterically stabilized liposomes (SL). Spontaneous lung metastasis and angiogenesis assays show that YIGSR peptide anchored liposomes are significantly (P ≤ 0.01) effective in the prevention of lung metastasis and angiogenesis compared to free 5-fluorouracil (5-FU) and SL. YIGSR-SL was very effective in regression of tumors in BALB/c mice bearing B16F10 melanoma cells. Results indicate that YIGSR peptide anchored sterically stabilized liposomes bearing 5-FU are significantly (P ≤ 0.01) active against primary tumor and metastasis than the SL and free drug. Thus, YIGSR peptide anchored sterically stabilized liposomes hold potential of targeted cancer chemotherapeutics. © 2010 Informa UK Ltd.

Kamat P.K.,University of Louisville | Kalani A.,University of Louisville | Rai S.,Central Drug Research Institute CDRI | Swarnkar S.,Scripp Institute | And 3 more authors.
Molecular Neurobiology | Year: 2016

Synapses are formed by interneuronal connections that permit a neuronal cell to pass an electrical or chemical signal to another cell. This passage usually gets damaged or lost in most of the neurodegenerative diseases. It is widely believed that the synaptic dysfunction and synapse loss contribute to the cognitive deficits in patients with Alzheimer’s disease (AD). Although pathological hallmarks of AD are senile plaques, neurofibrillary tangles, and neuronal degeneration which are associated with increased oxidative stress, synaptic loss is an early event in the pathogenesis of AD. The involvement of major kinases such as mitogen-activated protein kinase (MAPK), extracellular receptor kinase (ERK), calmodulin-dependent protein kinase (CaMKII), glycogen synthase-3β (GSK-3β), cAMP response element-binding protein (CREB), and calcineurin is dynamically associated with oxidative stress-mediated abnormal hyperphosphorylation of tau and suggests that alteration of these kinases could exclusively be involved in the pathogenesis of AD. N-methyl-d-aspartate (NMDA) receptor (NMDAR) activation and beta amyloid (Aβ) toxicity alter the synapse function, which is also associated with protein phosphatase (PP) inhibition and tau hyperphosphorylation (two main events of AD). However, the involvement of oxidative stress in synapse dysfunction is poorly understood. Oxidative stress and free radical generation in the brain along with excitotoxicity leads to neuronal cell death. It is inferred from several studies that excitotoxicity, free radical generation, and altered synaptic function encouraged by oxidative stress are associated with AD pathology. NMDARs maintain neuronal excitability, Ca2+ influx, and memory formation through mechanisms of synaptic plasticity. Recently, we have reported the mechanism of the synapse redox stress associated with NMDARs altered expression. We suggest that oxidative stress mediated through NMDAR and their interaction with other molecules might be a driving force for tau hyperphosphorylation and synapse dysfunction. Thus, understanding the oxidative stress mechanism and degenerating synapses is crucial for the development of therapeutic strategies designed to prevent AD pathogenesis. © 2014, Springer Science+Business Media New York.

Kamat P.K.,University of Louisville | Rai S.,Central Drug Research Institute CDRI | Swarnkar S.,Scripps Research Institute | Shukla R.,Central Drug Research Institute CDRI | Nath C.,Central Drug Research Institute CDRI
Molecular Neurobiology | Year: 2014

Okadaic acid (OKA), a polyether C38 fatty acid toxin extracted from a black sponge Hallichondria okadaii, is a potent and selective inhibitor of protein phosphatase, PP1 and PP2A. OKA has been proved to be a powerful probe for studying the various regulatory mechanisms and neurotoxicity. Because of its property to inhibit phosphatase activity, OKA is associated with protein phosphorylation; it is implicated in hyperphosphorylation of tau and in later stages causes Alzhiemer’s disease (AD)-like pathology. AD is a progressive neurodegenerative disorder, pathologically characterized by extracellular amyloid beta (Aβ) plaques and intracellular neurofibrillary tangles (NFTs). The density of tau tangles in AD pathology is associated with cognitive dysfunction. Recent studies have highlighted the importance of serine/threonine protein phosphatases in many processes including apoptosis and neurotoxicity. Although OKA causes neurotoxicity by various pathways, the exact mechanism is still not clear. The activation of major kinases, such as Ser/Thr, MAPK, ERK, PKA, JNK, PKC, CaMKII, Calpain, and GSK3β, in neurons is associated with AD pathology. These kinases, associated with abnormal hyperphosphorylation of tau, suggest that the cascade of these kinases could exclusively be involved in the pathogenesis of AD. The activity of serine/threonine protein phosphatases needs extensive study as these enzymes are potential targets for novel therapeutics with applications in many diseases including cancer, inflammatory diseases, and neurodegeneration. There is a need to pay ample attention on MAPK kinase pathways in AD, and OKA can be a better tool to study cellular and molecular mechanism for AD pathology. This review elucidates the regulatory mechanism of PP2A and MAPK kinase and their possible mechanisms involved in OKA-induced apoptosis, neurotoxicity, and AD-like pathology. © 2014, Springer Science+Business Media New York.

Ali M.,Jamia Hamdard University | Afzal M.,Dabur India Ltd | Bhattacharya S.M.,Central Drug Research Institute CDRI | Ahmad F.J.,All India Institute of Medical Sciences | Dinda A.K.,Jamia Hamdard University
Expert Opinion on Drug Delivery | Year: 2013

Introduction: Currently emphasized conventional chemotherapies for the elimination of lymphatic filariasis (LF) are imperfect due to unfocused targeting of poorly water-soluble antifilarial drugs. The profound location of drug targets (filarial parasites or wolbachia) within the complex anatomy of lymphatic tissues often necessitates prolonged treatment schedules with high doses leading to undesired side effects and poor patient compliance. Therefore, we need to reformulate antifilarial drugs taking the advantages of nanotechnology through a wide range of nanomedical carriers, which improve drug efficacy, increase bioavailability, and diminish toxicity. Areas covered: Connotations of drug delivery systems (DDSs) to target lymphatic filaroids or wolbachia and systemic microfilaria have been discussed. The potentials of liposomes and solid lipid nanoparticles for the treatment of LF are highlighted. Various critical factors, viz optimal size range, surface properties, preferred pH, mechanism of reticuloendothelial avoidance, and control of the release of antifilarial agents for safe elimination of parasites, are enclosed to design a novel DDS for LF. The review of nanotechnological approaches to improve antifilarial chemotherapy will help to resolve existing technological gaps. Expert opinion: Precincts in the antifilarial discovery programs can never be overcome by conventional methods. Nanomedicine encompasses wide-range solution for each single problem (i.e., from poor solubility to nonspecific targeting of antifilarial agents) for the cure of LF at low costs and may reduce the economic burden of LF diseases. Advances in nanotechnology loom will certainly come forward as silver bullets in the near future for quick diagnosis, control, and elimination of this tropically neglected disease. © 2013 Informa UK, Ltd.

Kamat P.K.,Central Drug Research Institute CDRI | Tota S.,Central Drug Research Institute CDRI | Shukla R.,Central Drug Research Institute CDRI | Ali S.,Jamia Hamdard University | And 2 more authors.
Pharmacology Biochemistry and Behavior | Year: 2011

Mitochondrial abnormalities have been identified in a large proportion of neurodegenerative diseases. Recently we have reported that intracerebroventricular (ICV) administration of okadaic acid (OKA) causes memory impairment in rat. However involvement of mitochondrial function in OKA induced memory impairment and neuronal damage has not been determined. OKA (200 ng) was administered by ICV route. After 13th day of OKA administration memory function was evaluated by Morris Water Maze test. Following completion of behavioral studies on 16th day, mitochondrial membrane potential, Ca 2+ and reactive oxygen species were evaluated in mitochondrial preparation of cortex, hippocampus, striatum and cerebellum of rat brain. While ATP, mitochondrial activity, lipid peroxidation and nitrite were investigated in synaptosomal preparation of rat brain areas. The activities and mRNA expression of apoptotic factors, caspase-3 and caspase-9, were studied in rat brain regions. The neuronal damage was also confirmed by histopathological study. OKA treated rats showed memory impairment including increased Ca 2+ and reactive oxygen species and decreased mitochondrial membrane potential, ATP and mitochondrial activity in mitochondrial preparation. There was a significant increase in lipid peroxidation and nitrite in synaptosomal preparations. Preventive treatment daily for 13 days with antidementic drugs, donepezil (5 mg/kg, p.o) and memantine (10 mg/kg, p.o), significantly attenuated OKA induced mitochondrial dysfunction, apoptotic cell death, memory impairment and histological changes. Mitochondrial dysfunction appeared as a key factor in OKA induced memory impairment and apoptotic cell death. This study indicates that clinically used antidementic drugs are effective against OKA induced adverse changes at behavioral, cellular, and histological levels and mitochondrial dysfunction. © 2011 Elsevier B.V. All rights reserved.

Kamat P.K.,Central Drug Research Institute CDRI | Tota S.,Central Drug Research Institute CDRI | Saxena G.,Central Drug Research Institute CDRI | Shukla R.,Central Drug Research Institute CDRI | Nath C.,CSIR - Central Electrochemical Research Institute
Brain Research | Year: 2010

Okadaic acid (OKA) is a potent and selective inhibitor of protein phosphatases, PP2A and PP1. In the present study, we evaluated effect of intracerebroventricular (ICV) bilateral injection of OKA (100 and 200 ng) on memory function and oxidative stress in rats. ICV injection of OKA (200 ng) produced memory impairment as evidenced by no significant decrease in latency time to reach the hidden platform in water maze test. It produced increase in malondialdehyde (MDA), nitrite level, reactive oxygen species (ROS) generation, mitochondrial calcium ion [Ca2]i level and decreased glutathione (GSH) level in rat brain areas, indicating oxidative stress. Furthermore, we evaluated the effect of anti-dementia drugs memantine, a NMDA antagonist, and donepezil, a cholinesterase inhibitor, on OKA ICV induced memory impairment. Administration of memantine (10 mg/kg, p.o.) and donepezil (5 mg/kg, p.o.) for 13 days starting from the OKA injection improved performance in memory tests and also significantly restored GSH, MDA, nitrite levels, ROS generation and [Ca2+]i level. This study demonstrates that the clinically used anti-dementic drugs are effective in OKA induced free radical generation and memory impairment in rats. Thus, OKA ICV induced memory impairment in rat appeared as a useful test model to screen anti-dementia drugs. © 2009 Elsevier B.V. All rights reserved.

Shameem M.,CSIR - Central Electrochemical Research Institute | Shameem M.,Central Drug Research Institute CDRI | Patel A.B.,CSIR - Central Electrochemical Research Institute
PLoS ONE | Year: 2012

Background and Purpose: The effects of nicotine on cerebral metabolism and its influence on smoking behavior is poorly understood. An understanding of the chronic effects of nicotine on excitatory and inhibitory metabolic demand, and corresponding neurotransmission may provide clues for designing strategies for the optimal smoking cessation intervention. The objective of the current study was to investigate neuronal and astroglial metabolism in mice exposed to nicotine (0.5 and 2.0 mg/kg, sc) three times in a day for 4 weeks. Experimental Approach/Principal Findings: Metabolic measurements were carried out by co-infusing [U-13C6]glucose and [2-13C]acetate, and monitoring 13C labeling of amino acids in brain tissue extract using 1H-[13C] and 13C-[1H]-NMR spectroscopy. Concentration of 13C-labeled glutamate-C4 was increased significantly from glucose and acetate with chronic nicotine treatment indicating an increase in glucose oxidation by glutamatergic neurons in all brain regions and glutamate-glutamine neurotransmitter cycle in cortical and subcortical regions. However, chronic nicotine treatment led to increased labeling of GABA-C2 from glucose only in the cortical region. Further, increased labeling of glutamine-C4 from [2-13C]acetate is suggestive of increased astroglial activity in subcortical and cerebellum regions of brain with chronic nicotine treatment. Conclusions and Significance: Chronic nicotine exposure enhanced excitatory activity in the majority of brain regions while inhibitory and astroglial functions were enhanced only in selected brain regions. © 2012 Shameem, Patel.

Tyagi E.,Central Drug Research Institute CDRI | Agrawal R.,Central Drug Research Institute CDRI | Nath C.,Central Drug Research Institute CDRI | Shukla R.,Central Drug Research Institute CDRI
Innate Immunity | Year: 2010

This study investigated the influence of the cholinergic system on neuro-inflammation using nicotinic and muscarinic receptor agonists and antagonists. Intracerebroventricular (ICV) injection of lipopolysaccharide (LPS, 50 μg) was used to induce neuro-inflammation in rats and estimations of pro-inflammatory cytokines, α7 nicotinic acetylcholine receptor (nAChR) mRNA expression were done in striatum, cerebral cortex, hippocampus and hypothalamus at 24 h after LPS injection. Nicotine (0.2, 0.4 and 0.8 mg/kg, i.p.) or oxotremorine (0.2, 0.4 and 0.8 mg/kg, i.p.) were administered 2 h prior to sacrifice. We found that only nicotine was able to block the proinflammatory cytokines induced by LPS whereas, oxotremorine was found ineffective. Methyllycaconitine (MLA; 1.25, 2.5 and 5 mg/kg, i.p.), an α7 nAChR antagonist or dihydro-2-erythroidine (DH2E; 1.25, 2.5 and 5 mg/kg, i.p.), an α422 nAChR antagonist, was given 20 min prior to nicotine in LPS-treated rats. Methyllycaconitine antagonized the anti-inflammatory effect of nicotine whereas DH2E showed no effect demonstrating that α7 nAChR is responsible for attenuation of LPS-induced pro-inflammatory cytokines. This study suggests that the inhibitory role of the central cholinergic system on neuro-inflammation is mediated via α7 nicotinic acetylcholine receptor and muscarinic receptors are not involved. © 2010 SAGE Publications.

Kumar A.,Central Drug Research Institute CDRI | Gupta L.P.,Central Drug Research Institute CDRI | Kumar M.,Central Drug Research Institute CDRI
RSC Advances | Year: 2013

An efficient route for the synthesis of diaryl-pyridinium-azaarene- butenolate zwitterionic derivatives via metal-free, iodine-mediated C(sp 3)-H bond activation of alkyl-azaarenes on addition to the α,β-unsaturated carbonyls has been reported. This journal is © The Royal Society of Chemistry 2013.

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