A K Agrawal

Indian Institute of Toxicology Research, Lakhnau, Uttar Pradesh, India

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Publications (47)99.57 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Salsolinol (SAL), a catechol isoquinoline has invited considerable attention due to its structural similarity with dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Its high endogenous presence in Parkinsonian brain implicated its possible association with the disease process. SAL is also present in alcohol beverages and certain food materials and can get access to brain especially in conditions of immature or impaired BBB. Besides this, the effect of SAL on neural stem cells (NSCs) which are potential candidates for adult neurogenesis and transplantation mediated rejuvenating attempts for Parkinson's disease (PD) brain has not been known so far. NSCs in both the cases have to overcome suppressive cues of diseased brain for their survival and function.In this study we explored the toxicity of SAL towards NSCs focusing on apoptosis and status of PI3K survival signaling.NSCs cultured from embryonic day 11 rat fetal brain including those differentiated to TH(+ve)colonies, when challenged with SAL (1μM - 100μM), elicited a concentration and time dependent cell death/loss of mitochondrial viability. 10μM SAL on which significant mitochondrial impairment initiated was further used to study mechanism of toxicity. Morphological impairment, enhanced TUNEL positivity, cleaved caspase-3 and decreased Bcl-2:Bax suggested apoptosis. Sal toxicity coincided with reduced pAkt level and its downstream effectors: pCREB, pGSK-3β, Bcl-2 and neurotrophins GDNF, BDNF suggesting repressed PI3K/Akt signaling.Multiple neurotrophic factor support in the form of Olfactory Ensheathing Cell's Conditioned Media (OEC CM) potentially protected NSCs against SAL through activating PI3K/Akt pathway. This was confirmed on adding LY294002 the PI3K inhibitor which abolished the protection.We inferred that SAL exerts substantial toxicity towards NSCs. These findings will lead to better understanding of endogenous threats that might affect the fate of transplanted NSCs and their probable antidotes.
    NeuroToxicology 12/2012; · 2.65 Impact Factor
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    ABSTRACT: In view of extensive uses of lambda-cyhalothrin, a new generation type II synthetic pyrethroid, human exposure is quite imminent. The present study has therefore been carried out to investigate effect of lambda-cyhalothrin on brain dopaminergic and serotonergic systems and functional alterations associated with them. Post-lactational exposure to lambda-cyhalothrin (1.0 mg/kg or 3.0 mg/kg body weight, p.o.) from PD22 to PD49 caused a significant decrease in the motor activity and rota-rod performance in rats on PD50 as compared to controls. Decrease in motor activity in lambda-cyhalothrin treated rats was found to persist 15 days after withdrawal of exposure on PD65 while a trend of recovery in rota-rod performance was observed. A decrease in the binding of ³H-Spiperone, known to label dopamine-D2 receptors in corpus striatum associated with decreased expression of tyrosine hydroxylase (TH)-immunoreactivity and TH protein was observed in lambda-cyhalothrin treated rats on PD50 and PD65 compared to controls. Increase in the binding of ³H-Ketanserin, known to label serotonin-2A receptors in frontal cortex was observed in lambda-cyhalothrin exposed rats on PD50 and PD65 as compared to respective controls. The changes were more marked in rats exposed to lambda-cyhalothrin at a higher dose (3.0 mg/kg) and persisted even 15 days after withdrawal of exposure. The results exhibit vulnerability of developing rats to lambda-cyhalothrin and suggest that striatal dopaminergic system is a target of lambda-cyhalothrin. Involvement of serotonin-2A receptors in the neurotoxicity of lambda-cyhalothrin is also suggested. The results further indicate that neurobehavioral changes may be more intense in case exposure to lambda-cyhalothrin continues.
    Toxicology Letters 02/2012; 211(1):1-9. · 3.15 Impact Factor
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    ABSTRACT: This study is focused on understanding the mechanism of neurobehavioral toxicity of lambda-cyhalothrin, a new generation type II synthetic pyrethroid in developing rats following their exposure from post-lactational day (PLD)22 to PLD49 and investigate whether neurobehavioral alterations are transient or persistent. Post-lactational exposure to lambda-cyhalothrin (1.0 or 3.0 mg/kg body weight, p.o.) affected grip strength and learning activity in rats on PLD50 and the persistent impairment of grip strength and learning was observed at 15 days after withdrawal of exposure on PLD65. A decrease in the binding of muscarinic-cholinergic receptors in frontocortical, hippocampal, and cerebellar membranes associated with decreased expression of choline acetyltransferase (ChAT) and acetylcholinesterase (AChE) in hippocampus was observed following exposure to lambda-cyhalothrin on PLD50 and PLD65. Exposure to lambda-cyhalothrin was also found to increase the expression of growth-associated protein-43 in hippocampus of rats on PLD50 and PLD65 as compared to controls. A significant increase in lipid peroxidation and protein carbonyl levels and decreased levels of reduced glutathione and activity of superoxide dismutase, catalase, and glutathione peroxidase in brain regions of lambda-cyhalothrin exposed rats were distinctly observed indicating increased oxidative stress. Inhibition of ChAT and AChE activity may cause down-regulation of muscarinic-cholinergic receptors consequently impairing learning activity in developing rats exposed to lambda-cyhalothrin. The data further indicate that long-term exposure to lambda-cyhalothrin at low doses may be detrimental and changes in selected behavioral and neurochemical end points may persist if exposure to lambda-cyhalothrin continues.
    Neurotoxicity Research 02/2012; 22(4):292-309. · 2.87 Impact Factor
  • Neurotoxicity Research 01/2012; · 2.87 Impact Factor
  • Neuroscience Research - NEUROSCI RES. 01/2011; 71.
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    ABSTRACT: Transplantation of neural stem cell (NSC)-derived dopamine (DA) neurons is associated with low survival of cells, which could be due to limited striatal innervations and uneven distribution of graft because of its dense neuronal core, limited host-graft interaction, poor axonal outgrowth, lack of continuous neurotrophic factors supply, and an absence of cell adhesion molecules mediated appropriate developmental cues. Olfactory ensheathing cells (OEC) express a variety of growth factors and cell adhesion molecules and promote axonal regrowth and functional recovery in spinal cord injury in animal models and patients. In the present study, we explored the possibility to increase the survival, function, axonal outgrowth and striatal reinnervation of NSC by co-grafting with OEC in 6-OHDA lesioned parkinsonian rats. In the presence of OEC, significantly enhanced survival of NSC-derived DA neurons and axonal fiber outgrowth was evident in the striatum of NSC+OEC co-grafted rats at 24 weeks post-grafting as compared with NSC alone grafted rats. The increased survival of NSC and their striatal reinnervation was further manifested in the form of significant and substantial restitution of motor function and neurochemical recovery in the co-grafted group. Significant enhanced expression of p75NTR (from OEC) and tyrosine hydroxylase (TH) (from NSC) confirmed the co-localization and survival of both types of cells at the transplantation site in co-grafted rats. Co-grafting results co-related well with our in vitro studies, which suggest that OEC not only significantly increase survival, neurite outgrowth and DA release of NSC-derived DA neuron but also protect against 6-OHDA neurotoxicity in co-culture conditions. These results collectively suggest that OEC increase the survival and function of transplanted NSC in 6-OHDA lesioned parkinsonian rats.
    Journal of Neurochemistry 03/2009; 109(2):436-51. · 3.97 Impact Factor
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    ABSTRACT: The present invention relates to bioactive extracts its fractions and isolation of compound from RauwolSa tetraphylla. The extracts and fractions are useful for the treatment of psychosis based on in-vivo validation on animal model and proportional binding affinities for dopaminergic - D2, Cholinergic (muscarinic) and Serotonergic (5HT2A) receptors for antipsychotic activity. The present invention relates to novel antipsychotic activity in the leaf alkaloids of Formula 1 and 2 named tetrahydroalstonine, 10-methoxytetrahydroalstonine, isoreserpiline, 10- derαethoxyreserpiline, 11-demethoxyreserpiline, reserpiline and α -yohimbine. The present invention also relates to processes for obtaining antipsychotic extracts as well as for the isolation of alkaloids of formula 1 and 2 from the leaves of Rauwolfia tetraphylla. The present invention particularly relates to significant antipsychotic activity in the MeOH extract, ethylacetate and chloroform fractions of R. tetraphylla and in the isolated compounds α -yohimbine, reserpiline and in a mixture 10- demethoxyreserpiline and 11-demethoxyreserpiline in 1:1.5 ratios for treating psychosis without any extra pyramidal symptoms (EPS).►1. R1=R2 = OMe R3 = α-H (Isoreserpiline) ► 2. R1=R2 = OMe R3 = β-H (Reserpiline) "3. R1 = OMe R2 = HR3 = β-H (11-Demethoxy reserpiline) "4. R1 = H R2 = OMe R3 = β-H (10-Demethoxy reserpiline) "5. R1 = R2 = H R3 = α -H (Tetrahydroalstonine) * 7. R1 = OMe R2 = H R3 = α -H (10-Methoxytetrahudroalstonine)
    Ref. No: US & Indian Patent Application filed: IN0658DEL2009 Prov. Dated: 31/03/2009) 31/03/2010, WO PCT/IN2010/000208 31/03/2010., Year: 01/2009
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    ABSTRACT: Neural progenitor cell transplantation has emerged as a promising approach for cell replacement therapy in the brain of neurodegenerative diseases. These are multipotent stem cells with self-renewal capabilities and can give rise to cells of all the three lineages of nervous system and can be maintained and differentiated to desirable neuronal subtypes in vitro with known trophic factors. However, like fetal cells, neural progenitor cells after differentiating to specific neuronal type also require continuous neurotrophic factor support for their long-term survival following transplantation. Recent reports suggest that olfactory ensheathing cells are capable of providing continuous neurotrophic factor to the transplanted neural progenitor cells for their long-term survival. In the present investigation, an attempt has been made to validate functional restoration in kainic acid lesioned rat model of cognitive dysfunction following co-transplantation of neural progenitor cells with olfactory ensheathing cells.Animals lesioned with kainic acid in CA3 subfield of hippocampal region were transplanted with neural progenitor cells, olfactory ensheathing cells or neural progenitor cells + olfactory ensheathing cells together. Twelve weeks post-transplantation functional restoration was assessed using neurobehavioral, neurochemical, and immunohistochemical approaches. Significant recovery in learning and memory (89%) was observed in co-transplanted group when compared to lesioned group. This was accompanied by significantly higher expression of choline acetyltransferase and restoration in cholinergic receptor binding in co-transplanted group (61%) over the animals transplanted either olfactory ensheathing cells or neural progenitor cells alone. Role of olfactory ensheathing cells in supplementing neurotrophic factors was further substantiated in vitro by pronounced differentiation of neural progenitor cells to choline acetyltransferase/acetylcholine esterase immunoreactive cells when co-cultured with olfactory ensheathing cells as compared to neural progenitor cells alone. The results strengthened the hypothesis that co-transplantation of olfactory ensheathing cells and neural progenitor cells may be a better approach for functional restoration in kainic acid induced rat model of cognitive dysfunction.
    International Journal of Developmental Neuroscience 09/2008; · 2.69 Impact Factor
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    ABSTRACT: Neurogenesis occurs in dentate gyrus of adult hippocampus under the influence of various mitogenic factors. Growth factors besides instigating the proliferation of neuronal progenitor cells (NPCs) in dentate gyrus, also supports their differentiation to cholinergic neurons. In the present study, an attempt has been made to investigate the neurotrophic effect of bFGF in Kainic acid (KA) induced cognitive dysfunction in rats. Stereotaxic lesioning using (KA) was performed in hippocampal CA3 region of rat's brain. Four-weeks post lesioning rats were assessed for impairment in learning and memory using Y maze followed by bFGF infusion in dentate gyrus region. The recovery was evaluated after bFGF infusion using neurochemical, neurobehavioural and immunohistochemical approaches and compared with lesioned group. Significant impairment in learning and memory (P < 0.01) observed in lesioned animals, four weeks post lesioning exhibited significant restoration (P < 0.001) following bFGF infusion twice at one and four week post lesion. The bFGF infused animals exhibited recovery in hippocampus cholinergic (76%)/ dopaminergic (46%) receptor binding and enhanced Choline acetyltransferase (ChAT) immunoreactivity in CA3 region. The results suggest restorative potential of bFGF in cognitive dysfunctions, possibly due to mitogenic effect on dentate gyrus neurogenic area leading to generation and migration of newer cholinergic neurons.
    Neurochemical Research 07/2008; 33(7):1169-77. · 2.13 Impact Factor
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    R K Chaturvedi, S Shukla, K Seth, A K Agrawal
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    ABSTRACT: Transplantation of neural stem cells (NSC) derived dopamine (DA) neurons has emerged as an alternative approach to fetal neural cell transplantation in Parkinson's disease (PD). However, similar to fetal neural cell, survival of these neurons following transplantation is also limited due to limited striatal reinnervation (graft with dense neuronal core), limited host-graft interaction, poor axonal outgrowth, lack of continuous neurotrophic factors supply and principally an absence of cell adhesion molecules mediated appropriate developmental cues. In the present study, an attempt has been made to increase survival and function of NSC derived DA neurons, by co-grafting with Zuckerkandl's organ (a paraneural organ that expresses neurotrophic factors as well as cell adhesion molecules); to provide continuous NTF support and developmental cues to transplanted DA neurons in the rat model of PD. 24 weeks post transplantation, a significant number of surviving functional NSC derived DA neurons were observed in the co-transplanted group as evident by an increase in the number of tyrosine hydroxylase immunoreactive (TH-IR) neurons, TH-IR fiber density, TH-mRNA expression and TH-protein level at the transplantation site (striatum). Significant behavioral recovery (amphetamine induced stereotypy and locomotor activity) and neurochemical recovery (DA-D2 receptor binding and DA and DOPAC levels at the transplant site) were also observed in the NSC+ZKO co-transplanted group as compared to the NSC or ZKO alone transplanted group. In vivo results were further substantiated by in vitro studies, which suggest that ZKO increases the NSC derived DA neuronal survival, differentiation, DA release and neurite outgrowth as well as protects against 6-OHDA toxicity in co-culture condition. The present study suggests that long-term and continuous NTF support provided by ZKO to the transplanted NSC derived DA neurons, helped in their better survival, axonal arborization and integration with host cells, leading to long-term functional restoration in the rat model of PD.
    Experimental Neurology 05/2008; 210(2):608-23. · 4.65 Impact Factor
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    ABSTRACT: Marsilea minuta Linn. (Marsileaceae) has been referred in Indian traditional medicine system (Ayurveda) for the treatment of insomnia and other mental disorders. Marsiline isolated from Marsilea minuta was reported to have sedative and anticonvulsant property. The ethanol extract of Marsilea minuta was standardised for marsiline (1.15%, w/w) and studied for its antidepressant activity. Antidepressant activity was studied using forced swimming test (FST), tail suspension test (TST), learned helplessness test (LHT) and 5-hydroxytryptophan (5-HTP) induced head twitches response in rodents. Standardised extract of Marsilea minuta in doses of 100, 200 and 400 mg/kg/day were administered orally for three consecutive days and evaluated on day 3, 1h after the last dose treatment. Imipramine (15 mg/kg/day, i.p.) was used as the standard drug. Neurochemical mechanism of antidepressant activity was elucidated by using radioligand receptor binding assays for 5-HT2A and benzodiazepine receptors in rat frontal cortex. Immobility time in FST and TST was significantly (P<0.05) reduced by ethanol extract of Marsilea minuta treated animals. A decrease in number of escape failures in LHT was also observed in Marsilea minuta treated rats. Head twitch response induced by 5-HTP was significantly attenuated by Marsilea minuta (400 mg/kg, p.o.) and imipramine showing the involvement of serotonergic system. This effect was corroborated with radioligand receptor binding study where Marsilea minuta (400 mg/kg, p.o.) significantly (P<0.05) down regulated 5-HT2A receptor in frontal cortex, whereas, no marked effect was observed for benzodiazepine receptor. The antidepressant effect exhibited by Marsilea minuta extract may be due to its effect on 5-HT2A density in rat frontal cortex.
    Journal of Ethnopharmacology 04/2008; 117(1):51-7. · 2.76 Impact Factor
  • International Journal of Developmental Neuroscience - INT J DEV NEUROSCI. 01/2008; 26(8):889-889.
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    ABSTRACT: During transplantation of VMC in Parkinson's disease their degeneration is very high due to lack of trophic support and mismatch conditions. To overcome this problem, Glial cell line-derived Neurotrophic Factor (GDNF) known to increase the functional viability and regeneration of dopaminergic cells. In the present study an attempt has been made to validate the role of GDNF cotransplanted with fetal VMC in functional restoration in rat model of Parkinson's disease. A significant restoration was observed in apomorphine induced rotation in rats co transplanted with GDNF and VMC (66%) as compare to VMC alone (42%). Apomorphine induced locomotor activity was restored by 67, 38% in cotransplanted and VMC alone transplanted rats, respectively. Level of dopamine and 3,4 dihydroxy-phenyl acetic acid (DOPAC) in the striatum were significantly restored by 67 and 62, 42 and 33% in cotransplanted and VMC alone transplanted rats, respectively. A significant restoration was observed in striatum dopamine receptors by 69% in rats cotransplanted with VMC & GDNF, and 45% in those transplanted with VMC alone. GDNF alone transplantation did not show significant restoration in either of the parameters. Functional viabilty of dopaminergic neurons was further confirmed by Tyrosine Hydroxylase (TH) immunopositivity in striatal region where a significantly high expression was observed in cotransplanted animals when compared with VMC alone.Results of the present study suggests that cotransplantation of GDNF and VMC may help in better functional restoration in 6-OHDA lesioned rat model of Parkinson's disease studied at 4 weeks post transplantation.
    Journal of Neurochemistry 01/2008; 81:112-112. · 3.97 Impact Factor
  • Neuroscience Research - NEUROSCI RES. 01/2007; 58.
  • Kavita Seth, Nishi Srivastava, Ashok K. Agrawal
    Neuroscience Research - NEUROSCI RES. 01/2007; 58.
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    S. Shukla, R. K. Chaturvedi, A. K. Agrawal
    Parkinsonism & Related Disorders - PARKINSONISM RELAT DISORD. 01/2007; 13.
  • Neuroscience Research - NEUROSCI RES. 01/2007; 58.
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    ABSTRACT: In the present study, an attempt has been made to explore the neuroprotective and neuroreparative (neurorescue) effect of black tea extract (BTE) in 6-hydroxydopamine (6-OHDA)-lesioned rat model of Parkinson's disease (PD). In the neuroprotective (BTE + 6-OHDA) and neurorescue (6-OHDA + BTE) experiments, the rats were given 1.5% BTE orally prior to and after intrastriatal 6-OHDA lesion respectively. A significant recovery in d-amphetamine induced circling behavior (stereotypy), spontaneous locomotor activity, dopamine (DA)-D2 receptor binding, striatal DA and 3-4 dihydroxy phenyl acetic acid (DOPAC) level, nigral glutathione level, lipid peroxidation, striatal superoxide dismutase and catalase activity, antiapoptotic and proapoptotic protein level was evident in BTE + 6-OHDA and 6-OHDA + BTE groups, as compared to lesioned animals. BTE treatment, either before or after 6-OHDA administration protected the dopaminergic neurons, as evident by significantly higher number of surviving tyrosine hydroxylase immunoreactive (TH-ir) neurons, increased TH protein level and TH mRNA expression in substantia nigra. However, the degree of improvement in motor and neurochemical deficits was more prominent in rats receiving BTE before 6-OHDA. Results suggest that BTE exerts both neuroprotective and neurorescue effects against 6-OHDA-induced degeneration of the nigrostriatal dopaminergic system, suggesting that possibly daily intake of BTE may slow down the PD progression as well as delay the onset of neurodegenerative processes in PD.
    Neurobiology of Disease 06/2006; 22(2):421-34. · 5.62 Impact Factor
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    ABSTRACT: In the present study, an attempt has been made to explore the neuroprotective and neurorescue effects of nerve growth factor (NGF) on grafted cells and on host nigral dopaminergic neurons, respectively. NGF was co-transplanted with fetal ventral mesencephalic cells (VMC) in the striatum of 6-hydroxydopamine (6-OHDA) lesioned rat model of Parkinson's disease (PD). In the other groups fetal VMC and NGF were transplanted alone. Twelve weeks post-transplantation, a significant restoration was observed in D-amphetamine induced rotations (stereotypy), spontaneous locomotor activity, striatal and nigral dopamine (DA) and 3,4-dihydroxy-phenyl acetic acid (DOPAC) levels in co-transplanted rats as compared to VMC alone transplanted rats. Higher number of surviving tyrosine hydroxylase immunoreactive (TH-ir) neurons and significantly increased fiber outgrowth from graft was evident in co-transplanted rats as compared to VMC alone transplanted rats. Further, a significant increase was also observed in substantia nigra TH-ir neurons count in co-transplanted rats, exhibiting a potential neuroprotective and neurorescue effects of NGF on nigrostriatal dopaminergic neurons. The results suggest that NGF at the time of transplantation exhibits neuroprotective effect on transplanted VMC as well as neurorescue effect on remaining host nigral dopaminergic neurons, leading to better functional restoration.
    Neuroscience Letters 06/2006; 398(1-2):44-9. · 2.03 Impact Factor
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    ABSTRACT: Parkinson's disease (PD) is one of the commonest neurodegenerative diseases, and oxidative stress has been evidenced to play a vital role in its causation. In the present study, we evaluated whether ethanolic extract of Nardostachys jatamansi roots (ENj), an antioxidant and enhancer of biogenic amines, can slow the neuronal injury in a 6-OHDA-rat model of Parkinson's. Rats were treated with 200, 400, and 600 mg/kg body weight of ENj for 3 weeks. On day 21, 2 microl of 6-OHDA (12 microg in 0.01% in ascorbic acid-saline) was infused into the right striatum, while the sham-operated group received 2 microl of vehicle. Three weeks after the 6-OHDA injection, the rats were tested for neurobehavioural activity and were sacrificed after 6 weeks for the estimation of lipid peroxidation, reduced glutathione content, the activities of glutathione-S-transferase, glutathione reductase, glutathione peroxidase, superoxide dismutase and catalase, quantification of catecholamines, dopaminergic D2 receptor binding and tyrosine hydroxylase expression. The increase in drug-induced rotations and deficits in locomotor activity and muscular coordination due to 6-OHDA injections were significantly and dose-dependently restored by ENj. Lesioning was followed by an increased lipid peroxidation and significant depletion of reduced glutathione content in the substantia nigra, which was prevented with ENj pretreatment. The activities of glutathione-dependent enzymes, catalase and superoxide dismutase in striatum, which were reduced significantly by lesioning, were dose-dependently restored by ENj. A significant decrease in the level of dopamine and its metabolites and an increase in the number of dopaminergic D2 receptors in striatum were observed after 6-OHDA injection, and both were significantly recovered following ENj treatment. All of these results were exhibited by an increased density of tyrosine hydroxylase immunoreactive (TH-IR) fibers in the ipsilateral striatum of the lesioned rats following treatment with ENj; 6-OHDA injection had induced almost a complete loss of TH-IR fibers. This study indicates that the extract of Jatamansi might be helpful in attenuating Parkinsonism.
    Pharmacology Biochemistry and Behavior 02/2006; 83(1):150-60. · 2.61 Impact Factor

Publication Stats

465 Citations
99.57 Total Impact Points

Institutions

  • 2008–2009
    • Indian Institute of Toxicology Research
      • Division of Developmental Toxicology
      Lakhnau, Uttar Pradesh, India
  • 2007
    • Weill Cornell Medical College
      New York City, New York, United States
  • 2004
    • Jiwaji University
      Гвалиор, Madhya Pradesh, India
  • 1995
    • Central Drug Research Institute
      Lakhnau, Uttar Pradesh, India