Anumantha G Kanthasamy

Iowa State University, Ames, Iowa, United States

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Publications (132)496.88 Total impact

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    ABSTRACT: Interest in nanoneuromedicine has grown rapidly due to the immediate need for improved biomarkers and therapies for psychiatric, developmental, traumatic, inflammatory, infectious and degenerative nervous system disorders. These, in whole or in part, are a significant societal burden due to growth in numbers of affected people and in disease severity. Lost productivity of the patient and his or her caregiver, and the emotional and financial burden cannot be overstated. The need for improved health care, treatment and diagnostics are immediate. A means to such an end is nanotechnology. Indeed, recent developments of health-care enabling nanotechnologies and nanomedicines range from biomarker discovery including neuroimaging to therapeutic applications for degenerative, inflammatory and infectious disorders of the nervous system. This review focuses on the current and future potential of the field to positively affect clinical outcomes. Copyright © 2015. Published by Elsevier Inc.
    Nanomedicine : nanotechnology, biology, and medicine. 01/2015;
  • Bulletin of the American Physical Society. 01/2015; 60.
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    ABSTRACT: Parkinson's diseaseParkinson's disease (PDPD ) is mainly characterized by a progressive degeneration of dopaminergicdopaminergic neuronsdopaminergic neurons in the substantia nigrasubstantia nigra resulting in chronic deficits in motor functions. Administration of the neurotoxinneurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTPMPTP ) produces PD symptoms and recapitulates the main features of PD in human and animal modelsanimal models . MPTP is converted to 1-methyl-4-phenylpyridine1-methyl-4-phenylpyridine (MPP(+) MPP(+) ), which is the active toxic compound that selectively destroys dopaminergic neurons. Here, we describe methods and protocols to evaluate MPTP/MPP(+)-induced dopaminergic neurodegenerationneurodegeneration in both murine primary mesencephalicmesencephalic culturesprimary mesencephalic cultures and animal models. The ability of MPTP/MPP(+) to cause dopaminergic neuronal cell deathcell death is assessed by immunostaining of tyrosine hydroxylasetyrosine hydroxylase (THTH ).
    Methods in molecular biology (Clifton, N.J.) 01/2015; 1254:239-52. · 1.29 Impact Factor
  • Bulletin of the American Physical Society. 01/2015; 60.
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    Bonto Faburay, Dongseob Tark, Anumantha G Kanthasamy, Juergen A Richt
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    ABSTRACT: Abstract Protein misfolding cyclic amplification (PMCA) is an in vitro simulation of prion replication, which relies on the use of normal brain homogenate derived from host species as substrate for the specific amplification of abnormal prion protein, PrP(Sc). Studies showed that recombinant cellular PrP, PrP(C), expressed in Escherichia coli lacks N-glycosylation and an glycophosphatidyl inositol anchor (GPI) and therefore may not be the most suitable substrate in seeded PMCA reactions to recapitulate prion conversion in vitro. In this study, we expressed two PRNP genotypes of sheep, V136L141R154Q171 and A136F141R154Q171, and one genotype of white-tailed deer (Q95G96, X132,Y216) using the baculovirus expression system and evaluated their suitability as substrates in seeded-PMCA. It has been reported that host-encoded mammalian RNA molecules and divalent cations play a role in the pathogenesis of prion diseases, and RNA molecules have also been shown to improve the sensitivity of PMCA assays. Therefore, we also assessed the effect of co-factors, such as prion-specific mRNA molecules and a divalent cation, manganese, on protein conversion. Here, we report that baculovirus-expressed recombinant PrP(C) shows a glycoform and GPI-anchor profile similar to mammalian brain-derived PrP(C) and supports amplification of PrP(Sc) and PrP(CWD) derived from prion-affected animals in a single round of seeded PMCA in the absence of exogenous co-factors. Addition of species-specific in vitro transcribed PrP mRNA molecules stimulated the conversion efficiency resulting in increased PrP(Sc) or PrP(CWD) production. Addition of 2 to 20 μM of manganese chloride (MnCl2) to unseeded PMCA resulted in conversion of recombinant PrP(C) to protease-resistant PrP. Collectively, we demonstrate, for the first time, that baculovirus expressed sheep and deer PrP can serve as a substrate in protein misfolding cyclic amplification for sheep and deer prions in the absence of additional exogenous co-factors.
    Prion 12/2014; 8(6). · 1.97 Impact Factor
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    ABSTRACT: The pathological role of alpha-synuclein (α-Syn) aggregation in neurodegeneration is well recognized, but the physiological function of normal α-Syn remains unknown. Since α-Syn protein contains multiple divalent metal binding sites, herein we conducted a comprehensive characterization of the role of α-Syn in manganese-induced dopaminergic neurotoxicity. We established transgenic N27 dopaminergic neuronal cells by stably expressing human wild-type α-Syn at normal physiological levels. Alpha-Syn-expressing dopaminergic cells significantly attenuated Mn-induced neurotoxicity for 24-h exposures relative to vector control cells. To further explore cellular mechanisms, we studied the mitochondria-dependent apoptotic pathway. Analysis of a key mitochondrial apoptotic initiator, cytochrome c, revealed that α-Syn significantly reduces the Mn-induced cytochrome c release into cytosol. The downstream caspase cascade, involving caspase-9 and caspase-3 activation, during Mn exposure was also largely attenuated in Mn-treated α-Syn cells in a time-dependent manner. Alpha-Syn cells also showed a dramatic reduction in the Mn-induced proteolytic activation of the pro-apoptotic kinase PKCδ. The generation of Mn-induced reactive oxygen species did not differ between α-Syn and vector control cells, indicating that α-Syn exerts its protective effect independent of altering ROS generation. Inductively coupled plasma-mass spectrometry (ICP-MS) revealed no significant differences in intracellular Mn levels between treated vector and α-Syn cells. Notably, the expression of wild-type α-Syn in primary mesencephalic cells also rescued cells from Mn-induced neurotoxicity. However, prolonged exposure to Mn promoted protein aggregation in α-Syn-expressing cells. Collectively, these results demonstrate that wild-type α-Syn exhibits neuroprotective effects against Mn-induced neurotoxicity during the early stages of exposure in a dopaminergic neuronal model of PD. © The Author 2014. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please email: journals.permissions@oup.com.
    Toxicological sciences : an official journal of the Society of Toxicology. 11/2014;
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    ABSTRACT: The oxidative stress-sensitive protein kinase Cδ (PKCδ) has been implicated in dopaminergic neuronal cell death. However, little is known about the epigenetic mechanisms regulating PKCδ expression in neurons. Here, we report a novel mechanism by which the PKCδ gene can be regulated by histone acetylation. Treatment with histone deacetylase inhibitor (HDACi) sodium butyrate (NaBu) induced PKCδ expression in cultured neurons, brain slices, and animal models. Several other HDACi also mimicked NaBu. The chromatin immunoprecipitation analysis revealed that hyperacetylation of histone H4 by NaBu is associated with the PKCδ promoter. Deletion analysis of PKCδ promoter mapped the NaBu-responsive element to an 81-bp minimal promoter region. Detailed mutagenesis studies within this region revealed that four GC boxes conferred hyperacetylation-induced PKCδ promoter activation. Cotransfection experiments and Sp inhibitors studies demonstrated that Sp1, Sp3 and Sp4 regulated NaBu-induced PKCδ upregulation. However, NaBu did not alter the DNA binding activities of Sp proteins or their expression. Interestingly, a one-hybrid analysis revealed that NaBu enhanced transcriptional activity of Sp1/Sp3. Overexpression of p300/CBP potentiated the NaBu-mediated transactivation potential of Sp1/Sp3, whereas expressing several HDACs attenuated this effect, suggesting that p300/CBP and HDACs act as co-activators or co-repressors in histone acetylation-induced PKCδ upregulation. Finally, using genetic and pharmacological approaches, we showed that NaBu upregulation of PKCδ sensitizes neurons to cell death in a human dopaminergic cell model and brain slice cultures. Together, these results indicate that histone acetylation regulates PKCδ expression to augment nigrostriatal dopaminergic cell death, which could contribute to the progressive neuropathogenesis of Parkinson's disease.
    Journal of Biological Chemistry 10/2014; · 4.60 Impact Factor
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    ABSTRACT: Recently, we demonstrated that dimeric apocynin prevented loss of motor function in the leucine-rich repeat kinase 2 (LRRK2(R1441G)) transgenic (tg) mouse (treated with 200mg/kg, three times per week) [B.P. Dranka et al., Neurosci. Lett. 549 (2013) 57-62]. Here we extend those studies by treating LRRK2(R1441G) mice with an orally-available, mitochondrially-targeted apocynin derivative. We hypothesized that the increased mitochondrial permeability of Mito-apocynin, due to the triphenylphosphonium moiety, would allow improvement of Parkinson's disease (PD) symptoms at lower doses than those required for diapocynin. Tests of motor coordination (pole test, Rotor-Rod) revealed a significant deficit in coordinated motor function in LRRK2(R1441G) mice by 15 months of age. Decreased performance on the pole test and Rotor-Rod in the LRRK2(R1441G) mice was prevented with Mito-apocynin treatment (3mg/kg, three times per week). Decreased olfactory function is an early indication of PD in human patients. LRRK2(R1441G) tg mice displayed deficits in sense of smell in both the hidden treat test, and a radial arm maze test. Interestingly, treatment with Mito-apocynin prevented this hyposmia, and animals retained normal ability to identify either a scented treat or a food pellet as well as wild type littermates. Together, these data demonstrate that the mitochondria-targeted apocynin analog is effective in preventing early PD-like symptoms in the LRRK2(R1441G) mouse model.
    Free Radical Biology and Medicine 09/2014; · 5.71 Impact Factor
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    ABSTRACT: Oxidative stress is a major pathophysiological mediator of degenerative processes in many neurodegenerative diseases including Parkinson's disease (PD). Aberrant cell signaling governed by protein phosphorylation has been linked to oxidative damage of dopaminergic neurons in PD. Although several studies have associated activation of certain protein kinases with apoptotic cell death in PD, very little is known about protein kinase regulation of cell survival and protection against oxidative damage and degeneration in dopaminergic neurons. Here, we characterized the PKD1-mediated protective pathway against oxidative damage in cell culture models of PD. Dopaminergic neurotoxicant 6-hydroxy dopamine (6-OHDA) was used to induce oxidative stress in the N27 dopaminergic cell model and in primary mesencephalic neurons. Our results indicated that 6-OHDA induced the PKD1 activation loop (PKD1S744/S748) phosphorylation during early stages of oxidative stress and that PKD1 activation preceded cell death. We also found that 6-OHDA rapidly increased phosphorylation of the C-terminal S916 in PKD1, which is required for PKD1 activation loop (PKD1S744/748) phosphorylation. Interestingly, negative modulation of PKD1 activation by RNAi knockdown or by the pharmacological inhibition of PKD1 by kbNB-14270 augmented 6-OHDA-induced apoptosis, while positive modulation of PKD1 by the overexpression of full length PKD1 (PKD1WT) or constitutively active PKD1 (PKD1S744E/S748E) attenuated 6-OHDA-induced apoptosis, suggesting an anti-apoptotic role for PKD1 during oxidative neuronal injury. Collectively, our results demonstrate that PKD1 signaling plays a cell survival role during early stages of oxidative stress in dopaminergic neurons and therefore, positive modulation of the PKD1-mediated signal transduction pathway can provide a novel neuroprotective strategy against PD.
    PLoS ONE 05/2014; 9(5):e96947. · 3.53 Impact Factor
    This article is viewable in ResearchGate's enriched format
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    ABSTRACT: Prion diseases are infectious and inevitably fatal neurodegenerative diseases characterized by prion replication, widespread protein aggregation and spongiform degeneration of major brain regions controlling motor function. Oxidative stress has been implicated in prion-related neuronal degeneration but the molecular mechanisms underlying prion-induced oxidative damage are not well understood. In this study, we evaluated the role of oxidative stress-sensitive, pro-apoptotic protein kinase Cδ (PKCδ) in prion-induced neuronal cell death using cerebellar organotypic slice cultures (COSC) and mouse models of prion diseases. We found a significant upregulation of PKCδ in RML scrapie infected COSC as evidenced by increased levels of both PKCδ protein and its mRNA. We also found an enhanced regulatory phosphorylation of PKCδ at its two regulatory sites, Thr505 in the activation loop and Tyr311 at the caspase-3 cleavage site. The prion infection also induced proteolytic activation of PKCδ in our COSC model. Immunohistochemical analysis of scrapie-infected COSC revealed loss of PKCδ positive Purkinje cells and enhanced astrocyte proliferation. Further examination of PKCδ signaling in the RML scrapie adopted in vivo mouse model showed increased proteolytic cleavage and Tyr 311 phosphorylation of the kinase. Notably, we observed a delayed onset of scrapie-induced motor symptoms in PKCδ knockout (PKCδ(-/-)) mice as compared with wild type (PKCδ(+/+)) mice, further substantiating the role of PKCδ in prion disease. Collectively, these data suggest that PKCδ signaling likely plays a role in the neurodegenerative processes associated with prion diseases.
    Prion 03/2014; 8(1). · 1.97 Impact Factor
  • Bulletin of the American Physical Society. 01/2014;
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    ABSTRACT: Research in autophagy continues to accelerate,(1) and as a result many new scientists are entering the field. Accordingly, it is important to establish a standard set of criteria for monitoring macroautophagy in different organisms. Recent reviews have described the range of assays that have been used for this purpose.(2,3) There are many useful and convenient methods that can be used to monitor macroautophagy in yeast, but relatively few in other model systems, and there is much confusion regarding acceptable methods to measure macroautophagy in higher eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers of autophagosomes versus those that measure flux through the autophagy pathway; thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from fully functional autophagy that includes delivery to, and degradation within, lysosomes (in most higher eukaryotes) or the vacuole (in plants and fungi). Here, we present a set of guidelines for the selection and interpretation of the methods that can be used by investigators who are attempting to examine macroautophagy and related processes, as well as by reviewers who need to provide realistic and reasonable critiques of papers that investigate these processes. This set of guidelines is not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to verify an autophagic response.
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    ABSTRACT: Epidemiological evidence indicates chronic environmental exposure to transition metals may play a role in chronic neurodegenerative conditions such as Parkinson's disease (PD). Chronic inhalation exposure to welding fumes containing metal mixtures may be associated with development of PD. A significant amount of vanadium is present in welding fumes, as vanadium pentoxide (V2O5), and incorporation of vanadium in the production of high strength steel has become more common. Despite the increased vanadium use in recent years, the neurotoxicological effects of this metal are not well characterized. Recently, we demonstrated that V2O5 induces dopaminergic neurotoxicity via protein kinase C delta (PKCδ)-dependent oxidative signaling mechanisms in dopaminergic neuronal cells. Since anosmia (inability to perceive odors) and non-motor deficits are considered to be early symptoms of neurological diseases, in the present study, we examined the effect of V2O5 on the olfactory bulb in animal models. To mimic the inhalation exposure, we intranasally administered C57 black mice a low-dose of 182μg of V2O5 three times a week for one month, and behavioral, neurochemical and biochemical studies were performed. Our results revealed a significant decrease in olfactory bulb weights, tyrosine hydroxylase (TH) levels, levels of dopamine (DA) and its metabolite, 3, 4-dihydroxyphenylacetic acid (DOPAC) and increases in astroglia of the glomerular layer of the olfactory bulb in the treatment groups relative to vehicle controls. Neurochemical changes were accompanied by impaired olfaction and locomotion. These findings suggest that nasal exposure to V2O5 adversely affects olfactory bulbs, resulting in neurobehavioral and neurochemical impairments. These results expand our understanding of vanadium neurotoxicity in environmentally-linked neurological conditions.
    NeuroToxicology 12/2013; · 3.05 Impact Factor
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    ABSTRACT: In many neurodegenerative diseases such as Parkinson’s (PD), Huntington’s and Alzheimer’s, there is a progressive loss of structure or function of neurons, including death of neurons.. The prevalence of these diseases is increasing along with the median age of our population. Mitochondrial dysfunction, oxidative and nitrative stress have been implicated in number of neurodegenerative diseases including PD. The existing treatment approaches for these diseases are symptomatic and fail to prevent the progression of the neurodegenerative process. Mitochondrial targeted antioxidants have been recently shown to protect against Parkinsonian toxicant, -methyl-4-phenylpyridinium (MPP+) -induced production of reactive oxygen and nitrogen species production (ROS/RNS). Polyanhydride nanoparticles can be designed as a delivery system to elicit unique cellular responses such as particle internalization and directed intracellular trafficking. Through encapsulation of the payload within the polyanhydride particles, sustained release of these compounds can be achieved. Altering the polymer chemistry, functionalizing the particle surface, and/or controlling particle size enable the release of payload to targeted regions within the cell. In this work we investigate the ability of biodegradable polyanhydride nanoparticles to enhance the delivery of mitochondrial targeted antioxidants to protect against MPP+. The antioxidant utilized in these studies was apocyanin functionalized with a mitochondrial targeting ligand, mitoapocyanin. Using poly(sebacic acid) nanoparticles, we designed a delivery system for targeted release of mitoapocyanin to mitochondria of cells. The performance of the designed delivery system was evaluated for neuroprotection against MPP+-induced cell death in both the MN9D dopaminergic cell line and mouse primary neurons. Cellular uptake of particles was evaluated by confocal microscopy of particles loaded with quantum dots. Intracellular trafficking of the particles to the mitochondria was evaluated by co-localization of the particle and mitochondria by confocal microscopy and confirmed by transmission electron microscopy.
    13 AIChE Annual Meeting; 11/2013
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    ABSTRACT: Parkinson's disease (PD) is a progressive neurodegenerative disease in the elderly, and no cure or disease-modifying therapies exist. Several lines of evidence suggest that mitochondrial dysfunction and oxidative stress have a central role in the dopaminergic neurodegeneration of PD. In this context, mitochondria-targeted therapies that improve mitochondrial function may have great promise in the prevention and treatment of PD. In this review, we discuss the recent developments in mitochondria-targeted antioxidants and their potential beneficial effects as a therapy for ameliorating mitochondrial dysfunction in PD.
    Biochimica et Biophysica Acta 09/2013; · 4.66 Impact Factor
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    ABSTRACT: Mixed lineage kinases (MLKs) are members of the mitogen-activated protein kinase kinase kinase (MAP3K) family and are reported to activate MAP kinase pathways. There have been at least 9 members of the MLK family identified to date, although the physiological functions of all the family members are yet unknown. However, MLKs in general have been implicated in neurodegenerative diseases, including Parkinson and Alzheimer diseases. Recent reports suggest that some of the MLK members could play a role in cancer via modulating cell migration, invasion, cell cycle, and apoptosis. This review article will first describe the biology of MLK members and then discuss the current progress that relates to their functions in cancer.
    Genes & cancer 09/2013; 4(9-10):334-341.
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    ABSTRACT: Parkinson's disease (PD) is a chronic neurodegenerative disease characterized by a slow and progressive degeneration of dopaminergic neurons in substantia nigra (SN). The pathophysiological mechanisms underlying PD remain unclear. Pin1, a major peptidyl prolyl isomerase, has recently been associated with certain diseases. Notably, Ryo et al. implicated Pin1 in PD pathology. Therefore, we sought to systematically characterize the role of Pin1 in PD using cell culture and animal models. To our surprise, we observed a dramatic upregulation of Pin1 mRNA and protein levels in dopaminergic MN9D neuronal cells treated with the parkinsonian toxicant MPP+ as well as in the substantia nigra of the MPTP-induced PD mouse model. Notably, a marked expression of Pin1 was also observed in the substantia nigra of human PD brains along with a high co-localization of Pin1 within dopaminergic neurons. In functional studies, siRNA-mediated knockdown of Pin1 almost completely prevented MPP+-induced caspase-3 activation and DNA fragmentation, indicating that Pin1 plays a proapoptotic role. Interestingly, multiple pharmacological Pin1 inhibitors, including juglone, attenuated MPP+-induced Pin1 upregulation, α-synuclein aggregation, caspase-3 activation and cell death. Furthermore, juglone treatment in the MPTP mouse model of PD suppressed Pin1 levels and improved locomotor deficits, dopamine depletion and nigral dopaminergic neuronal loss. Collectively, our findings demonstrate, for the first time, that Pin1 is upregulated in PD and has a pathophysiological role in the nigrostriatal dopaminergic system, and suggest that modulation of Pin1 levels may be a useful translational therapeutic strategy in PD.
    Journal of Biological Chemistry 06/2013; · 4.60 Impact Factor
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    ABSTRACT: The most prominent mechanism proposed for death of dopaminergic neurons in Parkinson's disease (PD) is elevated generation of reactive oxygen/nitrogen species (ROS/RNS). Recent studies suggest that ROS produced during PD pathogenesis may contribute to cytotoxicity in cell culture models of PD. We hypothesized that inhibition of ROS production would prevent PD symptoms in the LRRK2(R1441G) transgenic (tg) mouse model of PD. These mice overexpress a mutant form of leucine-rich repeat kinase 2 (LRRK2) and are reported to develop PD-like symptoms at approximately 10 months of age. Despite similar expression of the transgene, our colony did not recapitulate the same type of motor dysfunction originally reported. However, tests of motor coordination (pole test, Rotor-Rod) revealed a significant defect in LRRK2(R1441G) mice by 16 months of age. LRRK2(R1441G) tg mice, or wild type littermates, were given diapocynin (200mg/kg, a proposed NADPH oxidase inhibitor) three times per week by oral gavage starting at 12 weeks of age. Decreased performance on the pole test and Rotor-Rod in the LRRK2(R1441G) mice was prevented with diapocynin treatment. No loss in open field movement or rearing was found. As expected, tyrosine hydroxylase staining was similar in both the substantia nigra and striatum in all treatment groups. Together these data demonstrate that diapocynin is a viable agent for protection of neurobehavioral function.
    Neuroscience Letters 05/2013; · 2.06 Impact Factor
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    ABSTRACT: The role of normal cellular prion protein (PrP) remains to be fully elucidated; however, the protein is crucial for the infection and progression of prion diseases. Recent evidence indicates that PrP is a metalloprotein since the octapeptide repeat sequences in the protein have high affinity for various divalent cations and the binding sites appear to play a role in the pathogenesis of prion diseases. In our present study, we tested several divalent metals including manganese and cadmium and determined their effects on protein degradation and protein aggregation in mouse neuronal cells expressing PrP. Cadmium was more neurotoxic than manganese following 24 h exposure. Manganese did not show any significant effect on the inhibition of proteasomal activity or formation of high molecular weight ubiquitinated PrPs. Interestingly, treatment with cadmium profoundly inhibited proteasomal activity, which resulted in greatly increased formation of high molecular weight ubiquitinated PrPs. Immunohistochemical analysis also revealed a dramatic increase in formation of oligomers after cadmium treatment. Cadmium also increased the formation of ubiquitinated PrP, but it did not lead to the formation of proteinase-K resistant PrP. Collectively, our results show that a divalent metal, cadmium affects proteasomal function and PrP aggregation, which promote neurotoxicity.
    Toxicology Letters 11/2012; 214(3):288–295. · 3.36 Impact Factor
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    ABSTRACT: BACKGROUND: Parkinson's disease (PD) is a devastating neurodegenerative disorder characterized by progressive motor debilitation, which affects several million people worldwide. Recent evidence suggests that glial cell activation and its inflammatory response may contribute to the progressive degeneration of dopaminergic neurons in PD. Currently, there are no neuroprotective agents available that can effectively slow the disease progression. Herein, we evaluated the anti-inflammatory and antioxidant efficacy of diapocynin, an oxidative metabolite of the naturally occurring agent apocynin, in a pre-clinical 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. METHODS: Both pre-treatment and post-treatment of diapocynin were tested in the MPTP mouse model of PD. Diapocynin was administered via oral gavage to MPTP-treated mice. Following the treatment, behavioral, neurochemical and immunohistological studies were performed. Neuroinflammatory markers, such as ionized calcium binding adaptor molecule 1 (Iba-1), glial fibrillary acidic protein (GFAP), gp91phox and inducible nitric oxide synthase (iNOS), were measured in the nigrostriatal system. Nigral tyrosine hydroxylase (TH)-positive neurons as well as oxidative markers 3-nitrotyrosine (3-NT), 4-hydroxynonenal (4-HNE) and striatal dopamine levels were quantified for assessment of the neuroprotective efficacy of diapocynin. RESULTS: Oral administration of diapocynin significantly attenuated MPTP-induced microglial and astroglial cell activation in the substantia nigra (SN). MPTP-induced expression of gp91phox and iNOS activation in the glial cells of SN was also completely blocked by diapocynin. Notably, diapocynin markedly inhibited MPTP-induced oxidative markers including 3-NT and 4-HNE levels in the SN. Treatment with diapocynin also significantly improved locomotor activity, restored dopamine and its metabolites, and protected dopaminergic neurons and their nerve terminals in this pre-clinical model of PD. Importantly, diapocynin administered 3 days after initiation of the disease restored the neurochemical deficits. Diapocynin also halted the disease progression in a chronic mouse model of PD. CONCLUSIONS: Collectively, these results demonstrate that diapocynin exhibits profound neuroprotective effects in a pre-clinical animal model of PD by attenuating oxidative damage and neuroinflammatory responses. These findings may have important translational implications for treating PD patients.
    Journal of Neuroinflammation 10/2012; 9(1):241. · 4.90 Impact Factor

Publication Stats

3k Citations
496.88 Total Impact Points

Institutions

  • 2002–2015
    • Iowa State University
      • Department of Biomedical Sciences
      Ames, Iowa, United States
  • 2012–2013
    • Medical College of Wisconsin
      • Center for Free Radical Research
      Milwaukee, WI, United States
    • University of Michigan
      • Life Sciences Institute
      Ann Arbor, MI, United States
  • 2011
    • Shanghai University of Traditional Chinese Medicine
      Shanghai, Shanghai Shi, China
  • 2008
    • CUNY Graduate Center
      New York City, New York, United States
  • 1999–2000
    • Long Beach Memorial Medical Center
      Long Beach, California, United States
  • 1995–1997
    • University of California, Irvine
      • • Division of Neurology
      • • Department of Neurology
      Irvine, California, United States
  • 1991–1997
    • Purdue University
      • Department of Medicinal Chemistry and Molecular Pharmacology (MCMP)
      West Lafayette, Indiana, United States
  • 1989–1990
    • University of Madras
      • Department of Biochemistry
      Chennai, State of Tamil Nadu, India