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Developmental Heptachlor Exposure Increases Susceptibility of Dopamine Neurons to N-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine (MPTP)in a Gender-Specific Manner

Richardson, Jason R.; Caudle, W. Michael; Wang, Min Zheng; Dean, E. Danielle; Pennell, Kurt D.; Miller, Gary W.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
25.84%
Parkinson’s disease (PD) is primarily thought of as a disease of aging. However recent evidence points to the potential for exposure to xenobiotics during development to increase risk of PD. Here, we report that developmental exposure to the organochlorine pesticide heptachlor alters the dopamine system and increases neurotoxicity in an animal model of PD. Exposure of pregnant mice to heptachlor led to increased levels of the dopamine transporter (DAT) and vesicular monoamine transporter 2 (VMAT2) levels at both the protein and mRNA level in their offspring. Increased DAT and VMAT2 levels were accompanied by alterations of mRNA levels of nuclear transcription factors that control dopamine neuron development and regulate DAT and VMAT2 levels in adulthood. At 12 weeks of age, control and heptachlor-exposed offspring were administered a moderate dose (2×10 mg/kg) of the parkinsonism-inducing agent MPTP. Greater neurotoxicity as evidenced by a greater loss of striatal dopamine and potentiation of increased levels of glial fibrillary acidic protein and α-synuclein was observed in heptachlor-exposed offspring. The neurotoxicity observed was greater in the male offspring than the female offspring, suggesting that males are more susceptible to the long-term effects of developmental heptachlor exposure. These data suggest that developmental heptachlor exposure causes long-term alterations of the dopamine system thereby rendering it more susceptible to dopaminergic damage in adulthood.

Glial cell line-derived neurotrophic factor protects midbrain dopaminergic neurons against lipopolysaccharide neurotoxicity

Xing, Bin; Xin, Tao; Zhao, Lingling; Hunter, Randy L; Chen, Yan; Bing, Guoying
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
35.69%
Aberrant microglia activation causes dopaminergic neuronal loss and nitric oxide produced by microglia plays a critical role in dopaminergic neuronal degeneration. However, no study has determined if GDNF protects dopaminergic neurons via inhibiting nitric oxide generation in Parkinson’s disease animal model. We report that GDNF not only reduces lipopolysaccharide-induced degeneration of dopaminergic neurons, suppresses microglia activation and nitric oxide generation, but also reverses the inhibition of phosphoinositide 3-kinase (PI3K) in dopaminergic neurons and microglia. It suggests that the neuroprotective effect of GDNF on dopaminergic neurons may be related to its suppression of microglia activation-mediated nitric oxide via releasing the inhibition of PI3K in both neurons and microglia.

DJ-1 deficiency in astrocytes selectively enhances mitochondrial Complex I inhibitor-induced neurotoxicity

Mullett, Steven J.; Hinkle, David A.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
35.69%
Parkinson’s disease (PD) brains show evidence of mitochondrial respiratory Complex I deficiency, oxidative stress, and neuronal death. Complex I-inhibiting neurotoxins, such as the pesticide rotenone, cause neuronal death and parkinsonism in animal models. We have previously shown that DJ-1 over-expression in astrocytes augments their capacity to protect neurons against rotenone, that DJ-1 knock-down impairs astrocyte-mediated neuroprotection against rotenone, and that each process involves astrocyte-released factors. To further investigate the mechanism behind these findings, we developed a high-throughput, plate-based bioassay that can be used to assess how genetic manipulations in astrocytes affect their ability to protect co-cultured neurons. We used this bioassay to show that DJ-1 deficiency-induced impairments in astrocyte-mediated neuroprotection occur solely in the presence of pesticides that inhibit Complex I (rotenone, pyridaben, fenazaquin, and fenpyroximate); not with agents that inhibit Complexes II-V, that primarily induce oxidative stress, or that inhibit the proteasome. This is a potentially PD-relevant finding because pesticide exposure is epidemiologically-linked with an increased risk for PD. Further investigations into our model suggested that astrocytic glutathione and heme oxygenase-1 anti-oxidant systems are not central to the neuroprotective mechanism.

PRETREATMENT WITH NEAR-INFRARED LIGHT VIA LIGHT-EMITTING DIODE PROVIDES ADDED BENEFIT AGAINST ROTENONE- AND MPP+- INDUCED NEUROTOXICITY

Ying, Rong; Liang, Huan Ling; Whelan, Harry T; Eells, Janis T; Wong-Riley, Margaret TT
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
35.69%
Parkinson’s disease (PD) is a movement disorder caused by the loss of dopaminergic neurons in the substantia nigra pars compacta, leading to nigrostriatal degeneration. The inhibition of mitochondrial respiratory chain complex I and oxidative stress-induced damage have been implicated in the pathogenesis of PD. The present study used an in vitro animal model of PD induced by specific mitochondrial complex I inhibitors: rotenone or 1-methyl-4- phenylpyridinium (MPP+). The goal was to test our hypothesis that pretreatment with nearinfrared light (NIR) via light-emitting diode (LED) had a greater beneficial effect on primary neurons grown in media with rotenone or MPP+ than those with or without LED treatment during exposure to poisons. Striatal and visual cortical neurons from newborn rats were cultured in a media with or without 200 nM of rotenone or 250 μM of MPP+ for 48 hrs. They were treated with NIR-LED twice a day before, during, and both before and during the exposure to the poison. Results indicate that pretreatment with NIR-LED significantly suppressed rotenone- or MPP+-induced apoptosis in both striatal and cortical neurons (P < 0.001), and that pretreatment plus LED treatment during neurotoxin exposure was significantly better than LED treatment alone during exposure to neurotoxins. In addition...

Neuroprotective Effects of Protocatechuic Aldehyde against Neurotoxin-Induced Cellular and Animal Models of Parkinson’s Disease

Zhao, Xin; Zhai, Shenyu; An, Ming-Sheng; Wang, Yue-Hua; Yang, Ying-Fan; Ge, Hui-Qi; Liu, Jin-Hao; Pu, Xiao-Ping
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Publicado em 18/10/2013 EN
Relevância na Pesquisa
55.86%
Protocatechuic aldehyde (PAL) has been reported to bind to DJ-1, a key protein involved in Parkinson’s disease (PD), and exerts potential neuroprotective effects via DJ-1 in SH-SY5Y cells. In this study, we investigated the neuroprotective pharmacological effects of PAL against neurotoxin-induced cell and animal models of PD. In cellular models of PD, PAL markedly increased cell viability rates, mitochondrial oxidation-reduction activity and mitochondrial membrane potential, and reduced intracellular ROS levels to prevent neurotoxicity in PC12 cells. In animal models of PD, PAL reduced the apomorphine injection, caused turning in 6-OHDA treated rats, and increased the motor coordination and stride decreases in MPTP treated mice. Meanwhile, in an MPTP mouse model, PAL prevented a decrease of the contents of dopamine (DA) and its metabolites in the striatum and TH-positive dopaminergic neuron loss in the substantia nigra (SN). In addition, PAL increased the protein expression of DJ-1 and reduced the level of α-synuclein in the SN of MPTP lesioned mice. PAL also increased the spine density in hippocampal CA1 neurons. The current study demonstrates that PAL can efficiently protect dopaminergic neurons against neurotoxin injury in vitro and in vivo...

Molecular Tweezers Targeting Transthyretin Amyloidosis

Ferreira, Nelson; Pereira-Henriques, Alda; Attar, Aida; Klärner, Frank-Gerrit; Schrader, Thomas; Bitan, Gal; Gales, Luís; Saraiva, Maria João; Almeida, Maria Rosário
Fonte: Springer US Publicador: Springer US
Tipo: Artigo de Revista Científica
EN
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25.82%
Transthyretin (TTR) amyloidoses comprise a wide spectrum of acquired and hereditary diseases triggered by extracellular deposition of toxic TTR aggregates in various organs. Despite recent advances regarding the elucidation of the molecular mechanisms underlying TTR misfolding and pathogenic self-assembly, there is still no effective therapy for treatment of these fatal disorders. Recently, the “molecular tweezers”, CLR01, has been reported to inhibit self-assembly and toxicity of different amyloidogenic proteins in vitro, including TTR, by interfering with hydrophobic and electrostatic interactions known to play an important role in the aggregation process. In addition, CLR01 showed therapeutic effects in animal models of Alzheimer’s disease and Parkinson’s disease. Here, we assessed the ability of CLR01 to modulate TTR misfolding and aggregation in cell culture and in an animal model. In cell culture assays we found that CLR01 inhibited TTR oligomerization in the conditioned medium and alleviated TTR-induced neurotoxicity by redirecting TTR aggregation into the formation of innocuous assemblies. To determine whether CLR01 was effective in vivo, we tested the compound in mice expressing TTR V30M, a model of familial amyloidotic polyneuropathy...

Vanadium Exposure Induces Olfactory Dysfunction in an Animal Model of Metal Neurotoxicity

Ngwa, Hilary Afeseh; Kanthasamy, Arthi; Jin, Huajun; Anantharam, Vellareddy; Kanthasamy, Anumantha G.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
45.86%
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 182 µg 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...

Prion-induced neurotoxicity: Possible role for cell cycle activity and DNA damage response

Bujdoso, Raymond; Landgraf, Matthias; Jackson, Walker S; Thackray, Alana M
Fonte: Baishideng Publishing Group Inc Publicador: Baishideng Publishing Group Inc
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
35.95%
Protein misfolding neurodegenerative diseases arise through neurotoxicity induced by aggregation of host proteins. These conditions include Alzheimer’s disease, Huntington’s disease, Parkinson’s disease, motor neuron disease, tauopathies and prion diseases. Collectively, these conditions are a challenge to society because of the increasing aged population and through the real threat to human food security by animal prion diseases. It is therefore important to understand the cellular and molecular mechanisms that underlie protein misfolding-induced neurotoxicity as this will form the basis for designing strategies to alleviate their burden. Prion diseases are an important paradigm for neurodegenerative conditions in general since several of these maladies have now been shown to display prion-like phenomena. Increasingly, cell cycle activity and the DNA damage response are recognised as cellular events that participate in the neurotoxic process of various neurodegenerative diseases, and their associated animal models, which suggests they are truly involved in the pathogenic process and are not merely epiphenomena. Here we review the role of cell cycle activity and the DNA damage response in neurodegeneration associated with protein misfolding diseases...

Verhaltenspharmakologische und histologische Charakterisierung der Funktion von Dopamin und Glutamat bei der 'nigralen' und 'extranigralen' Pathologie in einem Tiermodell der Parkinson-Krankheit; Neuropharmacological and histological characterisation of the function of dopamine and glutamate in the ‘nigral’ and ‘extranigral’ pathology in an animal model of Parkinson’s disease

Pedersen, Vera
Fonte: Universität Tübingen Publicador: Universität Tübingen
Tipo: Dissertation; info:eu-repo/semantics/doctoralThesis
DE_DE
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86.07%
In der vorliegenden Arbeit wurde im Tiermodell die Rolle des dopamin (DA)ergen und glutamat (GLU)ergen Systems bei den neurodegenerativen Prozessen, die der Parkinson-Krankheit zugrundeliegen, untersucht. Die Versuche wurden mit verhaltenspharmakologischen Methoden an der Ratte durchgeführt und durch neurochemische, biochemische und histologische Techniken ergänzt. Es wurde ein Tiermodell weiterentwickelt, mit dem das frühe klinische Stadium der Parkinson-Krankheit erfasst werden kann. Das Modell weist durch seine vergleichbaren Verhaltensveränderungen sowie den spezifischen Degenerationsmustern und Veränderungen der Neurotransmittersysteme eine hohe Validität auf und ermöglicht die Untersuchung von selektiven Eingriffen in das DAerge und GLUerge Transmittersystem und deren Auswirkung auf die degenerativen Prozesse. Die Ergebnisse der einzelnen Versuche unterstützen die Eignung dieses Tiermodells zur präklinischen Untersuchung neuer Therapiestrategien für die Parkinson-Krankheit. Die Ergebnisse dieser Arbeit zeigen, dass die Degeneration der DAergen Neurotransmission entscheidend zur Progression der ‚nigralen‘ und ‚extranigralen‘ Pathologie bei der Parkinson-Krankheit beitragen kann. Pathologische neuroadaptative Mechanismen des kompromitierten DAergen Systems sind ebenfalls für die motorischen Komplikationen...

Creatine protects against rotenone induced cell death of cerebellar granule neurons

Fortalezas, Sofia Isabel Almeida
Fonte: Universidade de Lisboa Publicador: Universidade de Lisboa
Tipo: Dissertação de Mestrado
Publicado em //2012 ENG
Relevância na Pesquisa
35.86%
Tese de mestrado, Ciências Biofarmacêuticas, Universidade de Lisboa, Faculdade de Farmácia, 2012; Parkinson´s Disease (PD) is the second most prevalent neurodegenerative brain disorder worldwide. Nevertheless, there is lack of certainty on the pathophysiology of the neurodegenerative mechanisms underlying PD. Several neurotoxins, rotenone among them, have been shown to induce parkinsonism-like brain degeneration and are widely used in cellular and animal models of PD. In spite of an extensive association of PD with dopaminergic neuron degeneration of the substantia nigra pars compacta, other brain areas like the cerebellum have been more recently implicated in the pathology of the disease. Therefore, we used a rotenone/cerebellar granule neurons (CGN) model to study not only the potential of creatine (as ergogenic compound), epicatechin and kaempferol (as antioxidant compounds) to afford neuroprotection against rotenone neurotoxicity but also to better understand the cellular mechanisms underlying this neurotoxicity. Our results revealed a strong protection by creatine against rotenone-induced CGN death, while kaempferol did not afford a significant protection and epicatechin elicited at most a very weak protection. On the contrary...

Minocycline prevents nigrostriatal dopaminergic neurodegeneration in the MPTP model of Parkinson's disease

Du, Yansheng; Ma, Zhizhong; Lin, Suizhen; Dodel, Richard C.; Gao, Feng; Bales, Kelly R.; Triarhou, Lazarose C.; Chernet, Eyassu; Perry, Ken W.; Nelson, David L. G.; Luecke, Susan; Phebus, Lee A.; Bymaster, Frank P.; Paul, Steven M.
Fonte: The National Academy of Sciences Publicador: The National Academy of Sciences
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
66.07%
Parkinson's disease is a chronic neurodegenerative disorder characterized by the loss of dopamine neurons in the substantia nigra, decreased striatal dopamine levels, and consequent extrapyramidal motor dysfunction. We now report that minocycline, a semisynthetic tetracycline, recently shown to have neuroprotective effects in animal models of stroke/ischemic injury and Huntington's disease, prevents nigrostriatal dopaminergic neurodegeneration in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease. Minocycline treatment also blocked dopamine depletion in the striatum as well as in the nucleus accumbens after MPTP administration. The neuroprotective effect of minocycline is associated with marked reductions in inducible NO synthase (iNOS) and caspase 1 expression. In vitro studies using primary cultures of mesencephalic and cerebellar granule neurons (CGN) and/or glia demonstrate that minocycline inhibits both 1-methyl-4-phenylpyridinium (MPP+)-mediated iNOS expression and NO-induced neurotoxicity, but MPP+-induced neurotoxicity is inhibited only in the presence of glia. Further, minocycline also inhibits NO-induced phosphorylation of p38 mitogen-activated protein kinase (MAPK) in CGN and the p38 MAPK inhibitor...

X-Ray Fluorescence Imaging: A New Tool for Studying Manganese Neurotoxicity

Robison, Gregory; Zakharova, Taisiya; Fu, Sherleen; Jiang, Wendy; Fulper, Rachael; Barrea, Raul; Marcus, Matthew A.; Zheng, Wei; Pushkar, Yulia
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Publicado em 19/11/2012 EN
Relevância na Pesquisa
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The neurotoxic effect of manganese (Mn) establishes itself in a condition known as manganism or Mn induced parkinsonism. While this condition was first diagnosed about 170 years ago, the mechanism of the neurotoxic action of Mn remains unknown. Moreover, the possibility that Mn exposure combined with other genetic and environmental factors can contribute to the development of Parkinson's disease has been discussed in the literature and several epidemiological studies have demonstrated a correlation between Mn exposure and an elevated risk of Parkinson's disease. Here, we introduce X-ray fluorescence imaging as a new quantitative tool for analysis of the Mn distribution in the brain with high spatial resolution. The animal model employed mimics deficits observed in affected human subjects. The obtained maps of Mn distribution in the brain demonstrate the highest Mn content in the globus pallidus, the thalamus, and the substantia nigra pars compacta. To test the hypothesis that Mn transport into/distribution within brain cells mimics that of other biologically relevant metal ions, such as iron, copper, or zinc, their distributions were compared. It was demonstrated that the Mn distribution does not follow the distributions of any of these metals in the brain. The majority of Mn in the brain was shown to occur in the mobile state...

Toxin Models of Mitochondrial Dysfunction in Parkinson's Disease

Martinez, Terina N.; Greenamyre, J. Timothy
Fonte: Mary Ann Liebert, Inc. Publicador: Mary Ann Liebert, Inc.
Tipo: Artigo de Revista Científica
Publicado em 01/05/2012 EN
Relevância na Pesquisa
45.95%
Significance: Parkinson's disease (PD) is a neurodegenerative disorder characterized, in part, by the progressive and selective loss of dopaminergic neuron cell bodies within the substantia nigra pars compacta (SNpc) and the associated deficiency of the neurotransmitter dopamine (DA) in the striatum, which gives rise to the typical motor symptoms of PD. The mechanisms that contribute to the induction and progressive cell death of dopaminergic neurons in PD are multi-faceted and remain incompletely understood. Data from epidemiological studies in humans and molecular studies in genetic, as well as toxin-induced animal models of parkinsonism, indicate that mitochondrial dysfunction occurs early in the pathogenesis of both familial and idiopathic PD. In this review, we provide an overview of toxin models of mitochondrial dysfunction in experimental Parkinson's disease and discuss mitochondrial mechanisms of neurotoxicity. Recent Advances: A new toxin model using the mitochondrial toxin trichloroethylene was recently described and novel methods, such as intranasal exposure to toxins, have been explored. Additionally, recent research conducted in toxin models of parkinsonism provides an emerging emphasis on extranigral aspects of PD pathology. Critical Issues: Unfortunately...

Neuroprotective Effects of San-Huang-Xie-Xin-Tang in the MPP+/MPTP Models of Parkinson's Disease In Vitro and In Vivo

Lo, Yi-Ching; Shih, Yu-Tzu; Tseng, Yu-Ting; Hsu, Hung-Te
Fonte: Hindawi Publishing Corporation Publicador: Hindawi Publishing Corporation
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
65.89%
San-Huang-Xie-Xin-Tang (SHXT), composed of Coptidis rhizoma, Scutellariae radix, and Rhei rhizoma, is a traditional Chinese medicine used for complementary and alternative therapy of cardiovascular and neurodegenerative diseases via its anti-inflammatory and antioxidative effects. The aim of this study is to investigate the protective effects of SHXT in the 1–methyl–4–phenylpyridinium (MPP+)/1–methyl–4–phenyl–1,2,3,6–tetrahydropyridine (MPTP) models of Parkinson's disease. Rat primary mesencephalic neurons and mouse Parkinson disease model were used in this study. Oxidative stress was induced by MPP+ in vitro and MPTP in vivo. In MPP+-treated mesencephalic neuron cultures, SHXT significantly increased the numbers of TH-positive neurons. SHXT reduced apoptotic signals (cytochrome and caspase) and apoptotic death. MPP+-induced gp91phox activation and ROS production were attenuated by SHXT. In addition, SHXT increased the levels of GSH and SOD in MPP+-treated neurons. In MPTP animal model, SHXT markedly increased TH-positive neurons in the substantia nigra pars compacta (SNpc) and improved motor activity of mice. In conclusion, the present results reveal the evidence that SHXT possesses beneficial protection against MPTP-induced neurotoxicity in this model of Parkinson's disease via its antioxidative and antiapoptotic effects. SHXT might be a potentially alternative and complementary medicine for neuroprotection.

SiO2 nanoparticles change colour preference and cause Parkinson's-like behaviour in zebrafish

Li, Xiang; Liu, Bo; Li, Xin-Le; Li, Yi-Xiang; Sun, Ming-Zhu; Chen, Dong-Yan; Zhao, Xin; Feng, Xi-Zeng
Fonte: Nature Publishing Group Publicador: Nature Publishing Group
Tipo: Artigo de Revista Científica
Publicado em 22/01/2014 EN
Relevância na Pesquisa
35.83%
With advances in the development of various disciplines, there is a need to decipher bio-behavioural mechanisms via interdisciplinary means. Here, we present an interdisciplinary study of the role of silica nanoparticles (SiO2-NPs) in disturbing the neural behaviours of zebrafish and a possible physiological mechanism for this phenomenon. We used adult zebrafish as an animal model to evaluate the roles of size (15-nm and 50-nm) and concentration (300 μg/mL and 1000 μg/mL) in SiO2-NP neurotoxicity via behavioural and physiological analyses. With the aid of video tracking and data mining, we detected changes in behavioural phenotypes. We found that compared with 50-nm nanosilica, 15-nm SiO2-NPs produced greater significant changes in advanced cognitive neurobehavioural patterns (colour preference) and caused potentially Parkinson's disease-like behaviour. Analyses at the tissue, cell and molecular levels corroborated the behavioural results, demonstrating that nanosilica acted on the retina and dopaminergic (DA) neurons to change colour preference and to cause potentially Parkinson's disease-like behaviour.

In Vivo Evidence of Increased nNOS Activity in Acute MPTP Neurotoxicity: A Functional Pharmacological MRI Study

Siow, Tiing Yee; Chen, Chiao-Chi V.; Wan, Nina; Chow, Kai-Ping N.; Chang, Chen
Fonte: Hindawi Publishing Corporation Publicador: Hindawi Publishing Corporation
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
55.81%
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a neurotoxin commonly used to produce an animal model of Parkinson's disease. Previous studies have suggested a critical role for neuronal nitric oxide (NO) synthase- (nNOS-) derived NO in the pathogenesis of MPTP. However, NO activity is difficult to assess in vivo due to its extremely short biological half-life, and so in vivo evidence of NO involvement in MPTP neurotoxicity remains scarce. In the present study, we utilized flow-sensitive alternating inversion recovery sequences, in vivo localized proton magnetic resonance spectroscopy, and diffusion-weighted imaging to, respectively, assess the hemodynamics, metabolism, and cytotoxicity induced by MPTP. The role of NO in MPTP toxicity was clarified further by administering a selective nNOS inhibitor, 7-nitroindazole (7-NI), intraperitoneally to some of the experimental animals prior to MPTP challenge. The transient increase in cerebral blood flow (CBF) in the cortex and striatum induced by systemic injection of MPTP was completely prevented by pretreatment with 7-NI. We provide the first in vivo evidence of increased nNOS activity in acute MPTP-induced neurotoxicity. Although the observed CBF change may be independent of the toxicogenesis of MPTP...

Transgenic conversion of omega-6 into omega-3 fatty acids in a mouse model of Parkinson's disease

Bousquet, Melanie; Gue, Karl; Emond, Vincent; Julien, Pierre; Kang, Jing X.; Cicchetti, Francesca; Calon, Frederic
Fonte: The American Society for Biochemistry and Molecular Biology Publicador: The American Society for Biochemistry and Molecular Biology
Tipo: Artigo de Revista Científica
Publicado em /02/2011 EN
Relevância na Pesquisa
65.84%
We have recently identified a neuroprotective role for omega-3 polyunsaturated fatty acids (n-3 PUFAs) in a toxin-induced mouse model of Parkinson's disease (PD). Combined with epidemiological data, these observations suggest that low n-3 PUFA intake is a modifiable environmental risk factor for PD. In order to strengthen these preclinical findings as prerequisite to clinical trials, we further investigated the neuroprotective role of n-3 PUFAs in Fat-1 mice, a transgenic model expressing an n-3 fatty acid desaturase converting n-6 PUFAs into n-3 PUFAs. Here, we report that the expression of the fat-1 transgene increased cortical n-3:n-6 PUFA ratio (+28%), but to a lesser extent than dietary supplementation (92%). Such a limited endogenous production of n-3 PUFAs in the Fat-1 mouse was insufficient to confer neuroprotection against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine neurotoxicity as assessed by dopamine levels, tyrosine hydroxylase (TH)-positive neurons and fibers, as well as nigral Nurr1 and dopamine transporter (DAT) mRNA expression. Nevertheless, higher cortical docosahexaenoic acid (DHA) concentrations were positively correlated with markers of nigral dopaminergic neurons such as the number of TH-positive cells, in addition to Nurr1 and DAT mRNA levels. These associations are consistent with the protective role of DHA in a mouse model of PD. Taken together...

Neuroprotective Activities of Palmitoylethanolamide in an Animal Model of Parkinson's Disease

Esposito, Emanuela; Impellizzeri, Daniela; Mazzon, Emanuela; Paterniti, Irene; Cuzzocrea, Salvatore
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Publicado em 17/08/2012 EN
Relevância na Pesquisa
65.81%
The biochemical and cellular changes that occur following treatment with 1-methyl-4-phenyl-1,2,3,6-tetrahyropyridine (MPTP) are remarkably similar to that seen in idiopathic Parkinson's disease (PD). PD is characterized by the degeneration of dopaminergic nigrostriatal neurons, which results in disabling motor disturbances. Activation of glial cells and the consequent neuroinflammatory response is increasingly recognized as a prominent neuropathological feature of PD. There is currently no effective disease-modifying therapy. Targeting the signaling pathways in glial cells responsible for neuroinflammation represents a promising new therapeutic approach designed to preserve remaining neurons in PD. Chronic treatment with palmitoylethanolamide (PEA, 10 mg/kg, i.p.), initiated 24 hr after MPTP injection (20 mg/kg), protected against MPTP-induced loss of tyrosine hydroxylase positive neurons in the substantia nigra pars compacta. Treatment with PEA reduced MPTP-induced microglial activation, the number of GFAP-positive astrocytes and S100β overexpression, and protected against the alterations of microtubule-associated protein 2a,b-, dopamine transporter-, nNOS- positive cells in the substantia nigra. Furthermore, chronic PEA reversed MPTP-associated motor deficits...

RCSN Cell System for Identifying Dopaminergic Neurotoxicity

Segura Aguilar, Juan; Caviedes Codelia, Raúl; Caviedes Fernández, Pablo Andrés
Fonte: Springer Science+Business Media New York Publicador: Springer Science+Business Media New York
Tipo: Capítulo de libro
EN
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35.69%
Acceso restringido a texto completo; Dopaminergic toxicity represents a potential mechanism underlying Parkinson’s disease (PD) neuropathology. Nevertheless, the study of such a mechanism is hampered by the lack of permanent and stable in vitro models that bear relevant cellular traits, namely, neuronal dopaminergic function. Although various permanent cell lines exhibiting variable dopaminergic properties do exist, such properties are not necessarily stable and may require the application of complex and costly differentiation protocols for induction. The latter is particularly true when inducing in vitro differentiation from more undifferentiated tissue, such as stem cells. Also, cell lines may lose viability or eventually undergo permanent differentiation. This chapter discusses a permanently growing cell line, named RCSN-3, which was established from the substantia nigra of an adult Fisher 344 rat. The cell line retains dopaminergic traits, including dopamine production and secretion, and the presence of catecholamine reuptake transporters. Notably, these properties have remained expressed in RCSN-3 cells for decades. This chapter also addresses the contribution of RCSN-3 to dopaminergic-mediated toxic phenomena...

Enhanced Neuroprotective Effects of Coadministration of Tetrandrine with Glutathione in Preclinical Model of Parkinson's Disease

Li, Xiang-Yun; Mei, Guang-Hai; Dong, Qiang; Zhang, Yu; Guo, Zhuang-Li; Su, Jing-Jing; Tang, Yu-Ping; Jin, Xue-Hong; Zhou, Hou-Guang; Huang, Yan-Yan
Fonte: Hindawi Publishing Corporation Publicador: Hindawi Publishing Corporation
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
65.87%
Aim. In this study we examined the influence of tetrandrine (Tet) on the neuroprotective effects of glutathione (GSH) in the 6-hydroxydopamine- (6-OHDA-) lesioned rat model of Parkinson's disease (PD). Methods. Levels in the redox system, dopamine (DA) metabolism, dopaminergic neuronal survival, and apoptosis of the substantia nigra (SN) and striatum, as well as the rotational behavior of animals were examined after a 50-day administration of GSH + Tet (or GSH) and/or L-3,4-dihydroxyphenylalanine (L-dopa) to PD rats. Ethics Committee of Huashan Hospital, Fudan University approved the protocol (number SYXK2009-0082). Results. Administration of GSH or Tet alone did not show any significant effects on the factors evaluated in the PD rats. However, in the GSH + Tet group, we observed markedly decreased oxidative damage, inhibition of DA metabolism and enhanced DA synthesis, increased tyrosine hydroxylase- (TH-) immunopositive neuronal survival, and delayed apoptosis of dopaminergic neurons in the SN. Animal rotational behavior was improved in the GSH + Tet group. Additionally, coadministration of GSH + Tet appeared to offset the possible oxidative neurotoxicity induced by L-dopa. Conclusion. In this study, we demonstrated that tetrandrine allowed occurrence of the neuroprotective effect of glutathione probably due to inhibition of P-glycoprotein on 6-hydroxydopamine-lesioned rat models of Parkinson's disease...