Cited by 1,183Neuroinflammation and Neurodegeneration MechanismsParkinson's Disease Mechanisms and TreatmentsNuclear Receptors and Signaling

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Blockade of Microglial Activation Is Neuroprotective in the 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine Mouse Model of Parkinson Disease

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Wu, Du Chu, Jackson-Lewis, Vernice, Vila, Miquel, Tieu, Kim, Teismann, Peter, Vadseth, Caryn, Choi, Dong-Kug, Ischiropoulos, Harry, Przedborski, Serge·2002·The Journal of Neuroscience

DOI 10.1523/jneurosci.22-05-01763.2002PMC PMC6758858

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Abstract

1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) damages the nigrostriatal dopaminergic pathway as seen in Parkinson's disease (PD), a common neurodegenerative disorder with no effective protective treatment. Consistent with a role of glial cells in PD neurodegeneration, here we show that minocycline, an approved tetracycline derivative that inhibits microglial activation independently of its antimicrobial properties, mitigates both the demise of nigrostriatal dopaminergic neurons and the formation of nitrotyrosine produced by MPTP. In addition, we show that minocycline not only prevents MPTP-induced activation of microglia but also the formation of mature interleukin-1beta and the activation of NADPH-oxidase and inducible nitric oxide synthase (iNOS), three key microglial-derived cytotoxic mediators. Previously, we demonstrated that ablation of iNOS attenuates MPTP-induced neurotoxicity. Now, we demonstrate that iNOS is not the only microglial-related culprit implicated in MPTP-induced toxicity because mutant iNOS-deficient mice treated with minocycline are more resistant to this neurotoxin than iNOS-deficient mice not treated with minocycline. This study demonstrates that microglial-related inflammatory events play a significant role in the MPTP neurotoxic process and suggests that minocycline may be a valuable neuroprotective agent for the treatment of PD.

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“…decreases MPTP-mediated nitrotyrosine formation A significant part of the MPTP neurotoxic process is mediated by NO-related oxidative damage (Przedborski et al., 2000), the extent of which can be evaluated by assessing nitrotyrosine levels (Liberatore et al., 1999; Pennathur et al., 1999).”
BackgroundMethodResultInfluential
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Authors: Wu, D. C., Jackson-Lewis, V., Vila, M., Tieu, K., Teismann, P., Vadseth, C., Choi, D.-K., Ischiropoulos, H., & Przedborski, S.
Affiliations: Pediatrics and Genetics (US)
Children's Hospital of Philadelphia (US)
ORCID: Vila, Miquel
Tieu, Kim
Choi, Dong-Kug
Ischiropoulos, Harry
Przedborski, Serge
Venue: The Journal of Neuroscience
Publisher: Society for Neuroscience
Published: 2002-03-01
Volume: 22
Issue: 5
Pages: 1763-1771
ISSN: 0270-6474 (ISSN-L)
1529-2401
DOI: 10.1523/jneurosci.22-05-01763.2002
PMC: PMC6758858
OpenAlex: W2148726772
Cited by: 1,183
References: 44
Citations by year: 2026: 13 · 2025: 10 · 2024: 13 · 2023: 15 · 2022: 27 · 2021: 41 · 2020: 27 · 2019: 40 · 2018: 47 · 2017: 42 · 2016: 43 · 2015: 43 · 2014: 68 · 2013: 69 · 2012: 63
FWCI: 45.60
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: Journal of Neuroscience (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: U.S. Department of Defense
Parkinson's Disease Foundation (NS38370)
Muscular Dystrophy Association
Deutsche Forschungsgemeinschaft
National Institutes of Health (5r29ns037345-05, NS38370)
National Institute on Aging (R01-AG13966, R01AG013966)
National Institute of Neurological Disorders and Stroke (P50-NS38370, R01 NS 38586, R01 NS 42269, R29 NS37345, R01NS042269, R01NS038586, P50NS038370)
Topics: Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Health Sciences › Medicine › Clinical Neurology › Parkinson's Disease Mechanisms and Treatments
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Receptors and Signaling
Keywords: Parkinson's disease, microglial activation, minocycline, MPTP-induced neurotoxicity, neuroprotection, nitrotyrosine, IL-1β, NADPH oxidase, inducible nitric oxide synthase, nigrostriatal dopaminergic neurons, neuroinflammation, iNOS-deficient mice
MeSH terms: Animals, Anti-Bacterial Agents, Astrocytes, Corpus Striatum, Disease Models, Animal, Dose-Response Relationship, Drug, Interleukin-1, Mice, Inbred C57BL, Minocycline, Neurons, Substantia Nigra, Tyrosine, Tyrosine 3-Monooxygenase, 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine, Up-Regulation, Microglia, Mice, Knockout, Neuroprotective Agents, Nitric Oxide Synthase, NADPH Oxidases, Parkinsonian Disorders, Mice, Nitric Oxide Synthase Type II

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Blockade of Microglial Activation Is Neuroprotective in the 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine Mouse Model of Parkinson Disease

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