Blockade of Microglial Activation Is Neuroprotective in the 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine Mouse Model of Parkinson Disease
Open accessAbstract
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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Minocycline suppresses microglia activation.
“This effect is mainly ascribable to the minocycline-dependent suppression of microglia activation, which has been reported by several in vivo studies [251,258,259,260,261,262,263].”
From The Interplay between Gut Microbiota and Parkinson’s Disease: Implications on Diagnosis and Treatment (2022) · cites this paper as [262]
Minocycline reduces NADPH-oxidase activity.
“In this respect, microglial inactivation by minocycline correlates with decreased IL-1β formation, as well as reduced NADPH-oxidase and inducible nitric oxide synthase (iNOS) activity, suggesting that both anti-inflammatory and antioxidant pathways are involved [262,264].”
From The Interplay between Gut Microbiota and Parkinson’s Disease: Implications on Diagnosis and Treatment (2022) · cites this paper as [262]
Microglial inactivation by minocycline correlates with decreased IL-1β formation.
“In this respect, microglial inactivation by minocycline correlates with decreased IL-1β formation, as well as reduced NADPH-oxidase and inducible nitric oxide synthase (iNOS) activity, suggesting that both anti-inflammatory and antioxidant pathways are involved [262,264].”
From The Interplay between Gut Microbiota and Parkinson’s Disease: Implications on Diagnosis and Treatment (2022) · cites this paper as [262]
Minocycline reduces iNOS activity.
“In this respect, microglial inactivation by minocycline correlates with decreased IL-1β formation, as well as reduced NADPH-oxidase and inducible nitric oxide synthase (iNOS) activity, suggesting that both anti-inflammatory and antioxidant pathways are involved [262,264].”
From The Interplay between Gut Microbiota and Parkinson’s Disease: Implications on Diagnosis and Treatment (2022) · cites this paper as [262]
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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)
- 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
- 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 › Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › 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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