Minocycline Prevents Nigrostriatal Dopaminergic Neurodegeneration in the MPTP Model of Parkinson’s Disease
Open accessAbstract
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, SB203580, blocks NO toxicity of CGN. Our results suggest that minocycline blocks MPTP neurotoxicity in vivo by indirectly inhibiting MPTP/MPP(+)-induced glial iNOS expression and/or directly inhibiting NO-induced neurotoxicity, most likely by inhibiting the phosphorylation of p38 MAPK. Thus, NO appears to play an important role in MPTP neurotoxicity. Neuroprotective tetracyclines may be effective in preventing or slowing the progression of Parkinson's and other neurodegenerative diseases.
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Minocycline molecular changes explain increased striatal dopamine levels and cognitive and locomotor improvements in zebrafish, mouse, and rat models.
“Of note, these molecular changes seem to explain the increased striatal dopamine levels as well as the cognitive and locomotor improvements observed in zebrafish, mouse, and rat models [259,260,264,268,269,270,271].”
From The Interplay between Gut Microbiota and Parkinson’s Disease: Implications on Diagnosis and Treatment (2022) · cites this paper as [264]
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 [264]
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 [264]
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 [264]
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Accelerated Aging during Chronic Oxidative Stress: A Role for PARP-1
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- Authors
- Du, Y., Ma, Z., Lin, S., Dodel, R. C., Gao, F., Bales, K. R., Triarhou, L. C., Chernet, E., Perry, K. W., Nelson, D. L. G., Luecke, S., Phebus, L. A., Bymaster, F. P., & Paul, S. M.
- Affiliations
- Philipps University of Marburg (DE)
- Departments of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN 46202; Department of Neurology, Philipps-University, Marburg, 35033 Germany; Neuroscience Discovery Research, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285; and Department of Pathology, Indiana University, Indianapolis, IN 46202
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2001-11-27
- Volume
- 98
- Issue
- 25
- Pages
- 14669-14674
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC64739
- OpenAlex
- W2103738800
- Cited by
- 789
- References
- 40
- Citations by year
- 2026: 6 · 2025: 12 · 2024: 22 · 2023: 17 · 2022: 28 · 2021: 21 · 2020: 23 · 2019: 29 · 2018: 20 · 2017: 29 · 2016: 25 · 2015: 29 · 2014: 23 · 2013: 35 · 2012: 46
- FWCI
- 24.82
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- minocycline, Parkinson's disease, MPTP-induced neurotoxicity, nigrostriatal dopaminergic neurons, neuroprotection, inducible nitric oxide synthase, caspase-1, nitric oxide, p38 MAPK, MPP+, cerebellar granule cells, striatal dopamine depletion, nucleus accumbens
- MeSH terms
- Animals, Cells, Cultured, Dopamine, Humans, Imidazoles, Male, Mice, Inbred C57BL, Minocycline, Monoamine Oxidase, Nerve Degeneration, Neurons, Nitric Oxide, Phosphorylation, Pyridines, Visual Cortex, Neuroprotective Agents, Nitric Oxide Synthase, Caspase 1, MPTP Poisoning, Parkinsonian Disorders, Mitogen-Activated Protein Kinases, p38 Mitogen-Activated Protein Kinases, Mice, Nitric Oxide Synthase Type II
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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