Doxycycline Is Neuroprotective Against Nigral Dopaminergic Degeneration by a Dual Mechanism Involving MMP-3
Abstract
In Parkinson disease (PD), the dopaminergic (DAergic) neurons in the substantia nigra undergo degeneration. While the exact mechanism for the degeneration is still not completely understood, neuronal apoptosis and inflammation are thought to play roles. We have recently obtained evidence that matrix metalloproteinase (MMP)-3 plays a crucial role in the apoptotic signal in DAergic cells as well as activation of microglia. The present study tested whether doxycycline might modulate MMP-3 and provide neuroprotection of DAergic neurons. Doxycycline effectively suppressed the expression of MMP-3 induced in response to cellular stress in the DAergic CATH.a cells. This was accompanied by protection of CATH.a cells as well as primary cultured mesencephalic DAergic neurons via attenuation of apoptosis. The active form of MMP-3, released under the cell stress condition, was also decreased in the presence of doxycycline. In addition, doxycycline led to downregulation of MMP-3 in microglial BV-2 cells exposed to lipopolysaccharide (LPS). This was accompanied by suppression of production of nitric oxide and TNF-alpha, as well as gene expression of iNOS, TNF-alpha, IL-1beta, and COX-2. In vivo, doxycycline provided neuroprotection of the nigral DAergic neurons following MPTP treatment, as assessed by tyrosine hydroxylase immunocytochemistry and silver staining, and suppressed microglial activation and astrogliosis as assessed by Iba-1 and GFAP immunochemistry, respectively. Taken together, doxycycline showed neuroprotective effect on DAergic system both in vitro and in vivo and this appeared to derive from anti-apoptotic and anti-inflammatory mechanisms involving downregulation of MMP-3.
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DOX reduces IBA-1 expression.
“In vitro, DOX has shown anti-inflammatory properties by interfering with p38 MAP kinase and NF-κB pathways, reducing the expression of the activated microglia marker IBA-1 and inhibiting the production of the pro-oxidant and pro-inflammatory factors ROS, nitric oxide, iNOS, cyclooxygenase-2 (COX-2), IL-1β and TNF-α [280,281,282].”
From The Interplay between Gut Microbiota and Parkinson’s Disease: Implications on Diagnosis and Treatment (2022) · cites this paper as [281]
DOX interferes with p38 MAP kinase and NF-κB pathways.
“In vitro, DOX has shown anti-inflammatory properties by interfering with p38 MAP kinase and NF-κB pathways, reducing the expression of the activated microglia marker IBA-1 and inhibiting the production of the pro-oxidant and pro-inflammatory factors ROS, nitric oxide, iNOS, cyclooxygenase-2 (COX-2), IL-1β and TNF-α [280,281,282].”
From The Interplay between Gut Microbiota and Parkinson’s Disease: Implications on Diagnosis and Treatment (2022) · cites this paper as [281]
DOX represses MMP-3 in dopaminergic neurons and microglia in vitro and in vivo.
“Concerning neuroprotection, DOX exerts an anti-apoptotic activity by repressing the matrix metallopeptidase-3 (MMP-3) in dopaminergic neurons and microglia both in vitro and in vivo [281].”
From The Interplay between Gut Microbiota and Parkinson’s Disease: Implications on Diagnosis and Treatment (2022) · cites this paper as [281]
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- Authors
- Cho, Y., Son, H. J., Kim, E.-M., Choi, J. H., Kim, S. T., Ji, I. J., Choi, D. H., Joh, T. H., Kim, Y. S., & Hwang, O.
- Affiliations
- University of Ulsan (KR)
- Cornell University (US)
- Corresponding author
- Hwang, Onyou
- Venue
- Neurotoxicity Research
- Published
- 2009-07-07
- Volume
- 16
- Issue
- 4
- Pages
- 361-371
- ISSN
- 1029-8428 (ISSN-L)
- 1476-3524
- OpenAlex
- W2052289462
- Cited by
- 85
- References
- 50
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 1 · 2023: 3 · 2022: 5 · 2021: 12 · 2020: 5 · 2019: 2 · 2018: 3 · 2017: 7 · 2016: 6 · 2015: 9 · 2014: 5 · 2013: 7 · 2012: 7
- FWCI
- 3.41
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Neurotoxicity Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Neurological Disorders and Stroke (R01NS062827)
- Topics
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
- Keywords
- doxycycline, neuroprotection, Parkinson's disease, substantia nigra, dopaminergic neurons, matrix metalloproteinase-3, neuronal apoptosis, microglial activation, neuroinflammation, MPTP, astrocyte activation, nitric oxide, TNF-α, BV-2 cells
- MeSH terms
- Animals, Cells, Cultured, Dopamine, Dose-Response Relationship, Drug, Doxycycline, Enzyme-Linked Immunosorbent Assay, Female, L-Lactate Dehydrogenase, Male, Mice, Inbred C57BL, Nerve Tissue Proteins, Neurons, Nitrites, Pregnancy, Substantia Nigra, Tumor Necrosis Factor-alpha, 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine, Gene Expression Regulation, Enzymologic, Silver Staining, Cell Death, Rats, Sprague-Dawley, Neuroprotective Agents, Statistics, Nonparametric, Matrix Metalloproteinase 3, In Situ Nick-End Labeling, Mice, Rats
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