Microglial Activation Damages Dopaminergic Neurons through MMP-2/-9-Mediated Increase of Blood-Brain Barrier Permeability in a Parkinson’s Disease Mouse Model
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Chronic neuroinflammation has been considered to be involved in the progressive dopaminergic neurodegeneration in Parkinson’s disease (PD). However, the mechanisms remain unknown. Accumulating evidence indicated a key role of the blood–brain barrier (BBB) dysfunction in neurological disorders. This study is designed to elucidate whether chronic neuroinflammation damages dopaminergic neurons through BBB dysfunction by using a rotenone-induced mouse PD model. Results showed that rotenone dose-dependently induced nigral dopaminergic neurodegeneration, which was associated with increased Evans blue content and fibrinogen accumulation as well as reduced expressions of zonula occludens-1 (ZO-1), claudin-5 and occludin, three tight junction proteins for maintaining BBB permeability, in mice, indicating BBB disruption. Rotenone also induced nigral microglial activation. Depletion of microglia or inhibition of microglial activation by PLX3397 or minocycline, respectively, greatly attenuated BBB dysfunction in rotenone-lesioned mice. Mechanistic inquiry revealed that microglia-mediated activation of matrix metalloproteinases-2 and 9 (MMP-2/-9) contributed to rotenone-induced BBB disruption and dopaminergic neurodegeneration. Rotenone-induced activation of MMP-2/-9 was significantly attenuated by microglial depletion and inactivation. Furthermore, inhibition of MMP-2/-9 by a wide-range inhibitor, SB-3CT, abrogated elevation of BBB permeability and simultaneously increased tight junctions expression. Finally, we found that microglial depletion and inactivation as well as inhibition of MMP-2/-9 significantly ameliorated rotenone-elicited nigrostriatal dopaminergic neurodegeneration and motor dysfunction in mice. Altogether, our findings suggested that microglial MMP-2/-9 activation-mediated BBB dysfunction contributed to dopaminergic neurodegeneration in rotenone-induced mouse PD model, providing a novel view for the mechanisms of Parkinsonism.
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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 [258]
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- Authors
- Ruan, Z., Zhang, D., Huang, R., Sun, W., Hou, L., Zhao, J., & Wang, Q.
- Affiliations
- Dalian Medical University (CN)
- Corresponding author
- Zhao, Jie
- Wang, Qingshan
- Venue
- International Journal of Molecular Sciences
- Publisher
- MDPI AG
- Published
- 2022-03-03
- Volume
- 23
- Issue
- 5
- Pages
- 2793
- ISSN
- 1422-0067 (ISSN-L)
- PMC
- PMC8910886
- OpenAlex
- W4214951361
- Cited by
- 82
- References
- 54
- Citations by year
- 2026: 19 · 2025: 22 · 2024: 15 · 2023: 22 · 2022: 3
- FWCI
- 8.16
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- International Journal of Molecular Sciences (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Natural Science Foundation of China (81973087)
- Topics
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Keywords
- Parkinson's disease, microglial activation, dopaminergic neuron loss, blood-brain barrier permeability, MMP-2, MMP-9, tight junction proteins, rotenone-induced neurotoxicity, nigrostriatal pathway, neuroinflammation, PLX3397, minocycline, SB-3CT, motor impairment
- MeSH terms
- Animals, Blood-Brain Barrier, Disease Models, Animal, Dopamine, Mice, Inbred C57BL, Parkinson Disease, Permeability, Rotenone, Microglia, Matrix Metalloproteinase 2, Matrix Metalloproteinase 9, Mice, Dopaminergic Neurons
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