Rifampicin Inhibits Rotenone-Induced Microglial Inflammation via Enhancement of Autophagy
Abstract
Mitochondrial and autophagic dysfunction, as well as neuroinflammation, are associated with the pathophysiology of Parkinson's disease (PD). Rotenone, an inhibitor of mitochondrial complex I, has been associated as an environmental neurotoxin related to PD. Our previous studies reported that rifampicin inhibited microglia activation and production of proinflammatory mediators induced by rotenone, but the precise mechanism has not been completely elucidated. BV2 cells were pretreated for 2h with rifampicin followed by 0.1μM rotenone, alone or in combination with chloroquine. Here, we demonstrate that rifampicin pretreatment alleviated rotenone induced release of IL-1β and IL-6, and its effects were suppressed when autophagy was inhibited by chloroquine. Moreover, preconditioning with 50μM rifampicin significantly increased viability of SH-SY5Y cells cocultured with rotenone-treated BV2 cells in the transwell coculture system. Chloroquine partially abolished the neuroprotective effects of rifampicin pretreatment. Rifampicin pretreatment significantly reversed rotenone-induced mitochondrial membrane potential reduction and reactive oxygen species accumulation. We suggest that the mechanism for rifampicin-mediated anti-inflammatory and antioxidant effects is the enhancement of autophagy. Indeed, the ratio of LC3-II/LC3-I in rifampicin-pretreated BV2 cells was significantly higher than that in cells without pretreatment. Fluorescence and electron microscopy analyses indicate an increase of lysosomes colocalized with mitochondria in cells pretreated with rifampicin, which confirms that the damaged mitochondria were cleared through autophagy (mitophagy). Taken together, the data provide further evidence that rifampicin exerts neuroprotection against rotenone-induced microglia inflammation, partially through the autophagy pathway. Modulation of autophagy by rifampicin is a novel therapeutic strategy for PD.
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Rifampicin reduces IL-1β, TNF-α, IL-6 and ROS released by cells double treated with rotenone and rifampicin.
“Other studies reported a reduction in IL-1β, TNF-α, IL-6 and ROS released by cells double treated with rotenone and rifampicin, thus indicating a promotion of neuroprotection [293,294,295].”
From The Interplay between Gut Microbiota and Parkinson’s Disease: Implications on Diagnosis and Treatment (2022) · cites this paper as [293]
Rifampicin sustains cell viability by enhancing autophagy.
“Although not completely defined, rifampicin appears to sustain cell viability through different mechanisms: (i) by enhancing autophagy [293,295]; (ii) via PI3K/Akt/GSK-3β/CREB pathway modulation [296]; (iii) by upregulating the unfolded protein response marker GRP78 through the PERK/eIF2α/ATF4 pathway [297].”
From The Interplay between Gut Microbiota and Parkinson’s Disease: Implications on Diagnosis and Treatment (2022) · cites this paper as [293]
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- Authors
- Liang, Y., Zhou, T., Chen, Y., Lin, D., Jing, X., Peng, S., Zheng, D., Zeng, Z., Lei, M., Wu, X., Huang, K., Yang, L., Xiao, S., Liu, J., & Tao, E.
- Affiliations
- Sun Yat-sen University (CN)
- Corresponding author
- Tao, Enxiang
- ORCID
- Venue
- NeuroToxicology
- Publisher
- Elsevier BV
- Published
- 2017-12
- Volume
- 63
- Pages
- 137-145
- ISSN
- 0161-813X (ISSN-L)
- OpenAlex
- W2760845097
- Cited by
- 55
- References
- 43
- Citations by year
- 2026: 1 · 2025: 7 · 2024: 2 · 2023: 6 · 2022: 3 · 2021: 13 · 2020: 3 · 2019: 11 · 2018: 9
- FWCI
- 4.41
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- NeuroToxicology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China (81503052, 81571244, 81771378, 81371391)
- Public Welfare Research and Capacity Building Project of Guangdong Province (2014A020212164)
- Basic and Applied Basic Research Project of Guangdong Province (2016A030313322)
- Guangzhou Science and Technology Research Project (201607010219, 2017A030313840)
- Fundamental Research Fund for University Youth Scholars (17ykpy39)
- Topics
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- rifampicin, rotenone, microglial inflammation, autophagy, mitophagy, Parkinson's disease, neuroinflammation, neuroprotection, mitochondrial dysfunction, chloroquine, IL-1β, interleukin-6, reactive oxygen species, mitochondrial membrane potential, LC3-II/LC3-I ratio, BV-2 cells, SH-SY5Y cells, mitochondrial complex I inhibition
- MeSH terms
- Analysis of Variance, Autophagy, Chloroquine, Humans, Insecticides, Mitochondria, Neuroblastoma, Rifampin, Rotenone, Interleukin-6, Reactive Oxygen Species, Microglia, Antirheumatic Agents, Neuroprotective Agents, Coculture Techniques, Cell Line, Tumor, Microscopy, Electron, Transmission, Membrane Potential, Mitochondrial, Interleukin-1beta
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