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Pyrroloquinoline Quinone Inhibits Rotenone-Induced Microglia Inflammation by Enhancing Autophagy
Qi Zhang1, Jing Zhou1, Mi Shen1
1Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, Nantong University, 19 Qixiu Road, Nantong 226001, China.
Abstract:
Neuroinflammation is a feature common to neurodegenerative diseases, such as Parkinson's disease (PD), which might be responsive to therapeutic intervention. Rotenone has been widely used to establish PD models by inducing mitochondrial dysfunction and inflammation. Our previous studies have reported that pyrroloquinoline quinone (PQQ), a naturally occurring redox cofactor, could prevent mitochondrial dysfunction in rotenone induced PD models by regulating mitochondrial functions. In the present study, we aimed to investigate the effect of PQQ on neuroinflammation and the mechanism involved. BV2 microglia cells were pre-treated with PQQ followed by rotenone incubation. The data showed that PQQ did not affect the cell viability of BV2 cells treated with rotenone, while the conditioned medium (CM) of BV2 cells pre-treated with PQQ significantly increased cell viability of SH-SY5Y cells. In rotenone-treated BV2 cells, PQQ dose-dependently decreased lactate dehydrogenase (LDH) release and suppressed the up-regulation of pro-inflammation factors, such as interleukin-1β (IL-1β), IL-6 and tumor necrosis factor-α (TNF-α) in the cultured media, as well as nitric oxide (NO) release induced by rotenone. PQQ pretreatment also increased the ratio of LC3-II/LC3-I and expression of Atg5 in BV2 cells stimulated with rotenone. Additionally, the autophagosome observed by transmission electron microscopy (TEM) and co-localization of mitochondria with lysosomes indicated that mitophagy was induced by PQQ in rotenone-injured BV2 cells, and the PINK1/parkin mediated mitophagy pathway was regulated by PQQ. Further, autophagy inhibitor, 3-methyladenine (3-MA), partially abolished the neuroprotective effect of PQQ and attenuated the inhibition of inflammation with PQQ pretreatment. Taken together, our data extend our understanding of the neuroprotective effect of PQQ against rotenone-induced injury and provide evidence that autophagy enhancement might be a novel therapeutic strategy for PD treatment.
Insights
Pyrroloquinoline quinone (PQQ) reduces neuroinflammation in Parkinson's disease models by enhancing mitophagy. This study shows PQQ protects against rotenone-induced injury, suggesting autophagy enhancement as a therapeutic strategy for PD.
Area of Science:
- Neuroscience
- Cell Biology
- Pharmacology
Background:
- Neuroinflammation is a hallmark of neurodegenerative diseases like Parkinson's disease (PD).
- Rotenone exposure is a common method to induce PD models, causing mitochondrial dysfunction and inflammation.
- Pyrroloquinoline quinone (PQQ) has previously shown potential in preventing mitochondrial dysfunction in PD models.
Purpose of the Study:
- To investigate the anti-neuroinflammatory effects of PQQ in a rotenone-induced PD model.
- To elucidate the underlying mechanisms of PQQ's neuroprotective action, focusing on autophagy.
Main Methods:
- BV2 microglia cells were pre-treated with PQQ and then exposed to rotenone.
- Cell viability, inflammatory markers (LDH, IL-1β, IL-6, TNF-α, NO), and autophagy markers (LC3-II/LC3-I, Atg5) were assessed.
- Transmission electron microscopy (TEM) and co-localization studies were used to evaluate mitophagy; autophagy inhibitor 3-methyladenine (3-MA) was employed.
Main Results:
- PQQ protected SH-SY5Y cells from rotenone-induced damage via conditioned medium from treated BV2 cells.
- PQQ significantly reduced rotenone-induced release of LDH, pro-inflammatory cytokines (IL-1β, IL-6, TNF-α), and nitric oxide (NO).
- PQQ enhanced autophagy and mitophagy, indicated by increased LC3-II/LC3-I ratio, Atg5 expression, and mitochondrial-lysosomal co-localization, involving the PINK1/parkin pathway.
Conclusions:
- PQQ exhibits significant neuroprotective effects against rotenone-induced neuroinflammation and injury in microglia.
- PQQ-mediated enhancement of autophagy and mitophagy is a key mechanism underlying its neuroprotective action.
- Autophagy enhancement presents a promising therapeutic strategy for Parkinson's disease treatment.
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