Pyrroloquinoline Quinone Inhibits Rotenone-Induced Microglia Inflammation by Enhancing Autophagy

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.

Disclosing the Antioxidant and Neuroprotective Activity of an Anthocyanin-Rich Extract from Sweet Cherry (Prunus avium L.) Using In Vitro and In Vivo Models

“…These results are in agreement with other work that evaluated the effect of CM from BV-2 cells on SH-SY5Y cells for other classes of protective compounds [ 43 , 44 ].…”

Obesity impairs therapeutic efficacy of mesenchymal stem cells by inhibiting cardiolipin-dependent mitophagy and intercellular mitochondrial transfer in mouse models of allergic airway inflammation

“…These results point toward a new role of PQQ in inducing mitophagy in MSCs, besides regulating mitochondrial biogenesis and mtROS, as shown by others ( 60, 72 ). Our findings here are consistent with a recent report showing that PQQ induces autophagy in human microglia by regulating LC3 maturation and Atg5 expression, independent of its effect on mitochondrial biogenesis ( 61 ). Further, in neuroblastoma cells and mice models, PQQ induces AMPK1 expression, which is a crucial regulator of autophagosome formation ( 62 ).…”

“…4A). Earlier studies have reported that PQQ attenuates mtROS and improves mitochondrial health, and increases autophagy (60)(61)(62), so based on these rational we choose PQQ in subsequent experiments to explore its role in alleviating mitochondrial health of MSC-Ob. Initially, we tested various time points of PQQ to find the optimal dose by looking at its effect in lowering the mtROS.…”

Sirtuins Modulation: A Promising Strategy for HIV-Associated Neurocognitive Impairments

“…The following effects of PQQ are the increase of gene expression of PGC1α and downstream targets such as TFAM [ 152 ]. In microglia, it was proved that PQQ neuroprotective properties have been reported by activation of PINK1/parkin-mediated mitophagy in rotenone-exposed cells [ 172 ]. In the case of melatonin, a neurohormone produced by the pineal gland, it has been observed that SIRT3 activity rises without increasing its expression in an atherosclerosis mouse model [ 134 ] or in cadmium-exposed HepG2 cells [ 153 ].…”