Pyrroloquinoline Quinone Inhibits Rotenone-Induced Microglia Inflammation by Enhancing Autophagy.

Qi Zhang,Fei Ding,Shu Yu,Qiong Cheng,Mi Shen,Hui Xu,Jing Zhou

doi:10.3390/molecules25194359

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.

Highlights

Parkinson’s disease (PD) is a common neurodegenerative disease in the aged population, characterized with the dopaminergic neuron loss in substantia nigra pars compacta (SNpc) and the presence of Lewy bodies (LB)
A previous study indicated that rotenone could induce pro-inflammatory factors release in BV2 cells, which might be toxic to neuronal cells in the central nervous system (CNS) [23]
We demonstrated that Pyrroloquinoline quinone (PQQ) suppressed rotenone-induced microglial inflammation, and this effect was partially through enhancement of autophagy

Summary

Introduction

Parkinson’s disease (PD) is a common neurodegenerative disease in the aged population, characterized with the dopaminergic neuron loss in substantia nigra pars compacta (SNpc) and the presence of Lewy bodies (LB). Neuroinflammation is considered as one of the pathological mechanisms in neurodegenerative diseases, including PD [1]. In the central nervous system (CNS), microglia cells play an important role in innate immunity and produce most of the pro-inflammatory. Activated microglia cells mediate inflammation by producing pro-inflammatory mediators, including interleukin-1β (IL-1β), IL-6, tumor necrosis factor-α (TNF-α) and nitric oxide (NO) [4]. The factors that can affect microglia activation might display neuroprotection in neurodegenerative diseases. Pyrroloquinoline quinone (PQQ), a redox cofactor, was reported to attenuate microglia activation in lipopolysaccharide (LPS) treated mice and protect primary cortical neurons against neurotoxicity [5]

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