Abstract
BackgroundNeuroinflammation and mitochondrial impairment play important roles in the neuropathogenesis of Parkinson’s disease (PD). The activation of NLRP3 inflammasome and the accumulation of α-synuclein (α-Syn) are strictly correlated to neuroinflammation. Therefore, the regulation of NLRP3 inflammasome activation and α-Syn aggregation might have therapeutic potential. It has been indicated that Dl-3-n-butylphthalide (NBP) produces neuroprotection against some neurological diseases such as ischemic stroke. We here intended to explore whether NBP suppressed NLRP3 inflammasome activation and reduced α-Syn aggregation, thus protecting dopaminergic neurons against neuroinflammation.MethodsIn our study, we established a MPTP-induced mouse model and 6-OHDA-induced SH-SY5Y cell model to examine the neuroprotective actions of NBP. We then performed behavioral tests to examine motor dysfunction in MPTP-exposed mice after NBP treatment. Western blotting, immunofluorescence staining, flow cytometry and RT-qPCR were conducted to investigate the expression of NLRP3 inflammasomes, neuroinflammatory cytokines, PARP1, p-α-Syn, and markers of microgliosis and astrogliosis.ResultsThe results showed that NBP exerts a neuroprotective effect on experimental PD models. In vivo, NBP ameliorated behavioral impairments and reduced dopaminergic neuron loss in MPTP-induced mice. In vitro, treatment of SH-SY5Y cells with 6-OHDA (100uM,24 h) significantly decreased cell viability, increased intracellular ROS production, and induced apoptosis, while pretreatment with 5uM NBP could alleviated 6-OHDA-induced cytotoxicity, ROS production and cell apoptosis to some extent. Importantly, both in vivo and in vitro, NBP suppressed the activation of the NLRP3 inflammasome and the aggregation of α-Syn, thus inhibited neuroinflammation ameliorated mitochondrial impairments.ConclusionsIn summary, NBP rescued dopaminergic neurons by reducing NLRP3 inflammasome activation and ameliorating mitochondrial impairments and increases in p-α-Syn levels. This current study may provide novel neuroprotective mechanisms of NBP as a potential therapeutic agent.
Highlights
IntroductionThe characteristics of Parkinson’s disease (PD) are a gradual loss of dopaminergic neurons in the substantia nigra (SN) and an aggregation of a-synuclein (a-Syn) [1, 2]
Parkinson’s disease (PD) is the second neurodegenerative disorders
As NBP may provide neuroprotection by attenuating mitochondrial impairment and neuroinflammation, we aimed to explore whether NBP induces neuroprotection in PD models by modulating the NLRP3 inflammasome and how NBP interacts with a-Syn by influencing mitochondrial impairment
Summary
The characteristics of PD are a gradual loss of dopaminergic neurons in the substantia nigra (SN) and an aggregation of a-synuclein (a-Syn) [1, 2]. Several lines of evidence have indicated microglia activation in the SN regions of PD animal models and patients with PD, Abbreviations: AD, Alzheimer’s disease; a-Syn, alpha-Synuclein; GFAP, Glial fibrillary acidic protein; IBA1, Allograft inflammatory factor 1; IL-1b, interleukin1b; IL-4, interleukin-4; IL-6, interleukin-6; IL-18, interleukin-18; LBs, Lewy bodies; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; NBP, Dl-3-nbutylphthalide; ROS, reactive oxygen species; PD, Parkinson’s disease; PAR, Poly (ADP-ribose); PARP1, Poly (ADP-ribose) polymerase-1; SN, substantia nigra; TH, Tyrosine Hydroxylase; TNF-a, tumor necrosis factor-a; 6-OHDA, 6-hydroxydopamine. Neuroinflammation and mitochondrial impairment play important roles in the neuropathogenesis of Parkinson’s disease (PD). We here intended to explore whether NBP suppressed NLRP3 inflammasome activation and reduced a-Syn aggregation, protecting dopaminergic neurons against neuroinflammation
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