Dl-3-n-butylphthalide rescues dopaminergic neurons in Parkinson's disease models by inhibiting the NLRP3 inflammasome and ameliorating mitochondrial …
R Que, J Zheng, Z Chang, W Zhang, H Li, Z Xie… - Frontiers in …, 2021 - frontiersin.org
R Que, J Zheng, Z Chang, W Zhang, H Li, Z Xie, Z Huang, HT Wang, J Xu, D Jin, W Yang…
Frontiers in immunology, 2021•frontiersin.orgBackground Neuroinflammation 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 …
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 …
Background
Neuroinflammation 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.
Methods
In 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.
Results
The 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.
Conclusions
In 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.
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