Dl-3-n-Butylphthalide Rescues Dopaminergic Neurons in Parkinson’s Disease Models by Inhibiting the NLRP3 Inflammasome and Ameliorating Mitochondrial Impairment

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.

NLRP3/Caspase-1-Mediated Pyroptosis of Astrocytes Induced by Antipsychotics Is Inhibited by a Histamine H1 Receptor-Selective Agonist

“…Furthermore, we have demonstrated the involvement of NLRP3 signaling in antipsychotic-induced astrocyte death. Recent findings have revealed that pharmacological blockade of NLRP3 signaling by using salidroside, Dl-3-n-butylphthalide (NBP), gliquidone, or dimethyl fumarate significantly inhibited astrocyte-mediated neuroinflammation, reduced mitochondrial impairment, improved neuronal survival, and slowed the progression of various disease ( Cai et al, 2021 ; Kim et al, 2021 ; Que et al, 2021 ; Tastan et al, 2021 ). Therefore, we suggest that inhibition of NLRP3 signaling may help suppress antipsychotic-induced inflammation and astroglia death.…”

Retinal Nerve Fiber Layer Thickness and Associations With Cognitive Impairment in Parkinson’s Disease

“…Recently increasing evidences show that neuroimaging or neuroinflammatory markers are closely related with the pathological neurodegeneration in PD ( Lian et al, 2020 ; Yang et al, 2020 ; Anandhan et al, 2021 ; Li et al, 2021 ; Liu et al, 2021 ; Que et al, 2021 ; Wang et al, 2021 ; Zhu et al, 2021b ). These humoral inflammatory or imaging biomarkers may provide valuable information for early identification, differential diagnosis, assessment of severity and even prognosis prediction for PD patients ( Avenali et al, 2020 ; Beheshti et al, 2020 ).…”

Serum NLRP3 Inflammasome and BDNF: Potential Biomarkers Differentiating Reactive and Endogenous Depression

“…Mounting evidence has suggested that the TLR4/NLRP3 signaling pathways may be the new targets for the development and treatments for depression. The NOD-like receptor family protein 3 (NLRP3) inflammasome complex displays a critical role in the pathogenesis and development of inflammation and immune response ( 11 ). Upon activation, NLRP3 leads to the maturation of the pro-inflammatory cytokines pro-IL-1β and pro-IL-18 ( 12 ).…”

“…Upon activation, NLRP3 leads to the maturation of the pro-inflammatory cytokines pro-IL-1β and pro-IL-18 ( 12 ). Oxidative stress is presumed to activate the NLRP3 inflammasome and contribute to neuroinflammation ( 11 , 13 ). A novel aspect of the immune-inflammation process in the response to stress and depression: the NLRP3 inflammasome is a key molecular mechanism that translates psychological stressful stimuli into inflammatory responses ( 14 ).…”