Background: Emerging evidence indicates that inflammasome-induced inflammation plays a crucial role in the pathogenesis of Parkinson’s disease (PD). Several proteins including α-synuclein trigger the activation of NLRP3 inflammasome. However, few studies examined whether inflammasomes are activated in the periphery of PD patients and their possible value in the diagnosis or tracking of the progress of PD. The aim of this study was to determine the association between inflammasome-induced inflammation and clinical features in PD. Methods: There were a total of 67 participants, including 43 patients with PD and 24 controls, in the study. Participants received a complete evaluation of motor and non-motor symptoms, including Hoehn and Yahr (H-Y) staging scale. Blood samples were collected from all participants. The protein and mRNA expression levels of inflammasomes subtypes and components in peripheral blood mononuclear cells (PBMCs) were determined using western blotting and RT-qPCR. We applied Meso Scale Discovery (MSD) immunoassay to measure the plasma levels of IL-1β and α-synuclein. Results: We observed increased gene expression of NLRP3, ASC, and caspase-1 in PBMCs, and increased protein levels of NLRP3, caspase-1, and IL-1β in PD patients. Plasma levels of IL-1β were significantly higher in patients with PD compared with controls and have a positive correlation with H-Y stage and UPDRS part III scores. Furthermore, plasma α-synuclein levels were also increased in PD patients and have a positive correlation with both UPDRS part III scores and plasma IL-1β levels. Conclusions: Our data demonstrated that the NLRP3 inflammasome is activated in the PBMCs from PD patients. The related inflammatory cytokine IL-1β and total α-synuclein in plasma were increased in PD patients than controls, and both of them presented a positive correlation with motor severity in patients with PD. Furthermore, plasma α-synuclein levels have a positive correlation with IL-1β levels in PD patients. All these findings suggested that the NLRP3 inflammasome activation-related cytokine IL-1β and α-synuclein could serve as non-invasive biomarkers to monitor the severity and progression of PD in regard to motor function.

Emerging evidence indicates that nod-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome-induced inflammation plays a crucial role in the pathogenesis of Parkinson’s disease (PD). Thus, inhibition of NLRP3 inflammasome activation may offer a therapeutic benefit in the treatment of PD. Tenuigenin, a major active component of Polygala tenuifolia, has been shown to have potential anti-inflammatory activity, but the underlying mechanisms remain obscure. In the present study, the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of PD was established to explore the effect of tenuigenin on dopaminergic neurons in substantia nigra. We next activated NLRP3 inflammasome in both BV2 microglia cells and adult mice to investigate the mechanisms for the neuroprotective effect of tenuigenin. We demonstrated that treatment with tenuigenin increased striatal dopaminergic levels and improved motor impairment induced by MPTP. Also, tenuigenin significantly ameliorated the degeneration of dopaminergic neurons and inhibited NLRP3 inflammasome activation in substantia nigra of MPTP mouse model. We further found that tenuigenin reduced intracellular reactive oxygen species (ROS) production and suppressed NLRP3 inflammasome activation, subsequent caspase-1 cleavage, and interleukin-1β secretion in BV2 microglia cells. These data indicate that tenuigenin inhibits the activation of NLRP3 inflammasome via downregulating ROS. Correspondingly, in vivo data showed that tenuigenin attenuates microglia activation induced by lipopolysaccharide (LPS) in substantia nigra via suppressing NLRP3 inflammasome. Our findings reveal that tenuigenin protects dopaminergic neurons from inflammation partly through inhibition of NLRP3 inflammasome activation in microglia, and suggest the promising clinical use of tenuigenin for PD therapy.

The mitochondrion is susceptible to neurodegenerative disorders such as Parkinson's disease (PD). Mitochondrial dysfunction has been considered to play an important role in the dopaminergic degeneration in PD. However, there are no effective drugs to protect mitochondria from dysfunction during the disease development. In the present study, fucoidan, a sulfated polysaccharide derived from Laminaria japonica, was investigated and characterized for its protective effect on the dopamine system and mitochondrial function of dopaminergic neurons in a rotenone-induced rat model of PD. We found that chronic treatment with fucoidan significantly reversed the loss of nigral dopaminergic neurons and striatal dopaminergic fibers and the reduction of striatal dopamine levels in PD rats. Fucoidan also alleviated rotenone-induced behavioral deficits. Moreover, the mitochondrial respiratory function as detected by the mitochondrial oxygen consumption and the expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) and nuclear transcription factor 2 (NRF2) were reduced in the substantia nigra of PD rats, which were markedly reversed by fucoidan. Oxidative products induced by rotenone were significantly reduced by fucoidan. Taken together, these results demonstrate that fucoidan possesses the ability to protect the dopamine system in PD rats. The neuroprotective effect of fucoidan may be mediated via reserving mitochondrial function involving the PGC-1α/NRF2 pathway. This study provides new evidence that fucoidan can be explored in PD therapy.

Summary: Background: Fucoidan, a sulfated polysaccharide extracted from brown algae, possesses potent antiinflammatory effects.Aims: To examine the effect of fucoidan treatment on inflammation‐mediated dopaminergic neuronal damage and its potential mechanisms.Methods: Microglial activation and injury of dopaminergic neurons were induced by intranigral injection of lipopolysaccharide (LPS), and the effects of fucoidan treatment on animal behavior, microglial activation and survival ratio of dopaminergic neurons were investigated. We further observed the efficacy of fucoidan on tumor necrosis factor‐alpha (TNF‐α) and the production of reactive oxygen species (ROS) in LPS‐activated primary microglia.Results: Fucoidan significantly improved the behavioral manifestation, prevented the loss of dopaminergic neurons and inhibited the deleterious activation of microglia in the substantia nigra pars compacta of LPS‐treated rats. Further in vitro experiments indicated that the excessive production of TNF‐α and ROS in LPS‐induced primary microglia were significantly inhibited by fucoidan administration.Conclusion: This is the first study to demonstrate that fucoidan possesses neuroprotective effects on injured dopaminergic neurons in a LPS‐induced animal model of Parkinson's disease. The mechanisms underlying these effects may include its potent down‐regulation of intracellular ROS and subsequent proinflammatory cytokine release in LPS‐activated microglia.

Accumulation of amyloid β (Aβ) peptide, inflammation, and oxidative stress contribute to Alzheimer's disease (AD) and trigger complex pathogenesis. The ketone body β‐hydroxybutyrate (BHBA) is an endogenous metabolic intermediate that protects against stroke and neurodegenerative diseases, but the underlying mechanisms are unclear. The present study aims to elucidate the protective effects of BHBA in the early stage of AD model and investigate the underlying molecular mechanisms. Three‐and‐half‐month‐old double‐transgenic mice (5XFAD) overexpressing β‐amyloid precursor protein (APP) and presenilin‐1 (PS1) were used as the AD model. The 5XFAD mice received 1.5 mmol/kg/d BHBA subcutaneously for 28 days. Morris water maze test, nest construction, and passive avoidance experiments were performed to assess the therapeutic effects on AD prevention in vivo, and brain pathology of 5XFAD mice including amyloid plaque deposition and microglia activation were assessed. Gene expression profiles in the cortexes of 5XFAD‐ and BHBA‐treated 5XFAD mice were performed with high‐throughput sequencing and bioinformatic analysis. Mouse HT22 cells were treated with 2 mM BHBA to explore its in vitro protective effects of BHBA on hippocampal neurons against Aβ oligomer toxicity, ATP production, ROS generation, and mitochondrial aerobic respiratory function. APP, BACE1, and neprilysin (NEP) expression levels were evaluated in HT22 cells following treatment with BHBA by measuring the presence or absence of G protein‐coupled receptor 109A (GPR109A). BHBA improved cognitive function of 5XFAD mice in Morris water maze test, nesting construction and passive avoidance experiments, and attenuated Aβ accumulation and microglia overactivation in the brain. BHBA also enhanced mitochondrial respiratory function of hippocampal neurons and protected it from Aβ toxicity. The enzymes, APP and NEP were regulated by BHBA via G‐protein‐coupled receptor 109A (GPR109A). Furthermore, RNA sequencing revealed that BHBA‐regulated genes mainly annotated in aging, immune system, nervous system, and neurodegenerative diseases. Our data suggested that BHBA confers protection against the AD‐like pathological events in the AD mouse model by targeting multiple aspects of AD and it may become a promising candidate for the prevention and treatment of AD.

Accumulating evidence indicates that oxidative stress plays a critical role in Parkinson's disease (PD). Our previous work has shown that 100 Hz electro-acupuncture (EA) stimulation at ZUSANLI (ST36) and SANYINJIAO (SP6) protects neurons in the substantia nigra pars compacta from 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxicity in male C57BL/6 mice, a model of PD. In the present study we administered 100 Hz EA stimulation at the two acupoints to MPTP-lesioned mice for 12 sessions starting from the day prior to the first MPTP injection. We found that in the striatum of MPTP treated mice 100 Hz EA stimulation effectively inhibited the production of hydrogen peroxide and malonaldehyde, and increased glutathione concentration and total superoxide dismutase activity through biochemical methods. However, it decreased glutathione peroxidase activity via biochemical analysis and did not affect the level of 1-methyl-4-phenylpyridinium in the striatum revealed by high performance liquid chromatography with ultraviolet detection. These data suggest that 100 Hz EA stimulation at ST36 and SP6 has antioxidative effects in the MPTP model of PD. This data, along with our previous work, indicates that 100 Hz EA stimulation at ST36 and SP6 protects the nigrostriatal system by multiple mechanisms including antioxidation and antiapoptosis, and suggests that EA stimulation is a promising therapy for treating PD.