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

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.

Multimodal analysis of gene expression from postmortem brains and blood identifies synaptic vesicle trafficking genes to be associated with Parkinson's disease.

OBJECTIVE: We aimed to identify key susceptibility gene targets in multiple datasets generated from postmortem brains and blood of Parkinson's disease (PD) patients and healthy controls (HC). METHODS: We performed a multitiered analysis to integrate the gene expression data using multiple-gene chips from 244 human postmortem tissues. We identified hub node genes in the highly PD-related consensus module by constructing protein-protein interaction (PPI) networks. Next, we validated the top four interacting genes in 238 subjects (90 sporadic PD, 125 HC and 23 Parkinson's Plus Syndrome (PPS)). Utilizing multinomial logistic regression analysis (MLRA) and receiver operating characteristic (ROC), we analyzed the risk factors and diagnostic power for discriminating PD from HC and PPS. RESULTS: We identified 1333 genes that were significantly different between PD and HCs based on seven microarray datasets. The identified MEturquoise module is related to synaptic vesicle trafficking (SVT) dysfunction in PD (P < 0.05), and PPI analysis revealed that SVT genes PPP2CA, SYNJ1, NSF and PPP3CB were the top four hub node genes in MEturquoise (P < 0.001). The levels of these four genes in PD postmortem brains were lower than those in HC brains. We found lower blood levels of PPP2CA, SYNJ1 and NSF in PD compared with HC, and lower SYNJ1 in PD compared with PPS (P < 0.05). SYNJ1, negatively correlated to PD severity, displayed an excellent power to discriminating PD from HC and PPS. CONCLUSIONS: This study highlights that SVT genes, especially SYNJ1, may be promising markers in discriminating PD from HCs and PPS.

Cystatin C is a potential predictor of unfavorable outcomes for cerebral ischemia with intravenous tissue plasminogen activator treatment: A multicenter prospective nested case-control study.

BACKGROUND AND PURPOSE: The aim of this study was to explore whether cystatin C (CysC) could be used as a potential predictor of clinical outcomes in acute ischemic stroke (AIS) patients treated with intravenous tissue plasminogen activator (IV-tPA). METHODS: We performed an observational study including a retrospective analysis of data from 125 AIS patients with intravenous thrombolysis. General linear models were applied to compare CysC levels between groups with different outcomes; logistic regression analysis and receiver-operating characteristic curves were adopted to identify the association between CysC and the therapeutic effects. RESULTS: Compared with the "good and sustained benefit" (GSB) outcome group (defined as ≥4-point reduction in National Institutes of Health Stroke Scale or a score of 0-1 at 24 h and 7 days) and the "good functional outcome" (GFO) group (modified Rankin Scale score 0-2 at 90 days), serum CysC baseline levels were increased in the non-GSB and non-GFO groups. Logistic regression analysis found that CysC was an independent negative prognostic factor for GSB (odds ratio [OR] 0.010; p = 0.005) and GFO (OR 0.011; p = 0.021) after adjustment for potential influencing factors. Receiver-operating characteristic curves showed the CysC-involved combined models provided credible efficacy for predicting post-90-day favorable clinical outcome (area under the curve 0.86; p < 0.001). CONCLUSIONS: Elevated serum CysC is independently associated with unfavorable clinical outcomes after IV-tPA therapy in AIS. Our findings provide new insights into discovering potential mediators for neuropathological process or treatment in stroke.

Vascular, inflammatory and metabolic risk factors in relation to dementia in Parkinson's disease patients with type 2 diabetes mellitus.

There are limited data on vascular, inflammatory, metabolic risk factors of dementia in Parkinson's disease (PD) with type 2 diabetes mellitus (DM) (PD-DM). In a study of 928 subjects comprising of 215 PD with DM (including 31 PD-DM with dementia, PD-DMD), 341 PD without DM (including 31 PD with dementia, PDD) and 372 DM without PD (including 35 DM with dementia, DMD) patients, we investigated if vascular, inflammatory, metabolic, and magnetic resonance imaging (MRI) markers were associated with dementia in PD-DM. Lower fasting blood glucose (FBG<5mmol/L, OR=4.380; 95%CI: 1.748-10.975; p=0.002), higher homocysteine (HCY>15µmol/L, OR=3.131; 95%CI: 1.243-7.888; p=0.015) and hyperlipidemia (OR=3.075; 95%CI: 1.142-8.277; p=0.026), increased age (OR=1.043; 95%CI: 1.003-1.084; p=0.034) were the most significant risk factors in PDD patients. Lower low-density lipoprotein cholesterol (LDL-C<2mmol/L, OR=4.499; 95%CI: 1.568-12.909; p=0.005) and higher fibrinogen (>4g/L, OR=4.066; 95%CI: 1.467-11.274; p=0.007) were the most significant risk factors in PD-DMD patients. The area under the curve (AUC) for fibrinogen and LDL-C was 0.717 (P=0.001), with a sensitivity of 80.0% for the prediction of PD-DMD.In summary, we identified several factors including LDL-C and fibrinogen as significant risk factors for PD-DMD and these may have prognostic and treatment implications.

Contra-Directional Expression of Plasma Superoxide Dismutase with Lipoprotein Cholesterol and High-Sensitivity C-reactive Protein as Important Markers of Parkinson's Disease Severity.

Aim: Oxidative stress and inflammation play critical roles in the neuropathogenesis of PD. We aimed to evaluate oxidative stress and inflammation status by measuring serum superoxide dismutase (SOD) with lipoprotein cholesterol and high-sensitivity C-reactive protein (hsCRP) respectively in PD patients, and explore their correlation with the disease severity. Methods: We performed a cross-sectional study that included 204 PD patients and 204 age-matched healthy controls (HCs). Plasma levels of SOD, hsCRP, total cholesterol, high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) were measured. A series of neuropsychological assessments were performed to rate the severity of PD. Results: The plasma levels of SOD (135.7 ± 20.14 vs. 147.2 ± 24.34, P < 0.0001), total cholesterol, HDL-C and LDL-C in PD were significantly lower than those in HCs; the hsCRP level was remarkably increased in PD compared to HC (2.766 ± 3.242 vs. 1.637 ± 1.597, P < 0.0001). The plasma SOD was negatively correlated with the hsCRP, while positively correlated with total cholesterol, HDL-C, and LDL-C in PD patients. The plasma SOD were negatively correlated with H&Y, total UPDRS, UPDRS (I), UPDRS (II), and UPDRS (III) scores, but positively correlated with MoCA and MMSE scores. Besides, hsCRP was negatively correlated with MoCA; while total cholesterol, HDL-C and LDL-C were positively correlated with the MoCA, respectively. Conclusion: Our findings suggest that lower SOD along with cholesterol, HDL-C and LDL-C, and higher hsCRP levels might be important markers to assess the PD severity. A better understanding of SOD and hsCRP may yield insights into the pathogenesis of PD.

Models of poststroke depression and assessments of core depressive symptoms in rodents: How to choose?

Our previous studies have indicated that depression and declined cognition have been involved in some neurodegenerative diseases including Stroke, Parkinson's diseases and Vascular Parkinsonism. Post-stroke depression (PSD) is the most common psychiatric disorder following a stroke and has high morbidity and mortality. Studies on PSD are increasingly common, but the specific mechanisms remain unknown. Current research mainly includes clinical and animal aspects. Questionnaires and peripheral blood examination are two of the most common methods used to study clinical PSD. The results of questionnaires are influenced by multiple factors such as disease history, education background, occupation, economic status, family relationships and social support. There are certain limitations to blood sample testing; for example, it is influenced by cerebrovascular diseases and some other disruptions of the internal environment. It is difficult for either method to fully clarify the pathophysiological mechanism of PSD. Animal models provide alternative methods to further understand the pathophysiological mechanisms of PSD, such as the involvement of neuronal circuits and cytokines. More than ten animal models of PSD have been developed, and new models are constantly being introduced. Therefore, it is important to choose the appropriate model for any given study. In this paper, we will discuss the characteristics of the different models of PSD and comment on the advantages and disadvantages of each model, drawing from research on model innovation. Finally, we briefly describe the current assessment methods for the core symptoms of PSD models, point out the shortcomings, and present the improved sucrose preference test as a rational evaluation of anhedonia.