Sublingual Edaravone Dexborneol for the Treatment of Acute Ischemic Stroke: The TASTE-SL Randomized Clinical Trial.

Importance: Sublingual edaravone dexborneol, which can rapidly diffuse and be absorbed through the oral mucosa after sublingual exposure, is a multitarget brain cytoprotection composed of antioxidant and anti-inflammatory ingredients edaravone and dexborneol. Objective: To investigate the efficacy and safety of sublingual edaravone dexborneol on 90-day functional outcome in patients with acute ischemic stroke (AIS). Design, Setting, and Participants: This was a double-blind, placebo-controlled, multicenter, parallel-group, phase 3 randomized clinical trial conducted from June 28, 2021, to August 10, 2022, with 90-day follow-up. Participants were recruited from 33 centers in China. Patients randomly assigned to treatment groups were aged 18 to 80 years and had a National Institutes of Health Stroke Scale score between 6 and 20, a total motor deficit score of the upper and lower limbs of 2 or greater, a clinically diagnosed AIS symptom within 48 hours, and a modified Rankin Scale (mRS) score of 1 or less before stroke. Patients who did not meet the eligibility criteria or declined to participate were excluded. Intervention: Patients were assigned, in a 1:1 ratio, to receive sublingual edaravone dexborneol (edaravone, 30 mg; dexborneol, 6 mg) or placebo (edaravone, 0 mg; dexborneol, 60 µg) twice daily for 14 days and were followed up until 90 days. Main Outcomes and Measures: The primary efficacy outcome was the proportion of patients with mRS score of 1 or less on day 90 after randomization. Results: Of 956 patients, 42 were excluded. A total of 914 patients (median [IQR] age, 64.0 [56.0-70.0] years; 608 male [66.5%]) were randomly allocated to the edaravone dexborneol group (450 [49.2%]) or placebo group (464 [50.8%]). The edaravone dexborneol group showed a significantly higher proportion of patients experiencing good functional outcomes on day 90 after randomization compared with the placebo group (290 [64.4%] vs 254 [54.7%]; risk difference, 9.70%; 95% CI, 3.37%-16.03%; odds ratio, 1.50; 95% CI, 1.15-1.95, P = .003). The rate of adverse events was similar between the 2 groups (89.8% [405 of 450] vs 90.1% [418 of 464]). Conclusion and Relevance: Among patients with AIS within 48 hours, sublingual edaravone dexborneol could improve the proportion of those achieving a favorable functional outcome at 90 days compared with placebo. Trial Registration: ClinicalTrials.gov Identifier: NCT04950920.

Diagnostic utility of GDF15 in neurodegenerative diseases: A systematic review and meta-analysis.

INTRODUCTION: GDF15 may be a potential biomarker for neurodegenerative diseases. In this analysis, we aimed to quantitative analysis the levels of GDF15 in patients with neurological diseases and in health control, and then to determine its potential diagnostic utility. METHODS: Two researchers separately conducted a systematic search of the relevant studies up to January 2021 in Embase, PubMed, and Web of Science. Effect sizes were estimated to use the standardized mean difference (SMD) with 95% confidence interval (CI). Sensitivity and specificity were calculated by the summary receiver operating characteristics curve (SROC) method. The sensitivity analysis was performed by the "one-in/one-out" approach. Considering the considerable heterogeneity among studies, random-effects model was used for the meta-analysis investigation. RESULTS: A total of eight articles were included in this meta-analysis and systematic review. The pooled results of the random effect model indicated GDF15 levels were significantly higher in patients with neurodegenerative disease than healthy people (SMD = 0.92, 95% CI: 0.44-1.40, Z = 3.75, p < 0.001). Sensitivity and specificity of biomarker of GDF15 were 0.90 (95% CI: 0.75-0.97), 0.77 (95% CI: 0.67-0.65), and AUC = 0.87 (95% CI: 0.84-0.90), respectively. CONCLUSIONS: GDF15 levels were higher in patients with neurodegenerative disease than healthy people. And serum levels of GDF15 were a better marker for diagnostic utility of neurodegenerative disease.

Retracted: Astragalus Polysaccharide Protects Neurons and Stabilizes Mitochondrial in a Mouse Model of Parkinson Disease.

Retraction requested by author due to an admission of research fraud. Reference: Hong Liu, Si Chen, Cunju Guo, Wenqiang Tang, Wei Liu, Yiming Liu. Astragalus Polysaccharide Protects Neurons and Stabilizes Mitochondrial in a Mouse Model of Parkinson Disease. Med Sci Monit. 2018; 24: ANS5192-5199. 10.12659/MSM.908021.

GDF-15 promotes mitochondrial function and proliferation in neuronal HT22 cells.

The neuronal cell line HT22 is an excellent model for studying Parkinson's disease. Growth differentiation factor 15 (GDF15) plays a critical role in Parkinson's disease, but the molecular mechanism involved are not well understood. We constructed the GDF15 overexpression HT22 cells and detected the effects of overexpression of GDF15 on the viability, oxygen consumption, mitochondrial membrane potential of oligomycin-treated HT22 cells. In addition, we used a high-throughput RNA-sequencing to study the lncRNA and mRNA expression profiling and obtained key lncRNAs, mRNA, gene ontology (GO), and Kyoto encyclopedia of genes and genomes (KEGG) pathway. The expression of selected DElncRNAs was validated by quantitative real-time PCR (qRT-PCR). Our results showed that overexpression of GDF15 significantly reversed the cells viability, oxygen consumption, and mitochondrial membrane potential effect caused by oligomycin in HT22 cells. The 1093 DEmRNAs and 395 DElncRNAs in HT22 cells between GDF15-oligomycin non-intervention group and a normal control-oligomycin un-intervention group were obtained, and 394 DEmRNAs and 271 DElncRNAs in HT22 cells between GDF15-oligomycin intervention group and normal control-oligomycin intervention group were identified. Base on the GO and KEGG enrichment analysis of between GDF15-oligomycin intervention group and normal control-oligomycin intervention group, positive regulation of cell proliferation was most significantly enriched GO terms, and Cav1 was enriched in positive regulation of cell proliferation pathway. PI3K-Akt signaling pathway was one significantly enriched pathway in GDF15-oligomycin intervention group. The qRT-PCR results were consistent with RNA-sequencing, generally. GDF15 might promote mitochondrial function and proliferation of HT22 cells by regulating PI3K/Akt signaling pathway. Our study may be helpful in understanding the potential molecular mechanism of GDF15 in Parkinson's disease.

Astragalus Polysaccharide Protects Neurons and Stabilizes Mitochondrial in a Mouse Model of Parkinson Disease.

BACKGROUND Astragalus polysaccharides (APS) have a very good therapeutic effect in the treatment of neurodegenerative diseases and nerve injury disease. However, research on Parkinson disease (PD) treatment with APS is lacking. MATERIAL AND METHODS The present study was designed to explore the effects of APS on the protection of neurons and mitochondrial in a mouse model of PD using behavioral experiments, and observations of mitochondrial structure and transmembrane potential. RESULTS It was shown that APS could attenuate 1-methyl-4-pheyl-1,2,3,6-tetrahydropyridine (MPTP)-induced motor dysfunction (P<0.01), increase the proportion of TH-positive cells (P<0.01), reverse MPTP-induced mitochondrial structural damage, and reduce MPTP-induced high levels of reactive oxygen species (ROS) and increase MPTP-induced decrease in mitochondrial membrane potential. In addition, APS also decreased the bax/bcl2 ratio, and cytochrome-c and caspase-3 protein content (P<0.01) in substantia nigra in our mouse PD model. CONCLUSIONS APS provided a protective effect on neurons and mitochondrial in a mouse PD model.

[Analysis of SMPD1 gene mutations in Chinese patients with Parkinson's disease].

OBJECTIVE: To explore the role of sphingomyedlin phosphodiesterase 1 (SMPD1) gene mutations in the pathogenesis of Parkinson's disease (PD). METHODS: For 110 Chinese patients with PD, all exons of the SMPD1 gene were sequenced, and the results were compared with reference sequence from GenBank to identify possible mutations. RESULTS: A novel heterozygous mutation Ex2:c.677C>A/p.P226Q (likely pathogenic) was identified in a patient, which resulted in substitution of Glutamic acid by Proline at position 226. In addition, two known single nucleotide polymorphisms (SNPs) Ex1:c.107T>C/p.V36A (benign) and Ex6:c.1522G>A/p.G508R (benign), and three previously reported SMPD1 mutations Ex2:c.T371T>G/p.L124R (uncertain significance), Ex2:c.636T>C/P.(=)(benign) and Ex6:c.1598C>T/p.P533L (uncertain significance) were identified. The novel p.P226Q mutation and p.P533L mutation were predicted to have a possibly damaging effect on the structure and function of SMPD1 protein, which in turn may lead to PD. CONCLUSION: The mutation rate of the SMPD1 gene was 3.64% among Chinese PD patients. Genetic variants of SMPD1 may increase the risk of PD.

Baicalein ameliorated the upregulation of striatal glutamatergic transmission in the mice model of Parkinson's disease.

Parkinson's disease (PD) is a common neurodegenerative disorder, which is characterized by a loss of projecting dopaminergic neurons in the substantia nigra and diminished dopamine level in the striatum. Dopaminergic deficit consequently leads to the alterations of striatal basal glutamatergic synaptic transmission and plasticity in the medium spiny neurons. The cytokines and neurotoxins released from the reactive immune cells induced the loss of the projecting dopaminergic neurons in the substantia nigra, which triggering the pathogenesis of PD. The present study investigated the effect of treatment with baicalein (5,6,7-trihydroxyflavone) on the central cytokine synthesis, striatal glutamatergic transmission, and behavioral performance in the rotarod task in the mice injected with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Treatment with baicalein significantly attenuated the upregulation of striatal basal glutamatergic strength by decreasing the presynaptic glutamate release and recovering the insertion of postsynaptic glutamate receptor subunit GluR1 induced by MPTP. It also significantly improved the behavioral performance in the rotarod task in the mice injected with MPTP. Treatment with baicalein decreased the upregulation of cytokines (tumor necrosis factor-α and interleukin-1ß) in the substantia nigra and striatum in the mice injected with MPTP. These results indicated that baicalein might serve as novel approach for the treatment of the patients with PD.

Does estrogen receptor gene polymorphism play a role in Parkinson's disease?

This study was designed to investigate the frequency of estrogen receptor (ER) gene polymorphism in Chinese patients with Parkinson's disease (PD). Polymerase chain reaction (PCR) method and restriction fragment length polymorphism (RFLP) were used to detect the ER gene polymorphisms in 158 PD patients and 146 healthy controls. In the PD and control groups, "x" accounted for 83.5% and 80.8%, respectively (P>0.05). "xx" was found in 77.2% of the PD group and in 69.9% of the control group (P>0.05). The frequency of "p" in the PD and control group was 67.7% and 64.0%, respectively (P>0.05). "pp" was 51.9% in the PD group and 43.8% in the control group (P>0.05). "ppxx" was found in 49.4% of the PD and 43.0% of the control subjects (P>0.05). There was no significant difference in the "x", "xx", "p", "pp" or "ppxx" between males and females within the PD or control groups. In conclusion, we found no significant differences in the genotype or allele frequencies between patients with Parkinson's disease and healthy subjects. These findings suggest that the estrogen receptor gene polymorphism may not play a key role in the pathogenesis PD in Chinese patients.

Protective effect of estrogen on apoptosis in a cell culture model of Parkinson's disease.

OBJECTIVES: The protective effect of estrogen on the neurons in Parkinson's disease (PD) is unclear. The present study aimed to investigate the effect of estrogen on the apoptosis and dopaminergic function on a cultured cell model of PD. METHODS: The PD model was established by addition of 1-methyl-4-phenylpyridinium (MPP+) to PC12 cell culture. Estrogen was added to cell groups with MPP+ (Estrogen+MPP+), and without MPP+ (Estrogen only group). Cell viability, content of tyrosine hydroxylase (TH), apoptosis ratio, expression of apoptosis-suppression protein Bcl-x and apoptosis-acceleration protein IL-1 beta converting enzyme (ICE) were measured. RESULTS: Cell viability in the Estrogen+MPP+ group was similar to the control group but was higher than in the MPP+ group (P < 0.05). The apoptosis ratios in the Estrogen+MPP+ group (33.6%), and the control group (31.3%), were also similar, but it was lower than in the MPP+ group (63.5%, P < 0.05). Concentrations of Bcl-x were higher in the Estrogen+MPP+ group, whereas ICE concentrations were lower than in the MPP+ group (P < 0.05). CONCLUSIONS: Estrogen suppresses apoptosis and improves cell viability in MPP+ induced injuries in the PC12 cells. The beneficial effects of estrogen on the PD model are due to the suppression of pro-apoptotic protein ICE, and stimulation of anti-apoptotic protein Bcl-x.