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Rationale: Synucleinopathies, including Parkinson's disease (PD), multiple system atrophy (MSA), and dementia with Lewy bodies (DLB), share a distinct pathological feature, that is, a widespread accumulation of α‐synuclein (α‐syn) in the brain. There is a significant clinical unmet need for disease‐modifying treatments for synucleinopathies. Recently, a seaweed‐derived mixture of oligosaccharides sodium oligomannate, GV‐971, was approved for Phase 2 clinical trials for PD. This study aimed to further evaluate the therapeutic effects of GV‐971 on synucleinopathies using cellular and animal models and explore its associated molecular mechanisms. Methods: α‐Syn aggregation was assessed, in vitro and ex vivo, by ThT assay. A dopaminergic neuron cell line, Prnp‐SNCAA53T mice, and brain slices from PD and DLB patients were used to determine the efficacy of GV‐971 in ameliorating α‐syn pathology. Measurements of motor functions, including pole, cylinder, and rotarod tests, were conducted on Prnp‐SNCAA53T mice 4 weeks after intragastric administration of GV‐971 (200 mg day−1 kg−1). Results: GV‐971 effectively prevented α‐syn aggregation and even disassembled pre‐aggregated α‐syn fibrils, in vitro and ex vivo. In addition, GV‐971 was able to rescue α‐syn‐induced neuronal damage and reduced release of extracellular vesicles (EVs), likely via modulating Alix expression. In the Prnp‐SNCAA53T mouse model, when treated at the age of 5 months, GV‐971 significantly decreased α‐syn deposition in the cortex, midbrain, and cerebellum regions, along with ameliorating the motor dysfunctions. Conclusions: Our results indicate that GV‐971, when administered at a relatively early stage of the disease process, significantly reduced α‐syn accumulation and aggregation in Prnp‐SNCAA53T mice. Furthermore, GV‐971 corrected α‐syn‐induced inhibition of EVs release in neurons, contributing to neuronal protection. Future studies are needed to further assess GV‐971 as a promising disease‐modifying therapy for PD and other synucleinopathies. [ABSTRACT FROM AUTHOR]

Purpose: This study aimed to develop and evaluate triptolide nanoemulsion gels (TP-NE gels) as a transdermal drug delivery system., Methods: TP-NE was prepared and optimized via emulsification and the central composite design response surface method. The optimized TP-NE gel was evaluated in vitro and in vivo. TP-NE gel microstructure, in vitro and in vivo pharmacokinetics, and anti-rheumatoid arthritis effects were studied to evaluate the feasibility of its percutaneous administration., Results: The Optimized TP-NE was observed using a Malvern Autosizer Nano ZS 90 inspection system and a transmission electron microscope (TEM). The nanoemulsion had an average size of 162.9 ± 0.281 nm, a polydispersity index of 0.272 ± 0.024, a zeta potential of -30.03 ± 2.01 mV, and mostly spherical and uniform morphology. In addition, the TP-NE gel pharmacokinetics, assessed via a skin-blood two-site synchronous microdialysis, revealed that TP was higher in the skin than in the blood. TP-NE gel is crucial in reducing knee edema, inhibiting inflammation, and treating rheumatoid arthritis by regulating tumor necrosis factor-alpha, interleukin-1β, and -6 levels., Conclusion: The TP-NE gel is a promising local delivery method for rheumatoid arthritis (RA)-associated edema and inflammation and can serve as a prospective platform for percutaneous TP administration., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)