Dataset Information

Trojan Horse Delivery of 4,4'-Dimethoxychalcone for Parkinsonian Neuroprotection.

ABSTRACT: Parkinson's disease (PD) is characterized by the progressive deterioration of dopamine (DA) neurons, and therapeutic endeavors are aimed at preventing DA loss. However, lack of effective brain delivery approaches limits this strategy. In this study, a "Trojan horse" system is used for substantia nigra-targeted delivery of a blood brain barrier-penetrating peptide (RVG29) conjugated to the surface of nanoparticles loaded with the natural autophagy inducer 4,4'-dimethoxychalcone (DMC) (designated as RVG-nDMC). Here, the neuroprotective effects of DMC are demonstrated in PD. Specifically, RVG-nDMC penetrates the blood brain barrier with enhanced brain-targeted delivery efficiency and is internalized by DA neurons and microglia. In vivo studies demonstrate that RVG-nDMC ameliorates motor deficits and nigral DA neuron death in PD mice without causing overt adverse effects in the brain or other major organs. Moreover, RVG-nDMC reverses tyrosine hydroxylase ubiquitination and degradation, alleviates oxidative stress in DA neurons, and exerts antiinflammatory effects in microglia. The "Trojan horse" strategy for targeted delivery of DMC thus provides a potentially powerful and clinically feasible approach for PD intervention.

SUBMITTER: Zhang W

PROVIDER: S-EPMC8097374 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature

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Trojan Horse Delivery of 4,4'-Dimethoxychalcone for Parkinsonian Neuroprotection.

Zhang Wenlong W Chen Huaqing H Ding Liuyan L Gong Junwei J Zhang Mengran M Guo Wenyuan W Xu Pingyi P Li Shiying S Zhang Yunlong Y

Advanced science (Weinheim, Baden-Wurttemberg, Germany) 20210303 9

Parkinson's disease (PD) is characterized by the progressive deterioration of dopamine (DA) neurons, and therapeutic endeavors are aimed at preventing DA loss. However, lack of effective brain delivery approaches limits this strategy. In this study, a "Trojan horse" system is used for substantia nigra-targeted delivery of a blood brain barrier-penetrating peptide (RVG29) conjugated to the surface of nanoparticles loaded with the natural autophagy inducer 4,4'-dimethoxychalcone (DMC) (designated ...[more]

PMID: 33977069

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Project description:BackgroundStorage of secondary metabolites with a putative defensive role occurs in the so-called mantle dermal formations (MDFs) that are located in the more exposed parts of the body of most and very likely all members of an entire family of marine mollusks, the chromodorid nudibranchs (Gastropoda: Opisthobranchia). Given that these structures usually lack a duct system, the mechanism for exudation of their contents remains unclear, as does their adaptive significance. One possible explanation could be that they are adapted so as to be preferentially attacked by predators. The nudibranchs might offer packages containing highly repugnant chemicals along with parts of their bodies to the predators, as a defensive variant of the strategic theme of the Trojan horse.Methodology and principal findingsWe detected, by quantitative (1)H-NMR, extremely high local concentrations of secondary metabolites in the MDFs of six species belonging to five chromodorid genera. The compounds were purified by chromatographic methods and subsequently evaluated for their feeding deterrent properties, obtaining dose-response curves. We found that only distasteful compounds are accumulated in the reservoirs at concentrations that far exceed the values corresponding to maximum deterrent activity in the feeding assays. Other basic evidence, both field and experimental, has been acquired to elucidate the kind of damage that the predators can produce on both the nudibranchs' mantles and the MDFs.SignificanceAs a result of a long evolutionary process that has progressively led to the accumulation of defensive chemical weapons in localized anatomical structures, the extant chromodorid nudibranchs remain in place when molested, retracting respiratory and chemosensory organs, but offering readily accessible parts of their body to predators. When these parts are masticated or wounded by predators, breakage of the MDFs results in the release of distasteful compounds at extremely high concentration in a way that maximizes their repugnant impact.

Dataset Information

Trojan Horse Delivery of 4,4'-Dimethoxychalcone for Parkinsonian Neuroprotection.

Publications

Trojan Horse Delivery of 4,4'-Dimethoxychalcone for Parkinsonian Neuroprotection.

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