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Neuroprotective Effects of Cryptotanshinone in a Direct Reprogramming Model of Parkinson's Disease.

ABSTRACT: Parkinson's disease (PD) is a well-known age-related neurodegenerative disease. Considering the vital importance of disease modeling based on reprogramming technology, we adopted direct reprogramming to human-induced neuronal progenitor cells (hiNPCs) for in vitro assessment of potential therapeutics. In this study, we investigated the neuroprotective effects of cryptotanshinone (CTN), which has been reported to have antioxidant properties, through PD patient-derived hiNPCs (PD-iNPCs) model with induced oxidative stress and cell death by the proteasome inhibitor MG132. A cytotoxicity assay showed that CTN possesses anti-apoptotic properties in PD-hiNPCs. CTN treatment significantly reduced cellular apoptosis through mitochondrial restoration, such as the reduction in mitochondrial reactive oxygen species and increments of mitochondrial membrane potential. These effects of CTN are mediated via the nuclear factor erythroid 2-related factor 2 (NRF2) pathway in PD-hiNPCs. Consequently, CTN could be a potential antioxidant reagent for preventing disease-related pathological phenotypes of PD.

SUBMITTER: Lee JE

PROVIDER: S-EPMC7463464 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Neuroprotective Effects of Cryptotanshinone in a Direct Reprogramming Model of Parkinson's Disease.

Lee Joo-Eun JE Sim Hyuna H Yoo Hee Min HM Lee Minhyung M Baek Aruem A Jeon Young-Joo YJ Seo Kang-Sik KS Son Mi-Young MY Yoon Joo Seog JS Kim Janghwan J

Molecules (Basel, Switzerland) 20200807 16

Parkinson's disease (PD) is a well-known age-related neurodegenerative disease. Considering the vital importance of disease modeling based on reprogramming technology, we adopted direct reprogramming to human-induced neuronal progenitor cells (hiNPCs) for in vitro assessment of potential therapeutics. In this study, we investigated the neuroprotective effects of cryptotanshinone (CTN), which has been reported to have antioxidant properties, through PD patient-derived hiNPCs (PD-iNPCs) model with ...[more]

PMID: 32784741

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Project description:Parkinson's disease (PD) is characterized by a selective loss of dopamine (DA) neurons in the human midbrain causing motor dysfunctions. The exact mechanism behind dopaminergic cell death is still not completely understood and, so far, no cure or neuroprotective treatment for PD is available. Recent studies have brought attention to the variety of bioactive molecules produced by mesenchymal stem cells (MSCs), generally referred to as the secretome. Herein, we evaluated whether human MSCs-bone marrow derived (hBMSCs) secretome would be beneficial in a PD pre-clinical model, when compared directly with cell transplantation of hBMSCs alone. We used a 6-hydroxydpomanie (6-OHDA) rat PD model, and motor behavior was evaluated at different time points after treatments (1, 4, and 7 weeks). The impact of the treatments in the recovery of DA neurons was estimated by determining TH-positive neuronal densities in the substantia nigra and fibers in the striatum, respectively, at the end of the behavioral characterization. Furthermore, we determined the effect of the hBMSCs secretome on the neuronal survival of human neural progenitors in vitro, and characterized the secretome through proteomic-based approaches. This work demonstrates that the injection of hBMSCs secretome led to the rescue of DA neurons, when compared to transplantation of hBMSCs themselves, which can explain the recovery of secretome-injected animals' behavioral performance in the staircase test. Moreover, we observed that hBMSCs secretome induces higher levels of in vitro neuronal differentiation. Finally, the proteomic analysis revealed that hBMSCs secrete important exosome-related molecules, such as those related with the ubiquitin-proteasome and histone systems. Overall, this work provided important insights on the potential use of hBMSCs secretome as a therapeutic tool for PD, and further confirms the importance of the secreted molecules rather than the transplantation of hBMSCs for the observed positive effects. These could be likely through normalization of defective processes in PD, namely proteostasis or altered gene transcription, which lately can lead to neuroprotective effects.

Dataset Information

Neuroprotective Effects of Cryptotanshinone in a Direct Reprogramming Model of Parkinson's Disease.

Publications

Neuroprotective Effects of Cryptotanshinone in a Direct Reprogramming Model of Parkinson's Disease.

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