Celastrol Inhibits Dopaminergic Neuronal Death of Parkinson’s Disease through Activating Mitophagy

Lin, Ming‐Wei; Lin, Chi Chien; Chen, Yi‐Hung; Yang, Han-Bin; Hung, Shih-Ya

doi:10.3390/antiox9010037

Cited by 73 publications

(51 citation statements)

References 47 publications

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“…Mitophagy is the selective autophagic degradation of mitochondria; Lin et al (2020) observed that MPP + or MPTP-induced dopaminergic neuronal death, mitochondrial membrane polarization, ATP diminishing which was associated with mitophagy inhibition in SH-SY5Y cells [ 13 ]. For instance, PINK1 ( PARK2 ) and PARKIN ( PARK6 ) regulate mitochondrial function and remove damaged mitochondria by activating mitophagy [ 48 , 49 ].…”

Section: Pathogenesis and Symptoms Of Pdmentioning

confidence: 99%

“…The impairment of the autophagy-lysosome system is progressively observed as a key pathogenic mechanism in PD [ 62 ]. According to Lin et al (2020), the mechanism of celastrol against dopaminergic neuronal death was via increasing autophagosome formation and removing dysfunctional mitochondria by autophagy [ 13 ]. It suggests that autophagy activation is one of the important targets in PD treatment.…”

Section: Pathogenesis and Symptoms Of Pdmentioning

confidence: 99%

“…Lin et al (2020) administered 10 mg/kg/day of MPTP intraperitoneally for three days in male C57BL6 mice and evaluated the celastrol effect against MPTP-induced neurotoxicity. The cylinder test on the 11th day and rotarod test on the baseline and 11th day revealed that the MPTP group reduced forelimb usage and latency to fall (increased on the 11th day) compared to normal control and celastrol-treated mice [ 13 ]. Celastrol (3 mg/kg/day for three days) enhanced better PD motor symptoms induced by MPTP compared to MPTP alone treated mice [ 13 ].…”

Section: Neurotoxins Used To Induce Pd In Vivo Modelsmentioning

confidence: 99%

“…Pathologically the PD is also known as a mitochondrial disease of senescence [ 13 , 14 ]. Additionally, hereditary factors and protein aggregation are associated with neurodegeneration of dopaminergic neurons in PD [ 15 ].…”

Section: Introductionmentioning

confidence: 99%

“…Unfortunately, although levodopa therapy may initially improve PD’s motor symptoms, the benefits frequently wear off over time or become less consistent [ 20 ]. To date, no treatment is available to stop or slow the progression of PD [ 13 , 21 ]. New drug/treatment discovery for PD treatment is needed.…”

Section: Introductionmentioning

confidence: 99%

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Behavioral Tests in Neurotoxin-Induced Animal Models of Parkinson’s Disease

Prasad

Hung

2020

Antioxidants

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Currently, neurodegenerative diseases are a major cause of disability around the world. Parkinson’s disease (PD) is the second-leading cause of neurodegenerative disorder after Alzheimer’s disease. In PD, continuous loss of dopaminergic neurons in the substantia nigra causes dopamine depletion in the striatum, promotes the primary motor symptoms of resting tremor, bradykinesia, muscle rigidity, and postural instability. The risk factors of PD comprise environmental toxins, drugs, pesticides, brain microtrauma, focal cerebrovascular injury, aging, and hereditary defects. The pathologic features of PD include impaired protein homeostasis, mitochondrial dysfunction, nitric oxide, and neuroinflammation, but the interaction of these factors contributing to PD is not fully understood. In neurotoxin-induced PD models, neurotoxins, for instance, 6-hydroxydopamine (6-OHDA), 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), 1-Methyl-4-phenylpyridinium (MPP+), paraquat, rotenone, and permethrin mainly impair the mitochondrial respiratory chain, activate microglia, and generate reactive oxygen species to induce autooxidation and dopaminergic neuronal apoptosis. Since no current treatment can cure PD, using a suitable PD animal model to evaluate PD motor symptoms’ treatment efficacy and identify therapeutic targets and drugs are still needed. Hence, the present review focuses on the latest scientific developments in different neurotoxin-induced PD animal models with their mechanisms of pathogenesis and evaluation methods of PD motor symptoms.

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Section: Pathogenesis and Symptoms Of Pdmentioning

confidence: 99%

Section: Pathogenesis and Symptoms Of Pdmentioning

confidence: 99%

Section: Neurotoxins Used To Induce Pd In Vivo Modelsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Behavioral Tests in Neurotoxin-Induced Animal Models of Parkinson’s Disease

Prasad

Hung

2020

Antioxidants

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Degradation‐Based Protein Profiling: A Case Study of Celastrol

Ni,

Shi,

Liu

et al. 2024

Advanced Science

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Natural products, while valuable for drug discovery, encounter limitations like uncertainty in targets and toxicity. As an important active ingredient in traditional Chinese medicine, celastrol exhibits a wide range of biological activities, yet its mechanism remains unclear. In this study, they introduced an innovative “Degradation‐based protein profiling (DBPP)” strategy, which combined PROteolysis TArgeting Chimeras (PROTAC) technology with quantitative proteomics and Immunoprecipitation‐Mass Spectrometry (IP‐MS) techniques, to identify multiple targets of natural products using a toolbox of degraders. Taking celastrol as an example, they successfully identified its known targets, including inhibitor of nuclear factor kappa B kinase subunit beta (IKKβ), phosphatidylinositol‐4,5‐bisphosphate 3‐kinase catalytic subunit alpha (PI3Kα), and cellular inhibitor of PP2A (CIP2A), as well as potential new targets such as checkpoint kinase 1 (CHK1), O‐GlcNAcase (OGA), and DNA excision repair protein ERCC‐6‐like (ERCC6L). Furthermore, the first glycosidase degrader is developed in this work. Finally, by employing a mixed PROTAC toolbox in quantitative proteomics, they also achieved multi‐target identification of celastrol, significantly reducing costs while improving efficiency. Taken together, they believe that the DBPP strategy can complement existing target identification strategies, thereby facilitating the rapid advancement of the pharmaceutical field.

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Biosynthesis, total synthesis, structural modifications, bioactivity, and mechanism of action of the quinone‐methide triterpenoid celastrol

Lü

Liu

Zhou

et al. 2020

Medicinal Research Reviews

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Celastrol, a quinone‐methide triterpenoid, was extracted from Tripterygium wilfordii Hook. F. in 1936 for the first time. Almost 70 years later, it is considered one of the molecules most likely to be developed into modern drugs, as it exhibits notable bioactivity, including anticancer and anti‐inflammatory activity, and exerts antiobesity effects. In addition, the molecular mechanisms underlying its bioactivity are being widely studied, which offers new avenues for its development as a pharmaceutical reagent. Owing to its potential therapeutic effects and unique chemical structure, celastrol has attracted considerable interest in the fields of organic, biosynthesis, and medicinal chemistry. As several steps in the biosynthesis of celastrol have been revealed, the mechanisms of key enzymes catalyzing the formation and postmodifications of the celastrol scaffold have been gradually elucidated, which lays a good foundation for the future heterogeneous biosynthesis of celastrol. Chemical synthesis is also an effective approach to obtain celastrol. The total synthesis of celastrol was realized for the first time in 2015, which established a new strategy to obtain celastroid natural products. However, owing to the toxic effects and suboptimal pharmacological properties of celastrol, its clinical applications remain limited. To search for drug‐like derivatives, several structurally modified compounds were synthesized and tested. This review focuses primarily on the latest research progress in the biosynthesis, total synthesis, structural modifications, bioactivity, and mechanism of action of celastrol. We anticipate that this paper will facilitate a more comprehensive understanding of this promising compound and provide constructive references for future research in this field.

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Celastrol Inhibits Dopaminergic Neuronal Death of Parkinson’s Disease through Activating Mitophagy

Cited by 73 publications

References 47 publications

Behavioral Tests in Neurotoxin-Induced Animal Models of Parkinson’s Disease

Behavioral Tests in Neurotoxin-Induced Animal Models of Parkinson’s Disease

Degradation‐Based Protein Profiling: A Case Study of Celastrol

Biosynthesis, total synthesis, structural modifications, bioactivity, and mechanism of action of the quinone‐methide triterpenoid celastrol

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