Insights into the inhibitory mechanism of skullcapflavone II against α-synuclein aggregation and its mediated cytotoxicity

Parsafar, Soha; Aliakbari, Farhang; Seyedfatemi, Sepideh Sadat; Najarzadeh, Zahra; Hourfar, Hamdam; Bardania, Hassan; Farhadpour, Mohsen; Mohammadi, Mehdi; Morshedi, Dina

doi:10.1016/j.ijbiomac.2022.03.092

Cited by 10 publications

(6 citation statements)

References 63 publications

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“…Studies have shown that small molecules, − nanoparticles, − and peptides , can inhibit the fibrillization of αS. Liu et al found that brazilin can inhibit αS fibrillogenesis and reduce cytotoxicity induced by αS aggregates in a concentration-dependent manner .…”

Section: Introductionmentioning

confidence: 99%

“…And molecular dynamics simulations showed that brazilin directly interacts with the αS pentamer through hydrophobic interactions . Parsafar et al reported that Skullcapflavone II, which has multiple neuroprotective features, can inhibit αS aggregation and disaggregate preformed fibrils . Yang et al demonstrated that epigallochatechin gallate (EGCG) destabilizes αS protofibril and impedes the model membrane damage by attenuating the hydrogen-bonding and cation−π interactions between αS protofibril and membrane .…”

Section: Introductionmentioning

confidence: 99%

“…27 preformed fibrils. 29 Yang et al demonstrated that epigallochatechin gallate (EGCG) destabilizes αS protofibril and impedes the model membrane damage by attenuating the hydrogenbonding and cation−π interactions between αS protofibril and membrane. 30 Andrikopoulos et al synthesized β-casein-coated iron oxide nanoparticles (βCas IONPs) and demonstrated the inhibitory potential of βCas IONPs on amyloid β, human islet amyloid polypeptide, and αS aggregation experimentally and computationally.…”

Section: ■ Introductionmentioning

confidence: 99%

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Influence of Protonation on the Norepinephrine Inhibiting α-Synuclein 71–82 Oligomerization

Wang,

Zhu,

et al. 2023

J. Phys. Chem. B

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The pathogenesis of Parkinson’s disease (PD) is closely linked to the massive presence of Lewy vesicles and Lewy axons in the cytoplasm of neurons, mainly consisting of α-synuclein (αS). Norepinephrine (NE), whose secretion can be increased by exercise, has been demonstrated to prevent the fibrillation of αS and to break down the mature αS fibrils. In this work, we focus on the influence of protonation on the inhibitory ability of NE by using amyloid core fragment αS71–82 as a template. All-atom replica-exchange molecular dynamics simulations (accumulating to 33.6 μs) in explicit water were performed to explore the inhibitory effect of protonated and nonprotonated NE on αS oligomerization. Our results show that NE/NE+ can lead to a significant decrease in β-sheet content with increasing temperature, while isolated αS maintains relatively higher β-sheet conformations until 363 K, implying that both NE and NE+ can lower the critical temperature required for αS fibril decomposition. NE and NE+ also lead to the formation of less compact αS oligomers by preventing the backbone hydrogen bonds and the side-chain packing. The protonation would affect the binding affinity, interaction modes, and binding intensity of NE with αS. Interesting, NE and NE+ have a distinct binding free energy in the electrostatic and solvation terms, which mostly counter each other and produce a weak binding intensity with αS. Our work contributes to a better understanding of the inhibitory mechanism of NE and NE+ on αS oligomerization relevant to PD pathogenesis, which may provide clues for the design of antiamyloid medicine.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: ■ Introductionmentioning

confidence: 99%

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Influence of Protonation on the Norepinephrine Inhibiting α-Synuclein 71–82 Oligomerization

Wang,

Zhu,

et al. 2023

J. Phys. Chem. B

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“…O-αSN SH-SY5Y cells were cultured with (2 μg/ml) or without doxycycline supplementation to suppress or induce αSN expression, respectively [26]. Mixed primary glial cells were obtained from the brains of Wistar rat pups (no older than 72 h) and cultured as described [36]. To obtain primary microglia-rich mixed glial cultures, media were replaced with fresh media after 2-3 days, and cells were trypsinized and seeded on 24-well plates 14-21 days after their initial seeding.…”

Section: Methodsmentioning

confidence: 99%

The impact of α-synuclein aggregates on blood-brain barrier integrity in the presence of neurovascular unit cells

Hourfar¹,

Aliakbari²,

Aqdam³

et al. 2022

Preprint

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The role of the blood-brain barrier (BBB) is to control trafficking of biomolecules and protect the brain. This function can be compromised by pathological conditions. Parkinsonprimes disease (PD) is characterized by the accumulation of alpha-synuclein aggregates (alphaSN-AGs) such as oligomers and fibrils, which contribute to disease progression and severity. Here we study how alphaSN-AGs affect the BBB in in vitro co-culturing models consisting of human brain endothelial hCMEC/D3 cells alone and co-cultured with astrocytes and neurons/glial cells. When cultivated on their own, hCMEC/D3 cells were compromised by alphaSN-AGs, which decreased cellular viability, mitochondrial membrane potential, wound healing activity, TEER and permeability parameters, as well as increased the levels of ROS and NO. Co-culturing of these cells with activated microglia also increased BBB impairment according to TEER and systemic immune cell transmigration assays. In contrast, hCMEC/D3 cells co-cultured with astrocytes or dopaminergic neurons or simultaneously treated with their conditioned media showed increased resistance against alphaSN-AGs. Our work demonstrates the complex relationship between members of the neurovascular unit (NVU) (perivascular astrocytes, neurons, microglia, and endothelial cells), alphaSN-AGs and BBB.

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“…One important challenge in developing therapeutic strategies for αSN is the formation of intracellular plaques. That is, potent molecules that can inhibit αSN fibrillation must be delivered into neurons (5)(6)(7)(8). Numerous small molecules can hinder fibrillation, reducing the formation of toxic aggregates and subsequent neurodegeneration (5,(9)(10)(11)(12)(13).…”

Section: Introductionmentioning

confidence: 99%

The impact of hUC MSC–derived exosome-nanoliposome hybrids on α-synuclein fibrillation and neurotoxicity

Aliakbari,

Marzookian,

Parsafar

et al. 2024

Sci. Adv.

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Amyloid aggregation of α-synuclein (αSN) protein amplifies the pathogenesis of neurodegenerative diseases (NDs) such as Parkinson’s disease (PD). Consequently, blocking aggregation or redirecting self-assembly to less toxic aggregates could be therapeutic. Here, we improve brain-specific nanocarriers using a hybrid of exosomes (Ex) from human umbilical cord mesenchymal stem cells (hUC MSCs) and nanoliposomes containing baicalein (Ex-NLP–Ba) and oleuropein (Ex-NLP–Ole). The hybrids contained both lipid membranes, Ex proteins, and baicalein or oleuropein. Fluorescence resonance energy transfer analysis confirmed their proper integration. The hybrids reduced the extent of αSN fibrillation and interfered with secondary nucleation and disaggregation. They not only reduced αSN pathogenicity but also enhanced drug internalization into cells, surpassing the efficacy of NLP alone, and also crossed the blood-brain barrier in a cellular model. We conclude that Ex can be successfully extracted and efficiently merged with NLPs while retaining its original properties, demonstrating great potential as a theranostic drug delivery vehicle against NDs like PD.

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Insights into the inhibitory mechanism of skullcapflavone II against α-synuclein aggregation and its mediated cytotoxicity

Cited by 10 publications

References 63 publications

Influence of Protonation on the Norepinephrine Inhibiting α-Synuclein 71–82 Oligomerization

Influence of Protonation on the Norepinephrine Inhibiting α-Synuclein 71–82 Oligomerization

The impact of α-synuclein aggregates on blood-brain barrier integrity in the presence of neurovascular unit cells

The impact of hUC MSC–derived exosome-nanoliposome hybrids on α-synuclein fibrillation and neurotoxicity

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