Natural compound safranal driven inhibition and dis-aggregation of α-synuclein fibrils

Save, S.S.; Rachineni, Kavitha; Hosur, Ramakrishna V.; Choudhary, Sinjan

doi:10.1016/j.ijbiomac.2019.09.053

Cited by 31 publications

(14 citation statements)

References 65 publications

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“…Usually, the aromatic rings form a planar hydrophobic core that is thought to interact with apolar exposed regions in α-Syn or its assemblies. However, despite the presence of multiple aromatic groups is recurrent in natural α-Syn aggregation inhibitors and many of the reported screening efforts result in the identification of this kind of molecules, several natural compounds exhibiting a single aromatic ring have been shown to act as α-Syn aggregation modulators ( Supplementary Figure S3), including scyllo-inositol, gallic acid, dopamine, safranal and caffeic acid (Herrera et al, 2008;Di Giovanni et al, 2010;Liu et al, 2014;Ibrahim and McLaurin, 2016;Save et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of α-Synuclein Aggregation and Mature Fibril Disassembling With a Minimalistic Compound, ZPDm

Peña-Díaz

Pujols

Pinheiro

et al. 2020

Front. Bioeng. Biotechnol.

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Synucleinopathies are a group of disorders characterized by the accumulation of α-Synuclein amyloid inclusions in the brain. Preventing α-Synuclein aggregation is challenging because of the disordered nature of the protein and the stochastic nature of fibrillogenesis, but, at the same time, it is a promising approach for therapeutic intervention in these pathologies. A high-throughput screening initiative allowed us to discover ZPDm, the smallest active molecule in a library of more than 14.000 compounds. Although the ZPDm structure is highly related to that of the previously described ZPD-2 aggregation inhibitor, we show here that their mechanisms of action are entirely different. ZPDm inhibits the aggregation of wild-type, A30P, and H50Q α-Synuclein variants in vitro and interferes with α-Synuclein seeded aggregation in protein misfolding cyclic amplification assays. However, ZPDm distinctive feature is its strong potency to dismantle preformed α-Synuclein amyloid fibrils. Studies in a Caenorhabditis elegans model of Parkinson's Disease, prove that these in vitro properties are translated into a significant reduction in the accumulation of α-Synuclein inclusions in ZPDm treated animals. Together with previous data, the present work illustrates how different chemical groups on top of a common molecular scaffold can result in divergent but complementary anti-amyloid activities.

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Section: Discussionmentioning

confidence: 99%

Inhibition of α-Synuclein Aggregation and Mature Fibril Disassembling With a Minimalistic Compound, ZPDm

Peña-Díaz

Pujols

Pinheiro

et al. 2020

Front. Bioeng. Biotechnol.

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“…The hallmark of PD is represented by the presence of neuronal inclusions, termed Lewis Bodies, mainly composed of aggregates of misfolded alpha synuclein (α-syn) 4 . α-Syn is a 140 aa presynaptic protein which regulates the release of neurotransmitters from the synaptic vesicles 5 . From a structural point of view, α-syn is organised in three different regions: the N-terminal domain (aa 1-60), the central NAC domain (aa 61-95) and the C-terminal domain (aa 96-140) 6 .…”

Section: Introductionmentioning

confidence: 99%

Rational design of small molecules able to inhibit α-synuclein amyloid aggregation for the treatment of Parkinson’s disease

Vittorio

Adornato

Gitto

et al. 2020

Journal of Enzyme Inhibition and Medicinal Chemistry

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Parkinson’s disease is one of the most common neurodegenerative disorders in elderly age. One of the mechanisms involved in the neurodegeneration appears related to the aggregation of the presynaptic protein alpha synuclein (α-syn) into toxic oligomers and fibrils. To date, no highly effective treatment is currently available; therefore, there is an increasing interest in the search of new therapeutic tools. The modulation of α-syn aggregation represents an emergent and promising disease-modifying strategy for reducing or blocking the neurodegenerative process. Herein, by combining in silico and in vitro screenings we initially identified 3-(cinnamylsulfanyl)-5-(4-pyridinyl)-1,2,4-triazol-4-amine ( 3 ) as α-syn aggregation inhibitor that was then considered a promising hit for the further design of a new series of small molecules. Therefore, we rationally designed new hit-derivatives that were synthesised and evaluated by biological assays. Lastly, the binding mode of the newer inhibitors was predicted by docking studies.

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“…Active compounds derived from saffron include crocin, crocetin, picrocrocin, and safranal. Studies have reported that safranal has the potential to treat diseases such as Parkinson’s disease ( 28 ) and gastric ulcers ( 29 ). In this study, we further investigated the mechanisms involved in the anti-asthma effect of safranal.…”

Section: Discussionmentioning

confidence: 99%

Safranal Alleviated OVA-Induced Asthma Model and Inhibits Mast Cell Activation

Lertnimitphun

Zhang

et al. 2021

Front. Immunol.

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IntroductionAsthma is a chronic and recurring airway disease, which related to mast cell activation. Many compounds derived from Chinese herbal medicine has promising effects on stabilizing mast cells and decreasing inflammatory mediator production. Safranal, one of the active compounds from Crocus sativus, shows many anti-inflammatory properties. In this study, we evaluated the effect of safranal in ovalbumin (OVA)-induced asthma model. Furthermore, we investigate the effectiveness of safranal on stabilizing mast cell and inhibiting the production of inflammatory mediators in passive systemic anaphylaxis (PSA) model.MethodsOVA-induced asthma and PSA model were used to evaluate the effect of safranal in vivo. Lung tissues were collected for H&E, TB, IHC, and PAS staining. ELISA were used to determine level of IgE and chemokines (IL-4, IL-5, TNF-α, and IFN-γ). RNA sequencing was used to uncovers genes that safranal regulate. Bone marrow-derived mast cells (BMMCs) were used to investigate the inhibitory effect and mechanism of safranal. Cytokine production (IL-6, TNF-α, and LTC4) and NF-κB and MAPKs signaling pathway were assessed.ResultsSafranal reduced the level of serum IgE, the number of mast cells in lung tissue were decreased and Th1/Th2 cytokine levels were normalized in OVA-induced asthma model. Furthermore, safranal inhibited BMMCs degranulation and inhibited the production of LTC4, IL-6, and TNF-α. Safranal inhibits NF-κB and MAPKs pathway protein phosphorylation and decreases NF-κB p65, AP-1 nuclear translocation. In the PSA model, safranal reduced the levels of histamine and LTC4 in serum.ConclusionsSafranal alleviates OVA-induced asthma, inhibits mast cell activation and PSA reaction. The possible mechanism occurs through the inhibition of the MAPKs and NF-κB pathways.

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Natural compound safranal driven inhibition and dis-aggregation of α-synuclein fibrils

Cited by 31 publications

References 65 publications

Inhibition of α-Synuclein Aggregation and Mature Fibril Disassembling With a Minimalistic Compound, ZPDm

Inhibition of α-Synuclein Aggregation and Mature Fibril Disassembling With a Minimalistic Compound, ZPDm

Rational design of small molecules able to inhibit α-synuclein amyloid aggregation for the treatment of Parkinson’s disease

Safranal Alleviated OVA-Induced Asthma Model and Inhibits Mast Cell Activation

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