Purpurin modulates Tau-derived VQIVYK fibrillization and ameliorates Alzheimer’s disease-like symptoms in animal model

Viswanathan, Guru KrishnaKumar; Shwartz, Dana; Losev, Yelena; Arad, Elad; Shemesh, Chen; Pichinuk, Edward; Engel, Hamutal; Raveh, Avi; Jelinek, Raz; Cooper, Itzik; Gosselet, Fabien; Gazit, Ehud; Segal, Daniel

doi:10.1007/s00018-019-03312-0

Cited by 51 publications

(58 citation statements)

References 84 publications

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“…In vivo experiments demonstrated that purpurin significantly ameliorated the AD‐like neurodegenerative symptoms and rescued neurotoxicity of Tau‐engendered phenotypes by inhibiting Tau accumulation and reducing Tau phosphorylation. [ 76 ] At present, there are few studies on the preventive and therapeutic effects of purpurin on Alzheimer’s disease.…”

Section: Quinones and Its Role In Admentioning

confidence: 99%

Quinones as preventive agents in Alzheimer’s diseases: focus on NLRP3 inflammasomes

Chen

Gao

Peng

et al. 2020

Journal of Pharmacy and Pharmacology

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Objectives Alzheimer's disease (AD) is a hidden neurological degenerative disease, which main clinical manifestations are cognitive dysfunction, memory impairment and mental disorders. Neuroinflammation is considered as a basic response of the central nervous system. NLRP3 (Nucleotide-binding domain leucine-rich repeat (NLR) and pyrin domain containing receptor 3) inflammasome is closely related to the occurrence of neuroinflammation. Activation of the NLRP3 inflammasome results in the release of cytokines, pore formation and ultimately pyroptosis, which has demonstrated one of the critical roles in AD pathogenesis. Inhibition of the activity of NLRP3 is one of the focuses of the research. Therefore, NLRP3 represents an attractive pharmacological target, and discovery compounds with good NLRP3 inhibitory activity are particularly important. Key findings Quinones have good neuroprotective effects and prevent AD, which may be related to their regulation of inflammatory response. The molecular docking was used to explore 12 quinones with AD prevention and treatment and NLRP3. Docking results showed that the combination of anthraquinones and NLRP3 were the best, and the top two chemical compounds were Purpurin and Rhein, which are the most promising NLRP3 inhibitors. Summary These quinones may provide the theoretical basis for finding lead compounds for novel neuroprotective agents. Quinones as NLRP3 inflammasomes inhibitors Da-bao Chen et al.

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Section: Quinones and Its Role In Admentioning

confidence: 99%

Quinones as preventive agents in Alzheimer’s diseases: focus on NLRP3 inflammasomes

Chen

Gao

Peng

et al. 2020

Journal of Pharmacy and Pharmacology

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“…After 6 days of co-culture, the resulting hBLECs express TJ proteins at cell-cell contacts and transporters typically observed in the brain endothelium, maintaining the properties of in vivo BBB for at least 20 days [28], a period during which we performed transport experiments. This model is now widely used to investigate BBB physiology, as well as molecules and cells passage across the BBB [80][81][82][83][84][85]. The loading of the human BBB model with GM1 or OligoGM1, followed by the measure of permeability parameters, provided evidence to consider OligoGM1 as a molecule transported by the paracellular mechanism, and importantly with a rate 20-fold higher then ganglioside GM1 (Figure 3).…”

Section: Discussionmentioning

confidence: 99%

GM1 Oligosaccharide Crosses the Human Blood–Brain Barrier In Vitro by a Paracellular Route

Biase

Lunghi

Maggioni

et al. 2020

IJMS

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Ganglioside GM1 (GM1) has been reported to functionally recover degenerated nervous system in vitro and in vivo, but the possibility to translate GM1 s potential in clinical settings is counteracted by its low ability to overcome the blood-brain barrier (BBB) due to its amphiphilic nature. Interestingly, the soluble and hydrophilic GM1-oligosaccharide (OligoGM1) is able to punctually replace GM1 neurotrophic functions alone, both in vitro and in vivo. In order to take advantage of OligoGM1 properties, which overcome GM1 s pharmacological limitations, here we characterize the OligoGM1 brain transport by using a human in vitro BBB model. OligoGM1 showed a 20-fold higher crossing rate than GM1 and time-concentration-dependent transport. Additionally, OligoGM1 crossed the barrier at 4 • C and in inverse transport experiments, allowing consideration of the passive paracellular route. This was confirmed by the exclusion of a direct interaction with the active ATP-binding cassette (ABC) transporters using the "pump out" system. Finally, after barrier crossing, OligoGM1 remained intact and able to induce Neuro2a cell neuritogenesis by activating the TrkA pathway. Importantly, these in vitro data demonstrated that OligoGM1, lacking the hydrophobic ceramide, can advantageously cross the BBB in comparison with GM1, while maintaining its neuroproperties. This study has improved the knowledge about OligoGM1 s pharmacological potential, offering a tangible therapeutic strategy.However, transferring the GM1 neuronal potential from the preclinical models to the clinic depends on its ability to reach the brain structures when administered peripherally. This last aspect is actually severely limited by GM1 s amphiphilicity, which hampers the passage across the blood-brain barrier (BBB) [2,7,8]. This barrier is located at the brain microvessel level and strongly restricts the entry of cells and xenobiotics into the CNS. The BBB anatomical support is the specialized brain endothelial cells of these vessels. These cells do not show any fenestrations and are specifically characterized by the presence of tight junctions (TJ), composed of junctional proteins and TJ-associated proteins. Additionally, these cells express several proteins belonging to the ATP-binding cassette (ABC) transporters family, which act as efflux pumps and play an important role by limiting BBB crossing of several drugs and biological molecules [9,10]. The major efflux pumps expressed at the BBB are P-glycoprotein (P-gp, aka ABCB1), breast cancer resistance protein (BCRP, aka ABCG2), and the multidrug-resistance-associated proteins (MRPs, aka ABCCs).Importantly, the fate of peripherally administered GM1 observed in the rodent models has not been determined in humans, as often the two species display different BBB permeability rates for the same molecule [7,8]. One of the possible explanations for these discrepancies is the species difference recently reported between rodents and human for the expression of several receptors and transporters expressed in the BBB, in...

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“…After 6 days of co-culture with pericytes, the endothelial cells differentiated into BBB endothelial cells and were ready for experiments. This model named BLECs reproduces several features of the in vivo BBB[24][25][26].…”

mentioning

confidence: 83%

Efficacy Assessment of an Uncharged Reactivator of NOP-Inhibited Acetylcholinesterase Based on Tetrahydroacridine Pyridine-Aldoxime Hybrid in Mouse Compared to Pralidoxime

Calas¹,

Hanak²,

Jaffré³

et al. 2020

Biomolecules

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(1) Background: Human exposure to organophosphorus compounds employed as pesticides or as chemical warfare agents induces deleterious effects due to cholinesterase inhibition. One therapeutic approach is the reactivation of inhibited acetylcholinesterase by oximes. While currently available oximes are unable to reach the central nervous system to reactivate cholinesterases or to display a wide spectrum of action against the variety of organophosphorus compounds, we aim to identify new reactivators without such drawbacks. (2) Methods: This study gathers an exhaustive work to assess in vitro and in vivo efficacy, and toxicity of a hybrid tetrahydroacridine pyridinaldoxime reactivator, KM297, compared to pralidoxime. (3) Results: Blood–brain barrier crossing assay carried out on a human in vitro model established that KM297 has an endothelial permeability coefficient twice that of pralidoxime. It also presents higher cytotoxicity, particularly on bone marrow-derived cells. Its strong cholinesterase inhibition potency seems to be correlated to its low protective efficacy in mice exposed to paraoxon. Ventilatory monitoring of KM297-treated mice by double-chamber plethysmography shows toxic effects at the selected therapeutic dose. This breathing assessment could help define the No Observed Adverse Effect Level (NOAEL) dose of new oximes which would have a maximum therapeutic effect without any toxic side effects.

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Purpurin modulates Tau-derived VQIVYK fibrillization and ameliorates Alzheimer’s disease-like symptoms in animal model

Cited by 51 publications

References 84 publications

Quinones as preventive agents in Alzheimer’s diseases: focus on NLRP3 inflammasomes

Quinones as preventive agents in Alzheimer’s diseases: focus on NLRP3 inflammasomes

GM1 Oligosaccharide Crosses the Human Blood–Brain Barrier In Vitro by a Paracellular Route

Efficacy Assessment of an Uncharged Reactivator of NOP-Inhibited Acetylcholinesterase Based on Tetrahydroacridine Pyridine-Aldoxime Hybrid in Mouse Compared to Pralidoxime

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