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Quercetin conjugated with superparamagnetic iron oxide nanoparticles improves learning and memory better than free ...

quercitin spion superparamagnetic iron oxide nanoparticle bioavailability

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#1 Engadin

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Posted 07 May 2019 - 09:17 PM

Quercetin conjugated with superparamagnetic iron oxide nanoparticles improves learning and memory better than free quercetin via interacting with proteins involved in LTP



Biomedical application of quercetin (QT) as an effective flavonoid has limitations due to its low bioavailability. Superparamagnetic iron oxide nanoparticle (SPION) is a novel drug delivery system that enhances the bioavailability of quercetin. The effect of short time usage of quercetin on learning and memory function and its signaling pathways in the healthy rat is not well understood. The aim of this study was to investigate the effect of free quercetin and in conjugation with SPION on learning and memory in healthy rats and to find quercetin target proteins involved in learning and memory using Morris water maze (MWM) and computational methods respectively. Results of MWM show an improvement in learning and memory of rats treated with either quercetin or QT-SPION. Better learning and memory functions using QT-SPION reveal increased bioavailability of quercetin. Comparative molecular docking studies show the better binding affinity of quercetin to RSK2, MSK1, CytC, Cdc42, Apaf1, FADD, CRK proteins. Quercetin in comparison to specific inhibitors of each protein also demonstrates a better QT binding affinity. This suggests that quercetin binds to proteins leading to prevent neural cell apoptosis and improves learning and memory. Therefore, SPIONs could increase the bioavailability of quercetin and by this way improve learning and memory.





Long-Term Potentiation (LTP) is a cellular mechanism by which synaptic plasticity of neural cells is strengthened, resulting in the preservation of memories. Learning and memory are among the most important cognitive functions, which are gradually lost with aging. Learning and memory are mainly dependent on the synaptic plasticity by which long-term signal transduction leads to strengthening the synapses between neurons. This process is referred to LTP1 while it is affected by several factors such as high blood fat, oxidative stress, etc2,3,4. Therefore, in order to prevent memory impairment and the development of neurodegenerative diseases, maintenance of LTP seems necessary5. Neurotrophin signaling pathway is closely related to the LTP so that induction of LTP leads to organization of new signal transductions between neurons and inhibit memory impairment and neurodegeneration6,7. On the other hand, improvement of learning and memory can also be due to the prevention of apoptosis. Consistency, it has also been shown that prevention of neurodegenerative diseases in addition to inhibition of neural cell apoptosis, restores LTP8,9.


The biological activities of flavonoids in the central nervous system (CNS) are due to their abilities to protect susceptible neurons, increasing the function of existing neurons, stimulating neuronal regeneration, and induction of neurogenesis10,11,12,13. Quercetin (QT) (2-(3,4-dihydroxyphenyl)-3,5,7-trihydroxy-4H-chromen-4-one, Fig. 1) is one of the most abundant flavonoid compounds in the daily diet which has been known to protect neurons against the oxidative stress and apoptosis14. It is proposed that quercetin has inhibitory effects on proteins while this feature hasn’t been studied sufficiently. However, the major drawback of QT in vivo treatment is its low bioavailability so that it shows no significant effects on the induction of LTP15.


2D structure of QT obtained from PubChem


Interaction of QT with proteins involved in various signaling pathways has been reported previously16. In this regard, it has also been revealed that QT leads to decrease in cell apoptosis in the hippocampus which is the center of processing the spatial memory and this property can be considered as a preventive treatment against oxidative stress14,17. Besides, the exact molecular mechanism of QT action in the neural cells has not been revealed so far; hence, we decided to find cellular targets of QT through which QT treatment leads to the improvement of the learning and memory using bioinformatics tools. For this purpose, in addition to the use of experimental tests in order to confirm the beneficial effect of QT on learning and memory when there is no oxidant factor, docking software including HexAutoDock, and LigandScout were used to find interactions of QT with the proteins of considered signaling pathways. QT docking sites have been studied in some cases such as inhibitory effect on ATPase of sarcoplasmic reticulum18, protein disulfide isomerase19, inhibition of glucose efflux via binding to CLUT120, inhibition of Akt activity leading to the cell survival21, inhibition of Cs2+- ATPase22, etc. However, there is no clear finding of specific targets of quercetin within the cell. As the first study with this aim, we decided to assess interactions of quercetin with all proteins in neurotrophin and LTP signaling pathways computationally. First, we should be sure about the beneficial effects of quercetin on learning and memory in healthy organisms. Therefore, intact rats were used to assess the effect of QT on learning and memory in the absence of any oxidative agent through which the main beneficial effect of QT will be dependent on the interactions of QT with proteins. In addition, since quercetin has low bioavailability, we also assessed the efficiency of a delivery system, which had proposed previously on the enhancement of its bioavailability. A number of methods have been proposed in order to increase quercetins bioavailability.


The use of quercetin derivatives such as quercetin aglycones23, emulsifiers24,25, conjugates26,27,28 have been proposed which showed satisfactory results in terms of accessibility and bioavailability. A novel method for delivering therapeutic compounds is the use of nanotechnology. Manufacturing quercetin included nanostructures including conjugates29,30,31, nanotubes32 have been conducted in order to increase quercetin bioavailability and its solubility. However, there are few studies related to the use of quercetin-included nanoparticles in order to deliver this compound to brain tissue.


Nanoparticles (NPs) are important because of their unique properties such as high surface to mass ratio, ability to absorb, and also carry other compounds that leads NPs to be effective for carrying drugs, proteins, and probes33. However, NPs have also limited rate of passage from the blood-brain barrier (BBB)34. In this regard, nose to brain method has been studied in order to increase drug concentrations in brain tissue and prevent drug disruption in the gastrointestinal tract. This method has been introduced with a high success rate in drug delivery to the brain while the main disadvantage of this route is low permeation of drug compounds35,36. On the other hand, the use of nanoparticles helped to overcome drug resistance in some diseases in which therapeutic compounds could not transverse across the barriers such as the blood-brain barrier (BBB). Superparamagnetic iron oxide nanoparticles (SPION) have attracted a lot of attention in biomedical applications. SPION has unique properties including a high ratio of spin polarization and high conductivity and especially a superparamagnetic nature37. SPION as a carrier system has many advantages over other nanoparticle carrier systems. Iron oxide NP is biocompatible, biodegradable, and superparamagnetic and therefore controllable by an external magnetic field. This nanoparticle with different coatings has various biological applications including highly sensitive diagnostic tests, drug delivery, gene delivery, magnetic resonance imaging, cell tracking, tissue engineering, magnetic hyperthermia, magnetic resonance imaging (MRI), thermal therapy, targeting amyloid beta (Aβ) in the brain arteries, inhibiting the microglial cells, and DNA detection38,39,40,41. However, potentially they may be toxic and could destruct the functions of the main organelles and macromolecules of the cell, such as DNA, nucleus, and mitochondria42,43. The toxicity of SPIONs depends on important factors such as the size of the nanoparticles, the exposure time, the type of NP coating, and the type of tissue44. Our previous study showed that dextran-coated iron oxide nanoparticles have a minor cell toxicity at high dosage44. In another study, we showed that SPIONs could enhance the biodistribution of quercetin into the brain45. Small size, low toxicity, and targeted drug delivery possibility via magnetic fields are among the most important advantages for the SPION population46,47. We used quercetin-SIOPN conjugation system in order to enhance bioavailability of quercetin, which can also help to its inhibitory effects on proteins, especially in the brain. QT-SPION (QT-Fe3O4) has been used in order to improve learning and memory in rats with memory impairment48. Additionally, the enhanced bioavailability of this delivery system has been shown by Najafabadi et al.45. However, there is no report about its effects on learning and memory in intact rats.


Hereby, we studied the effect of QT and QT-SPION on learning and memory of intact rats in order to confirm beneficial effects of QT and designed delivery system on the improvement of learning and memory. In order to find specific targets of inhibitory activity of quercetin, a comprehensive screening was also conducted as the primary step for demonstrating potential inhibitory effects of quercetin on proteins in signaling pathways related to learning and memory.


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