BackgroundDiabetes mellitus plays a causative role in cognitive decline. Newly, neuroprotective effects of flavonoids have been widely investigated in neurodegenerative diseases. Quercetin (QC) is a phyto-derived bioactive flavone with numerous beneficial activities. However, its limited permeability to cross the blood–brain barrier, low oral bioavailability, poor aqueous solubility, and rapid gastrointestinal digestion lead to the administration of high dose of QC in clinical application.Materials and methodsIn order to overcome these limitations, we conjugated QC with superparamagnetic iron oxide nanoparticles (QCSPIONs) and supplemented streptozotocin-induced diabetic rats with it to improve diabetes-related memory impairment. In this regard, 40 rats were distributed into five groups with eight animals: control, diabetes, and diabetes treated with SPIONs, QC, and QCSPIONs. All treatments (at the dose of 25 mg/kg) were dissolved in deionized water and gavaged for 35 consecutive days.ResultsAt the end of the study, QCSPIONs possessed significantly better efficacy than free QC on the improvement of memory performance. In the Morris water maze test, QCSPIONs compared to free QC reduced much better the escape latency over training trials (P<0.01) and increased the time spent in the target quadrant in probe trial (P<0.001). In the passive avoidance test, it increased step-through latency (P<0.05) and reduced the time spent in the dark compartment (P<0.01). In addition, both free QC and QCSPIONs were able to prevent the changes in body weight and decrease blood glucose levels in diabetic rats (P<0.05).ConclusionOverall, according to these results, we conclude that QC in the conjugated state with lower dose offers significantly higher potency in ameliorating diabetes-related memory impairment. Thus, this study offers an effective combined therapy for improving learning and memory.

BackgroundQuercetin (QT) as a bioactive flavonoid has a potential therapeutic activity for numerous neuronal injuries and neurodegenerative diseases. However, the low absorption rate of QT, especially through the blood-brain barrier, restricts its bioactivity in the body. The current research took the advantage of superparamagnetic iron oxide nanoparticles (SPIONs) to enhance the bioavailability of quercetin.MethodsQuercetin conjugated with SPIONs was prepared by means of nanoprecipitation method and was characterized by X-ray diffractometer, scanning electron microscope, and Fourier transformed infrared spectrometer analyses. Wistar male rats were orally fed by gavage with QT and QT-SPION at 50 and 100 mg/kg daily doses for 7 days. Using high-performance liquid chromatography (HPLC) method, biodistribution of QT was evaluated in plasma and brain tissue.ResultsThe outcomes of this research revealed a higher concentration in the plasma and brain of the rats fed with QT-SPION in comparison to free QT.ConclusionThe results of this study confirm that SPION as a targeted drug delivery system enhances the bioavailability of quercetin in the brain about ten folds higher than free quercetin and could be used for the treatment of neurodegenerative disorders.

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.

Fndc5 has been recently recognized as a myokine which could be cleaved and secreted into blood stream. It is termed as irisin with an important role in thermogenesis and energy homeostasis. Increased expression of Fndc5 has been reported upon retinoic acid treatment during neural differentiation and its knockdown decreased neural differentiation and neurite outgrowth. This study tries to evaluate the effect of Fndc5 overexpression on rate of neural differentiation in mouse. (Thus, transduced cell line of mouse embryonic stem cell with ability to express Fndc5 under Doxycycline treatment was established. Subsequently, the effect of overexpression of Fndc5 on different stages of neural differentiation was studied). Our study showed an increase enhancement in neuronal precursor markers and mature neuron markers upon overexpression of Fndc5, concluding that Fndc5 facilitates neural differentiation. This effect might be related to increased expression of BDNF following overexpression of Fndc5. Our findings are consistent with recent studies reporting a similar role for Fndc5 in proliferation of neural cells and increase in the expression of neurotrophins like BDNF.

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