Neuroprotective effect of quercetin nanoparticles: A possible prophylactic and therapeutic role in alzheimer’s disease
Introduction
Alzheimer’s disease (AD) is the most common neurodegenerative disorder impairing memory and cognitive functions (Villemagne et al., 2018). Epidemiological researches have reported that individuals with low schooling levels, brain injury history or sedentary life styles are more likely to develop AD (Reitz et al., 2011). Diabetes mellitus, midlife obesity, hypertension and physical inactivity are the most common predisposing factors for AD are (Hüttenrauch et al., 2016). AD accounts for 80 % of dementia cases worldwide (Loureiro et al., 2017). Neuropathologically, the hallmarks of AD are amyloid plaques (APs) which are spherical extracellular accumulations of Amyloid-β protein and the intracellular neurofibrillary tangles (NFTs) which result from abnormal hyperphosphorylation of cytoskeletal tau protein (Ghoneim et al., 2015). The etiology of AD is still not fully known. However, there are several risk factors triggering the onset of AD, including genetic factors, inflammation, mis-folded proteins accumulation, beta-amyloid (Aβ) protein accumulation, synapse components alteration, and neuronal loss (Ferreiro et al., 2012). Mitochondrial and metabolic dysfunction, apoptosis and excite toxicity have been reported as influential factors in AD (Chen et al., 2014). Defective insulin signaling and decreased glucose utilization may also lead to neuronal dysfunction then death leading to dementia (Gamba et al., 2019). Tyrosine hydroxylase (TH) is the rate-limiting enzyme of catecholamine neurotransmitter biosynthesis. In dopaminergic cells in the brain, tyrosine is converted to l-DOPA by TH. Dopamine can then be converted into other catecholamines, such as noradrenaline and adrenaline. This means that decrease in TH expression is associated with reduced dopamine levels (Santana et al., 2019). Snowden and his coworkers (Snowden et al., 2018) reported that dopamine plays several important roles in the regulating mood and aiding cognitive and motor functions. Impairment TH causes depression and memory loss observed in patients with AD. Several studies reported compromised dopamine neurons in a transgenic model of AD and in AD patients even prior to the Aβ depositions (Nobili et al., 2017; Serra et al., 2018). Dementia is the main diagnostic symptom of AD, it occurs due to sever loss of synapses and neurons that selectively influence particular cell subpopulations in brain areas essential for learning and memory (Trujillo-Estrada et al., 2014).
The hippocampus is one of the earliest brain areas affected by these pathologies (Alawdi et al., 2017). Despite the tremendous efforts to understand the mechanisms and to develop therapeutic agents, there is no effective treatment for AD up till now (Pakdaman et al., 2015). Experimental work showed therapeutic lines such as acetylcholinesterase inhibitors, antioxidants or drugs improving glucose utilization may have a beneficial effect in rats model of AD (Ponce-Lopez et al., 2011).
Aluminum is widely used in the manufactured food, cosmetics (Becaria et al., 2003), food additives, tooth paste and many pharmaceutical products such as antacids (Abbasali et al., 2005). It crosses Blood Brain Barrier (BBB) and persists in the brain for up to five months (Tomljenovic, 2011; Ekong et al., 2017). Rats exposed to low levels of AlCl3 in the drinking water showed higher aluminum level in the brain than the control group (Darbre et al., 2013). Moreover, it induces BBB permeability leading to aluminum and other substances enter the brain (Cabus et al., 2015). Aluminum has neurotoxic effects in animals and humans and is implicated in the pathophysiology of AD, it exacerbates the deposition of beta amyloid (Aβ) with subsequent amyloid plaques (APs) formation (Praticò et al., 2002). The hypothesis that Al induces AD was raised in 1911 (Tomljenovic, 2011), and was approved again 1965 (Lidsky, 2014). Injection of Al salts into rabbits’ brains, showed a correlation between the cognitive deficits and the accumulation of neurofibrillary tangles (NT) (Duwe and Niedzwiecki, 2020). We believe, AlCl3 would create an animal AD model that simulates human AD (Abd El-Aleem et al., 2020). Hence, in this study we have used AlCl3 to induce AD in adult male, Sprague Dawley rats.
Quercetin is a natural flavonoid enriched in vegetables, fruits and other dietary products especially in onions, apples, Ginko Biloba and red wine (Palle and Neerati, 2017). Quercetin is a potent antioxidant, anti-inflammatory and radical-scavenger and potentially have a therapeutic effects in diabetes, infection, cancer, cardiovascular and neurodegenerative diseases (Kong et al., 2016). Interestingly, in vivo and in vitro models of AD showed that quercetin may have a role in AD related disorders. It decreases intracellular tau pathology, extracellular APs and gliosis in the amygdala and the hippocampus of aged triple transgenic AD mice (Sabogal-Guáqueta et al., 2015) and it protects nerve cells and hippocampal cultures against Aβ toxicity in vitro (Choi et al., 2014). However, the exact mechanisms of quercetin ameliorative effects on AD are not fully understood yet (Kong et al., 2016). In spite of these beneficial effects, the pharmacological application of quercetin is limited due to its low oral bioavailability (<2%), low brain permeability and its hydrophobic nature (Kumar et al., 2016). In this study, we have used the nanoparticle form of quercetin which might increase its bioavailability in the brain.
To date, nanoparticles have attracted particular attention in the therapeutics of AD due to their excellent stability, high bioavailability and ready ability of crossing the Blood Brain Barrier (BBB) especially for hydrophobic compounds as quercetin (Sun et al., 2016). In this study, quercetin nanoparticles (QNPs) were prepared by antisolvent precipitation method under sonication (Raval and Patel, 2011) and its bioavailability was enhanced by using Noyes-Whitney equation which state that decreasing the particle sizes would increase the particle surface areas (Palle and Neerati, 2017). This study aims to investigate the protective and the therapeutic effects of QNPs in AlCl3 induced AD and to shed a light on the possible mechanisms of actions.
Section snippets
Animals and chemicals
This study was carried out in the Histology and Cell Biology Department, Faculty of Medicine, Minia University. Adult male, Sprague Dawley rats, 6 per group, weight (150–200 g m) and age (6–8 weeks) matched were housed for seven days prior to the experimentation. All experiments were performed according to regulations under the appropriate animal licenses approved by the animal care committee of Faculty of Medicine-Minia University (Approval No.233: 7/2019), according to the international
Hippocampus mapping and histological features
Normal organization of the hippocampus formation was seen formed of the Cornu Ammonis (CA) and the dentate gyrus (DG) (Fig. 1). The cellular organization in each zone was studied at higher magnification (Fig. 2A–C). In CA1 cells were arranged as 3–4 layers composed of closely packed small pyramidal neurons with vesicular nuclei (Fig. 2A). In contrast, in CA3 cells are loosely packed large pyramidal neurons with vesicular nuclei (Fig. 2B). In DG cells are arranged as dense columns of granular
Discussion
Alzheimer’s disease (AD) became the most common cause of dementia in elderly (Henstridge et al., 2019), it is expected that the number of people with AD will triple by 2050 (Valdez, 2019). Up to date there is no effective therapy for AD (Qin et al., 2019). Quercetin is a multi-tasker agent with antioxidant, anti-inflammatory and neuroprotectant effects (Kong et al., 2016). However, its low bioavailability restricts its usage in clinical applications (Kumar et al., 2016). Nanotechnology
Conclusion
QNPs administration in AD model could preserve structure and function of hippocampal neurons by several mechanisms at cellular, subcellular and molecular levels. It blocked NFTs and APs formation, restored TH activity and enhanced regenerative changes with subsequent neuronal function improvement. Additionally, it affected extra neuronal structures; it regulated astrocyte and microglial activities, preserved myelin sheath and BBB intact. Thus, using nanoparticles of quercetin might provide a
Author contribution statement
Rehab Rifaai: Supervisor, helped in experimental design, data analysis and writing of the manuscript.
Sahar Mokhemer: PhD candidate who performed the experimental lab work and wrote the manuscript.
Entesar Ali: Supervisor, helped in experimental design, data analysis and writing of the manuscript.
Seham Abd El-Aleem: Supervisor, helped in data analysis and revision of the manuscript.
Nashwa El-Tahawy: Supervisor, helped in experimental design, data analysis and writing of the manuscript.
Data availability statement
The main data are included in this manuscript and in its supplementary files. All data are available from the corresponding author on reasonable request
Ethical statement
All experiments were performed according to regulations under the appropriate animal licenses approved by the animal care committee of Faculty of Medicine-Minia University (Approval No.233: 7/2019), according to the international guidelines (Act 1986). Animals were observed daily to assure animal wellbeing.
Declaration of Competing Interest
There is no conflict of interests.
Acknowledgments
We are grateful to Professor Usama Farghaly Aly for help in preparation QNPs. This research did not receive any specific grant from funding agencies.
References (111)
- et al.
Lack of widespread BBB disruption in Alzheimer’s disease models: focus on therapeutic antibodies
Neuron.
(2015) - et al.
Amyloid beta impairs mitochondrial anterograde transport and degenerates synapses in Alzheimer’s disease neurons
Biochimica et Biophysica Acta (BBA)-Mol. Basis Disease.
(2011) - et al.
The blood brain barrier in Alzheimer’s disease
Vascul. Pharmacol.
(2017) - et al.
Inhibition of iNOS gene expression by quercetin is mediated by the inhibition of IκB kinase, nuclear factor-kappa B and STAT1, and depends on heme oxygenase-1 induction in mouse BV-2 microglia
Eur. J. Pharmacol.
(2005) - et al.
Protective effects of bajijiasu in a rat model of Aβ25-35-induced neurotoxicity
J. Ethnopharmacol.
(2014) - et al.
Is Alzheimer’s Disease a Neurogenesis Disorder?
Cell Stem Cell
(2019) - et al.
Aluminium and breast cancer: Sources of exposure, tissue measurements and mechanisms of toxicological actions on breast biology
J. Inorg. Biochem.
(2013) - et al.
Early oligodendrocyte/myelin pathology in Alzheimer’s disease mice constitutes a novel therapeutic target
Am. J. Pathol.
(2010) - et al.
Mitochondrial trafficking of APP and alpha synuclein: relevance to mitochondrial dysfunction in Alzheimer’s and Parkinson’s diseases
Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease.
(2010) - et al.
Histological and immunohistochemical study of the effect of gold nanoparticles on the brain of adult male albino rat
J. Microsc. Ultrastruct.
(2015)
Are polyphenols antioxidants or pro-oxidants? What do we learn from cell culture and in vivo studies?
Arch. Biochem. Biophys.
Accumulation of orally administered quercetin in brain tissue and its antioxidative effects in rats
Free Radic. Biol. Med.
Estimating leaf chlorophyll content in sugar beet canopies using millimeter-to centimeter-scale reflectance imagery
Remote Sens. Environ.
Quercetin and rutin exhibit antiamyloidogenic and fibril-disaggregating effects in vitro and potent antioxidant activity in APPswe cells
Life Sci.
Glial fibrillary acidic protein isoform expression in plaque related astrogliosis in Alzheimer’s disease
Neurobiol. Aging
Quercetin inhibits lipopolysaccharide-induced nitric oxide production in BV2 microglial cells by suppressing the NF-κB pathway and activating the Nrf2-dependent HO-1 pathway
Int. Immunopharmacol.
Promises of a biocompatible nanocarrier in improved brain delivery of quercetin: Biochemical, pharmacokinetic and biodistribution evidences
Int. J. Pharm.
Quercetin nanoparticles attenuates scopolamine induced spatial memory deficits and pathological damages in rats
Bull. Fac. Pharm. Cairo Univ.
Lithium, phenserine, memantine and pioglitazone reverse memory deficit and restore phospho-GSK3β decreased in hippocampus in intracerebroventricular streptozotocin induced memory deficit model
Brain Res.
The flavonoid quercetin ameliorates Alzheimer’s disease pathology and protects cognitive and emotional function in aged triple transgenic Alzheimer’s disease model mice
Neuropharmacology.
In vivo mapping of brainstem nuclei functional connectivity disruption in Alzheimer’s disease
Neurobiol. Aging
Modulation of interleukin-1β mediated inflammatory response in human astrocytes by flavonoids: implications in neuroprotection
Brain Res. Bull.
Flavonols and flavones as BACE-1 inhibitors: structure–activity relationship in cell-free, cell-based and in silico studies reveal novel pharmacophore features
Biochimica et Biophysica Acta (BBA)-General Subjects.
Fabrication of surfactant-stabilized nanosuspension of naringenin to surpass its poor physiochemical properties and low oral bioavailability
Phytomedicine.
Inhibition of protein phosphatase 2A-and protein phosphatase 1-induced tau hyperphosphorylation and impairment of spatial memory retention in rats
Neuroscience.
Design of PLGA-functionalized quercetin nanoparticles for potential use in Alzheimer’s disease
Colloids Surf. B Biointerfaces
Mechanism of neurodegeneration through tau and therapy for Alzheimer’s disease
J. Sport Health Sci.
Physical activity delays hippocampal neurodegeneration and rescues memory deficits in an Alzheimer disease mouse model
Transl. Psychiatry
Developmental toxicity of aluminum from high doses of AlCl3 in mice
J. Applied Res.
Upregulation of the inducible nitric oxide synthase in rat hippocampus in a model of alzheimer’s disease
A Possible Mechanism of Aluminium Induced Alzheimer’s
Neuroprotective effect of nanodiamond in Alzheimer’s disease rat model: a pivotal role for modulating NF-κB and STAT3 signaling
Mol. Neurobiol.
Dual and multi-drug delivery nanoparticles towards neuronal survival and synaptic repair
Neural Regen. Res.
Sodium Lauryl Sulfate Profile
Aluminum and copper interact in the promotion of oxidative but not inflammatory events: implications for Alzheimer’s disease
J. Alzheimer Dis.
Neurovascular mechanisms and blood–brain barrier disorder in Alzheimer’s disease
Acta Neuropathol.
Dark microglia: a new phenotype predominantly associated with pathological states
Glia.
A histological study of toxic effects of aluminium sulfate on rat hippocampus
Biotechnic & histochem. Off. Pub. Biological Stain Com.
Effects of flavonoid compounds on β-amyloid-peptide-induced neuronal death in cultured mouse cortical neurons
Chonnam Med. J.
Microglia constitute a barrier that prevents neurotoxic protofibrillar Aβ42 hotspots around plaques
Nat. Commun.
Mechanisms of neuroprotection by quercetin: counteracting oxidative stress and more
Oxid. Med. Cell. Longev.
Protection of the blood-brain barrier by pentosan against amyloid-β-induced toxicity
J. Alzheimer Dis.
Aluminum Toxicity in Alzheimer‘s Disease, Breast Cancer and Vaccine Adjuvants
Neuroprotective effect of Moringa oleifera leaf extract on aluminium-induced temporal cortical degeneration
Metab. Brain Dis.
Mitochondrial-and endoplasmic reticulum-associated oxidative stress in Alzheimer’s disease: from pathogenesis to biomarkers
Int. J. Cell Biol.
Astrocytes: New Targets for the Treatment of Neurodegenerative Diseases
Curr. Pharm. Des.
Phagocytosis in the brain: homeostasis and disease
Front. Immunol.
Leonarduzzi G. A crosstalk between brain cholesterol oxidation and glucose metabolism in alzheimer’s disease
Front. Neurosci.
Protective effect of chronic caffeine intake on gene expression of brain derived neurotrophic factor signaling and the immunoreactivity of glial fibrillary acidic protein and Ki-67 in Alzheimer’s disease
Int. J. Clin. Exp. Pathol.
Effect of gallic acid on dementia type of Alzheimer disease in rats: electrophysiological and histological studies
Basic Clin. Neurosci.
Protective effects of blackberry and quercetin on sodium fluoride-induced oxidative stress and histological changes in the hepatic, renal, testis and brain tissue of male rat
J. Basic Clin. Physiol. Pharmacol.
Cited by (54)
The neuroprotective effect of quercetin nanoparticles in the therapy of neuronal damage stimulated by acrolein
2023, Saudi Journal of Biological SciencesNeuroprotective effect of quercetin nanoparticles: A possible prophylactic effect in cerebellar neurodegenerative disorders
2023, Journal of Chemical NeuroanatomyProanthocyanidins prevent tau protein aggregation and disintegrate tau filaments
2023, Chinese Journal of Chemical Engineering