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Corona, J.C. Neuroprotective Effects of Quercetin. Encyclopedia. Available online: https://encyclopedia.pub/entry/7758 (accessed on 11 May 2024).
Corona JC. Neuroprotective Effects of Quercetin. Encyclopedia. Available at: https://encyclopedia.pub/entry/7758. Accessed May 11, 2024.
Corona, Juan Carlos. "Neuroprotective Effects of Quercetin" Encyclopedia, https://encyclopedia.pub/entry/7758 (accessed May 11, 2024).
Corona, J.C. (2021, March 04). Neuroprotective Effects of Quercetin. In Encyclopedia. https://encyclopedia.pub/entry/7758
Corona, Juan Carlos. "Neuroprotective Effects of Quercetin." Encyclopedia. Web. 04 March, 2021.
Neuroprotective Effects of Quercetin
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This entry is adapted from the peer-reviewed paper 10.3390/molecules25235597

Quercetin is a flavonoid compound present in a wide variety of vegetables and fruit, such as onion, asparagus, red leaf lettuce, cilantro, lovage, dill, capers, apples, and berries. Quercetin represents the highest percentage of total flavonoid intake and is the most important component of flavonol subclass, often the base of other flavonoids. Thus, quercetin has been demonstrated to exert neuroprotective effects in several neurodegenerative disorders as well as antioxidant, anti-inflammatory, anti-cancer, anti-obesity, anti-viral and anti-microbial properties, and cardioprotective and hepatoprotective activities.

quercetin oxidative stress pediatric diseases neuroprotection

1. Introduction 

Flavonoids belong to a large group of natural polyphenolic phytochemicals which have been shown to produce several effects such as antioxidative and anti-inflammatory [1][2] and several studies have highlighted the potential beneficial role of flavonoids in numerous neurodegenerative diseases [3][4][5]. There are several subclasses of flavonoids which include the flavones (such as luteolin, rutin, chrysin, baicalin and oroxylin A), flavanones (such as naringenin and hesperidin), isoflavones (such as daidzein and genistein), proanthocyanidins (such as procyanidins), flavanols (such as catechin and epicatechin) and flavonols (such as kaempferol, myricetin and quercetin).

2. Antioxidant Effects of Quercetin

The antioxidant effects of quercetin are elicited owing to the presence of several hydroxyl groups and the basic flavonol skeleton. Quercetin is a potent scavenger of reactive oxygen species (ROS), including superoxide, peroxynitrite and hydrogen peroxide (H2O2), which is also a good lipid peroxidation inhibitor [6][7][8]. One of the antioxidant effects of quercetin depends on the level of glutathione (GSH). Thus, high GSH level promotes the formation of the 6-glutathionyl-Qu (GSQ) complex, which enhances the antioxidant effect, while a low level of GSH increases the extent of cellular damage [9][10].

The effects of quercetin against oxidative stress have been widely demonstrated in diverse conditions both in vitro and in vivo. Accordingly, it was shown that quercetin reduces the H2O2-mediated oxidative stress in yeast mutant cells [11]. Oxidative stress plays a role in the pathophysiology of mental diseases, such as depression or anxiety. Repeated predator stress exposure to mice produced freezing, anxiety-like and depressive-like behaviors. Quercetin showed a protective effect against depression and could alleviate the fear of traumatic events in these mice [12]. Treatment with quercetin showed a protective effect against the oxidative stress produced by cadmium exposure in rats via decrement of the malondialdehyde (MDA) content and an increment in the levels of antioxidant enzymes, superoxide dismutase (SOD), glutathione peroxidase (GPx) and catalase (CAT) [13]. Quercetin protected against doxorubicin-induced cardiomyopathy in rats by increasing the levels of antioxidant defense molecules such as the nuclear factor erythroid 2-related factor 2 (Nrf2), which is a regulator of cellular defense against oxidative stress as well as via the restoration of histological and biochemical defects [14]. Lipopolysaccharide-induced intestinal oxidative stress exerted in broiler chickens and quercetin could significantly inhibit oxidative stress and up-regulate the SOD and GPx levels. Moreover, quercetin relieved mitochondria damage and up-regulated mitochondrial DNA copy number-related gene expression. Furthermore, quercetin promoted Nrf2 activation and increased the gene expression level of heme oxygenase-1 (HO-1), NAD(P)H quinone dehydrogenase 1 (NQO1), and manganese (Mn) SOD2 [15]. Furthermore, quercetin protected against oxidative stress induced by bisphenol-A in rat cardiac mitochondria, considering the improved mitochondrial membrane potential (∆Ψm), GSH level and CAT activity [16]. In addition, quercetin reduced the generation of ROS and nitric oxide (NO) induced by cigarette smoke exposure both in vitro and in vivo, as well as reduced the levels of oxidative stress, leukocyte level and histological pattern changes of the pulmonary parenchyma [17]. Finally, it was demonstrated that quercetin could ameliorate diabetic encephalopathy in mice as a result of reduction in the learning and memory dysfunction, reduced fasting blood glucose and increased insulin sensitivity; in addition, quercetin inhibited oxidative stress and ameliorated neurodegeneration. Moreover, quercetin activated SIRT1, which is an enzyme that deacetylates proteins, which contribute to cellular regulation and inhibited the expression of the endoplasmic reticulum (ER) stress-related proteins [18].

3. Central Nervous System (CNS) Tumors

CNS tumors are a heterogeneous group of neoplasms representing the primary cause of death among children and adolescents. Among all brain tumors, glioblastoma, medulloblastoma, and ependymoma are the most common ones in pediatric populations [19][20][21]. Gliomas are tumors that originate from the glial cells (the supporting cells of CNS) and exists in diverse types based on the involved cell type, for example, astrocytoma, glioblastoma, ependymoma, oligodendroglioma and oligoastrocytoma [19]. Despite the conventional therapy including surgical resection followed by chemotherapy (mainly with temozolomide) and radiotherapy, the effectiveness of this treatment approach is extremely limited and the prognosis is poor with a median survival of 1 year after the therapy. In addition, the most common side-effects of this therapy include cognitive and endocrine dysfunctions, as well as secondary malignancies [20]. Therefore, new natural therapeutic strategies are warranted for use either alone or in combination with other pharmacological agents for the treatment of CNS tumors. Until date, multiple studies have demonstrated the antitumor effect of quercetin on different types of cancer, including breast, esophageal, colorectal, stomach, prostate, lung, ovarian, melanoma and leukemia [22][23][24][25][26]. In addition, quercetin has been reported to induce angiogenesis, the inhibition of proliferation, metastasis, chemoresistance as well as apoptosis both in vitro and in vivo [27].

4. Autism Spectrum Disorder (ASD)

ASD is a heterogeneous and complex neurodevelopmental condition characterized by significant deficiencies in social interaction, communication and repetitive patterns of behavior [28]. People with ASD spend less time engaged in social interaction when compared with non-ASD individuals. Notably, children with ASD do not attribute sufficient value to potential social interactions and favor other environmental stimuli that seems more valuable to them. The worldwide population prevalence of ASD is approximately 1%, and its onset occurs during childhood before the 3 years of age. Autism affects boys more than girls and it has high comorbidity correlation with other neurological disorders [29][30]. The etiology of ASD involves genetic factors or is associated with Rett Syndrome, Fragile X and Down Syndrome with de novo mutations and also environmental factors (exposure to toxins, neurotoxic metals and smoking) as well as certain types of medications during embryonic development, maternal stress, infections during pregnancy and metabolic- and immune- related nutritional factors [31][32][33][34]. The most common treatment in children and young adults with ASD include the use of antipsychotics and the medications used for ADHD and antidepressants [35][36][37]. However, there is evidence of inconsistent efficacy and significant side-effects for most of these pharmacological interventions [38]. In consequence, there is presently a huge interest in the search for alternative ASD treatments, with natural compounds with demonstrated neuroprotective potential via their antioxidant properties and tolerable side-effects [39].

4.1. Protective Effects of Diverse Compounds That Include Quercetin in ASD

It has been reported that oxidative stress in combination with genetic factors and inflammation could be involved in the pathophysiology of ASD [40][41]. Accordingly, the formulation NeuroProtek that contains the flavone luteolin and the flavonoids quercetin and rutin, was applied in 37 children with ASD. The liposomal formulation was found to be safe and well-tolerated, and it showed a positive impact through reduction of brain and gut inflammations [42]. An open-label pilot study of a formulation containing quercetin, luteolin, and the quercetin glycoside rutin was found to effectively to reduce the ASD symptoms with no major adverse effects recorded [43]. Moreover, the induction of developmental hypothyroidism can be used as a model of ASD and can disrupt hippocampal neurogenesis. A diet containing α-lipoic acid as an antioxidant and α-Glycosyl isoquercitrin (AGIQ), which is a mixture of quercetin glycoside consisting of isoquercitrin and its α-glucosylated derivatives along with >10 additional linear glucose moieties, possesses antioxidant effects. The AGIQ-recovered expression of some antioxidant enzyme genes such as NQO1 and thioredoxin 1 (Txn1) in the developmental hypothyroidism rats also restored of NeuN-positive post-mitotic granule cells, parvalbumin and somatostatin-positive interneurons and both antioxidants recovered expression of GABAergic interneuron-related gene orthodenticle homeobox 2 (Otx2) and also AGIQ-recovered expression of glutamate ionotropic receptor AMPA type subunit 3 (Gria3), thereby reversing the disruptive neurogenesis through compensatory responses [44]. Recently, in an experimental model of autism induced by valproic acid during the gestational period, the prenatal treatment with quercetin prevented the behavioral changes and also the treatment with quercetin prevented alterations in the total thiol content as well as changes in the activities of SOD, CAT and glutathione-S-transferase (GST) enzymes in the hippocampus, which in turn prevented the alterations in the CAT and GPx activity in the cerebellum to thereby prevent an increase in the level of ROS, nitrite and thiobarbituric acid reactive substances (TBARS) levels in the striatum and that in the nitrite and CAT alterations in the cerebral cortex [45]. Thus, compounds that contain quercetin can improve the antioxidant defense mechanism. However, more research is warranted to support the efficacy of quercetin alone or in combination with other flavonoids as a possible treatment option for ASD. The outcomes of the protective effects of quercetin in ASD are summarized in Table 1.

Table 1. Summary of protective effects of quercetin in CNS tumors, ASD and ADHD.

Type of Study in CNS Tumor

Effects

References

Human glioblastoma and rat glioma cell lines

Reduced cell proliferation and increased antioxidant system

[46][47][48]

Rat glioma and human glioblastoma cell lines

Induced cell death due to increased oxidative stress and activation of caspases

[49][50][51][52][53]

Glioblastoma cell lines

Anti-inflammatory activity by inhibition of the STAT signaling pathway

[54]

Glioblastoma and astrocytoma cell lines

In combination with other compounds induced apoptosis

[55][56][57][58]

Mouse model glioblastoma and cell line

Induced autophagy by LC3-I processing and dose-dependency

[52]

Rat glioma model

Increased tumor volume and reduced T lymphocyte infiltration and proliferation

[59]

Medulloblastoma cell lines and mouse model

Decreased cell migration and growth tumor and increased survival

[60][61]

Type of Study in ASD

Effects

References

Children

Safe, well-tolerated and with a positive impact through reduction of brain and gut inflammations

[42]

Children

In an open-label pilot study, it effectively reduced symptoms without any adverse effects

[43]

Developmental hypothyroidism rat model

Recovered expression of NQO1 and Txn1, restored NeuN-positive granule cells, parvalbumin and somatostatin-positive interneurons and recovered the expressions of Otx2 and Gria3

[44]

Prenatal model in rats induced by valproic acid

Prevented behavioral changes, alterations in total thiol content and changes of SOD, CAT and GST in the hippocampus, prevented the alterations of CAT and GPx in the cerebellum, prevented the increase of ROS, nitrite and TBARS levels in the striatum and prevented nitrite and CAT alterations in the cerebral cortex

[45]

Type of Study in ADHD

Effects

References

Children and adolescents

In a randomized controlled trial, it showed clinical benefits and tolerable side-effects

[62]

Children and adolescents

In a randomized double-blind controlled trial of 8 weeks, it did not improve symptoms

[63]

Adolescents

A preliminary study improved some symptoms in patients

[64]

SH-SY5Y cells

Increased ATP levels

[65]

SHR model

Reduced plasma MDA levels, aortic superoxide production and also improved NO-dependent acetylcholine relaxation, inhibited eNOS phosphorylation and reduced the blood pressure

[66]

SHR model

Reduced oxidative stress

[67]

Amphetamine-induced unilateral rotations in rats

Reduced rotations and also attenuated the rotenone-induced loss in striatal dopamine, up-regulated mitochondrial complex-I activity and increased CAT and SOD

[68]

SHR model and H9C2 cells

Prevented cardiac hypertrophy by suppressing AP1 transcription activity and by increasing activation of PPARγ, also the ultrastructural damage of mitochondria and myofibrils were attenuated

[69]

MPH-induced hyperlocomotion in mice

Blocked hyperlocomotion and an increase in lipid peroxidation levels in the striatum and prefrontal cortex regions

[70]

5. Attention-Deficit/Hyperactivity Disorder (ADHD)

ADHD is the most prevalent neuropsychiatric disorder, with a worldwide prevalence in children of 7.2% [71][72][73]. The characteristic symptoms of ADHD include hyperactivity, lack of attention and impulsivity [74]. In around 50% of children and adolescents diagnosed with ADHD, the symptoms persist throughout the adult life as well [72][75]. The symptoms of ADHD cause problems in personal, scholar, social, or work performance resulting in the consequences of isolation, lower socioeconomic status and increased risk of substance abuse in adolescence, as well as changes of development of comorbidity and antisocial and delinquent behavior [72][75]. Pharmacological treatment with psychostimulants and non-psychostimulants for this condition include the medications aimed at improving the symptoms of ADHD. Methylphenidate (MPH) and amphetamines increase extracellular dopamine and norepinephrine release in the hippocampus, prefrontal cortex, and striatum, which in turn improve neurotransmitter imbalance and symptoms [76][77][78]. The therapy with atomoxetine, which is a selective norepinephrine reuptake inhibitor, increases extracellular dopamine and norepinephrine release in the cerebellum, prefrontal cortex, hypothalamus and hippocampus, resulting in behavioral improvement [78][79][80]. Nevertheless, psychostimulants induce side-effects such as insomnia, appetite loss, headache, abdomen pain, sleep disturbance and anxiety [4][81]. In addition, non-psychostimulants can produce nausea, diarrhea, somnolence, vomiting, appetite loss, fatigue, dizziness, and changes in the cardiovascular events [4][82]. Extensive studies have suggested that the pathophysiology of ADHD is associated with oxidative stress [74][83][84][85]. Therefore, there is an increasing interest in the search for alternative treatments for ADHD, including the application of bioactive natural compounds owing to their antioxidant properties and considering that these alternative treatments options may have minimal side-effects. The neuroprotective mechanisms of quercetin in pediatric neurological diseases are summarized in Figure 1.

Molecules 25 05597 g001 550

Figure 1. Chemical structure of quercetin and neuroprotection in pediatric neurological diseases (CNS tumors, ASD and ADHD). Quercetin may act as a neuroprotector in pediatric neurological diseases via the regulation of oxidative stress, inflammation, proliferation and improving symptoms and also via increasing antioxidant defenses, autophagy or cell death.

5.1. Protective Effects of Diverse Compounds That Include Quercetin in ADHD

As indicated earlier, accumulating evidence indicate that oxidative stress is involved in the pathophysiology of ADHD [74][83][84][85] and also that the administration of MPH can induce oxidative stress in neurons and thereby neurodegeneration in the cerebral cortex and the hippocampus of animals [86]. Passionflower, which is commonly known as Passiflora incarnata, contains quercetin and other ingredients. In a randomized controlled trial with passionflower in children and adolescents with ADHD, significant clinical benefit and a tolerable side-effect profile was achieved as result of the advantages of passionflower as compared with MPH [62]. St. John’s wort (Hypericum perforatum extract) that contains quercetin among other flavonoids, was used in a randomized double-blinded controlled trial of 8 weeks-duration, but it showed no improvement in the ADHD symptoms [63]. Conversely, a preliminary study demonstrated that treatment with St. John’s wort improved some symptoms in ADHD patients [64]. In vitro, the treatment with St. John’s wort could significantly increase the ATP levels in SH-SY5Y cells [65]. The outcomes of the protective effects of quercetin in ADHD are summarized in Table 1.

The spontaneously hypertensive rat (SHR) is presently used as a validated animal model of ADHD [87]. It was demonstrated that the treatment of SHR with quercetin could reduce its plasma MDA levels and aortic superoxide production as well as improve NO-dependent acetylcholine relaxation, which inhibited endothelial NO synthase (eNOS) phosphorylation and reduced the blood pressure [66]. It was also observed that an increase in oxidative stress in SHR, could be reversed by the treatment with quercetin [67]. Moreover, treatment with quercetin in rats showed significant reduction in the amphetamine-induced unilateral rotations, attenuation of rotenone-induced loss in striatal dopamine, up-regulation of the mitochondrial complex-I activity and increase in the CAT and SOD levels [68]. Quercetin prevented cardiac hypertrophy via suppression of the activator protein 1 (AP1) transcription activity and promotion of the activation of peroxisome proliferator-activated receptor γ (PPARγ). Moreover, the ultrastructural damage of mitochondria and myofibrils in both the SHR and H9C2 cells were found to be attenuated [69]. It was previously demonstrated that PPARγ activation has neuroprotective and antioxidant effects [88]. Finally, chronic treatment with quercetin blocked MPH-induced hyperlocomotion and also blocked the increase in lipid peroxidation levels in the striatum and prefrontal cortex regions [70]. Thus, compounds that contain quercetin could improve the neuroprotection through the activation of antioxidant pathways and by its powerful scavenging properties. Nevertheless, further studies are warranted to verify the efficacy, effects, and dosages of quercetin either alone or in combination with other flavonoids as a possible treatment alternative agent against oxidative stress in ADHD.

6. Protective Effects of Other Flavonoids in Pediatric Neurological Diseases

There are increasing data with flavonoids to verify their efficacy and potential for CNS tumors treatment. Furthermore, it was demonstrated that flavonoids combined with anticancer drugs led to the enhanced anticancer effect. Thus, flavanols such as epigallocatechin gallate which is a constituent of green tea, alone or in combination with temozolomide inhibited neurosphere formation and cell migration of glioma stem-like cells and the treatment whit epigallocatechin gallate, also affected both migration and adhesion of medulloblastoma cells [89][90]. Besides, the flavone chrysin and the combination with cisplatin, induced apoptosis, cell cycle arrest and ∆Ψm loss in human glioma cells [91]. The flavonoid luteolin significantly inhibited glioma cell proliferation, induced apoptosis via MAPK and caspase activation and promote autophagy [92][93]. Moreover, luteolin induced ER stress and mitochondrial dysfunction leading to cell death in glioblastoma cell lines and in an animal model [94]. The combination of the flavonoids luteolin and silibinin effectively blocked angiogenesis and survival pathways leading to induction of apoptosis [95]. Also, the same combination of flavonoids, induced inhibition of growth of glioblastoma cells by the induction of apoptosis and the inhibition of invasion and migration [96].

Alternative approaches with flavonoids are on continuous research to confirm their efficacy and to understand its potential in ASD treatment. The green tea extract (Camellia sinensis) is an important source of flavonols, such as catechins, epicatechin, epigallocatechin and epicatechin-3-gallate and flavonol derivatives such as kaempferol, quercetin and myricetin [97]. Thus, the green tea extract treatment demonstrated amelioration of behavioral and oxidative stress aberrations in an animal model of valproate-induced autism [98]. The treatment of co-ultramicronized palmitoylethanolamide and the flavonoid luteolin in a murine model of autism was efficient in ameliorating social and non-social symptoms via modulation of TNFα and IL-1β immunoreactivity, reduction of GFAP, NF-κB and increased neurogenesis and neuroplasticity in the hippocampus [99]. Moreover, consumption of epigallocatechin-3-gallate, the major compound of catechin in green tea can reverse the behavioural alterations in the sodium valproate-induced autism rat model possibly due to antioxidant effects [100]. Naringenin is a flavanone abundantly found in oranges, grapefruit, and tomato skin. The administration orally for 29 days of naringenin, significantly restored behavioral and biochemical deficits in ASD phenotype in rats induced by propanoic acid [101]. Ginkgo biloba leaves, contains flavonoids (quercetin, kaempferol, and isorhamnetin), terpenoids, and ginkgolic acid. In an observational study of three patients treated with Ginkgo biloba extract, improved aberrant behavior and symptoms of autism [102]. In a double-blind placebo-controlled trial, ginkgo biloba extract was used in patients with autism and the results demonstrated ginkgo biloba no shown significant improvement in the treated group; however, ginkgo biloba was relatively safe and well-tolerated [103].

A growing interest in alternative treatments for ADHD include the research with diverse flavonoids due to their antioxidant properties and because they have minimal side-effects [4]. Baicalin, a major flavonoid isolated from Scutellaria baicalensis Georgi, has antioxidative properties. Thus, baicalin regulated the core symptoms of ADHD and also, improved LDH activity and the synaptosomal ATPase via regulating the AC/cAMP/PKA signaling pathway in the SHR [104][105]. Pycnogenol has antioxidants effects and is extracted from French maritime pine bark (Pinus pinaster), the main ingredients are procyanidins which are a class of flavonoids and phenolic acids. In a randomized, double-blind, placebo-controlled trials, pycnogenol normalized total antioxidant status, catecholamine concentration, reduced oxidative stress, improved hyperactivity and attention in children with ADHD [106][107]. Moreover, the treatment with pycnogenol improved attention, visual-motor coordination, concentration and also reduced significantly the hyperactivity in children with ADHD [108]. Oroxylin A is a flavonoid found in plants Scutellaria baicalensis, Scutellaria lateriflora and the Oroxylum indicum tree. Oroxylin A has activity as a dopamine reuptake inhibitor and is an antagonist of the GABA-A receptor and also has antioxidant effects. Treatment with oroxylin A and a derivate of oroxylin A, improved ADHD-like behaviors in the SHR [109][110].

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