• Users Online: 2391
  • Home
  • Print this page
  • Email this page

 Table of Contents  
Year : 2016  |  Volume : 11  |  Issue : 12  |  Page : 1976-1980

Myricetin protects hippocampal CA3 pyramidal neurons and improves learning and memory impairments in rats with Alzheimer's disease

1 Department of Biology, Faculty of Science, Arak University, Arak; Neuroscience Research Center, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
2 Department of Biology, Faculty of Science, Arak University, Arak, Iran
3 Neuroscience Research Center, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran

Date of Acceptance29-Nov-2016
Date of Web Publication5-Jan-2017

Correspondence Address:
Matin Ramezani
Department of Biology, Faculty of Science, Arak University, Arak; Neuroscience Research Center, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran
Login to access the Email id

Source of Support: The study was funded by the Department of Biology, Faculty of Science, Arak University, Iran, No. 38156-8-8349., Conflict of Interest: None

DOI: 10.4103/1673-5374.197141

Rights and Permissions

There is currently no treatment for effectively slowing the progression of Alzheimer's disease, so early prevention is very important. Numerous studies have shown that flavonoids can improve memory impairment. The present study investigated the effects of myricetin, a member of the flavonoids, on intracerebroventricular streptozotocin induced neuronal loss and memory impairment in rat models of Alzheimer's disease. Myricetin at 5 or 10 mg/kg was intraperitoneally injected into rats over 21 days. Control rats were treated with 10 mL/kg saline. Behavioral test (the shuttle box test) was performed on day 22 to examine learning and memory in rats. Immediately after that, hematoxylin-eosin staining was performed to observe the morphological change in hippocampal CA3 pyramidal neurons. Myricetin greatly increased the number of hippocampal CA3 pyramidal neurons and improved learning and memory impairments in rats with Alzheimer's disease. These findings suggest that myricetin is beneficial for treatment of Alzheimer's disease.

Keywords: nerve regeneration; myricetin; Alzheimer′s disease; streptozotocin; hippocampus; pyramidal neurons; CA3 region; behavioral test; neural regeneration

How to cite this article:
Ramezani M, Darbandi N, Khodagholi F, Hashemi A. Myricetin protects hippocampal CA3 pyramidal neurons and improves learning and memory impairments in rats with Alzheimer's disease. Neural Regen Res 2016;11:1976-80

How to cite this URL:
Ramezani M, Darbandi N, Khodagholi F, Hashemi A. Myricetin protects hippocampal CA3 pyramidal neurons and improves learning and memory impairments in rats with Alzheimer's disease. Neural Regen Res [serial online] 2016 [cited 2022 Jan 26];11:1976-80. Available from: http://www.nrronline.org/text.asp?2016/11/12/1976/197141

  Introduction Top

Alzheimer's disease is one of the most prevalent types of dementia. It usually occurs in people aged 65 years or older (Newman et al., 2007). Both environmental and genetic factors are relevant in the pathogenesis of AD. The unusual deposition of amyloid-beta (Aβ) plaques and the abnormal aggregation of tau proteins are neuropathological properties of AD (Vauzour, 2014). Neuronal degeneration and cognitive impairment are the most typical features of this disorder (Song et al., 2014), which can directly affect the patient's ability to recall or recognize new information processed in the hippocampus (Machado et al., 2009). The hippocampus is a part of the brain consisting of CA1, CA2, and CA3 fields and the subiculum. Information originating from dentate gyrus is transferred to CA3 and then integrated in CA1 (Mu et al., 2011).

Strong evidence has recently come to light to support the positive influences of flavonoids on the brain (Spencer, 2007; Macready et al., 2009; Rendeiro et al., 2009; Kumar et al., 2013; Vauzour, 2014; Rendeiro et al., 2015; Wang et al., 2016). Flavonoids are rich in compounds that reduce neurodegenerative efficacy (Vauzour et al., 2008). In addition, they strongly promote neural networks by stimulating neurogenesis (Vauzour et al., 2008; Oberbauer et al., 2013). They have also been reported to enhance cognitive functions (Macready et al., 2009). Flavonoids exist in many vegetables and fruits and greatly influence different brain functions, such as cerebrovascular blood flow and synaptic plasticity, which are related to learning and memory (Rendeiro et al., 2015). Particularly, they are able to control and conserve neuronal survival, differentiation, and long-term potentiation in memory (Krishnaveni, 2012). The first and most important characteristics of flavonoids are their antioxidant activity and their ability to suppress reactive oxygen species formation (Kumar et al., 2013).

Numerous studies have confirmed neurogenesis in hippocampal neurons (Eriksson et al., 1998; Dong et al., 2003; Bruel-Jungerman et al., 2007; Liu et al., 2011; Mu et al., 2011). A large body of evidence has shown that flavonoids play a key role in neuronal improvement because of their high proportion of antioxidant features (Jung et al., 2010; Kim et al., 2010; Choi et al., 2012; Huang et al., 2012; Rendeiro et al., 2015; Wang et al., 2016). Some studies have also shown that flavonoids prevent and restrict neuronal damage in the hippocampal pyramidal layer (Rendeiro et al., 2009; Tongjaroenbuangam et al., 2011; Lee et al., 2012; Ashrafpour et al., 2015; Wang et al., 2016).

Myricetin (3,3′,4′5,5′,7-hexahydroxylflavone) is a common natural flavonoid found in many fruits, vegetables, and herbs. It is well-known for its antioxidant activity and anti-apoptotic effects (Kang et al., 2010). Myricetin plays a substantial role in the treatment and prevention of some diseases due to its potent iron-chelating capability, antioxidant and free-radical scavenging activities (Yao et al., 2014). Myricetin, as a well-known flavonoid with anti-oxidative, anti-inflammatory, anti-apoptotic, and neuroprotective properties, reportedly plays an important role in the hippocampus of stressed mice (Ma et al., 2015).

According to these studies, we assumed that myricetin as a potential flavonoid is beneficial for learning and memory in experimental models of Alzheimer's disease. In addition, it can improve neurons in hippocampal CA3 pyramidal layers in rats with Alzheimer's disease. The present study examined the possible effects of myricetin on learning and memory impairments and hippocampal CA3 pyramidal neurons in Wistar rat models of Alzheimer's disease induced by intracerebroventricular (i.c.v.) streptozotocin (STZ).

  Materials and Methods Top


Fifty adult male Wistar rats, weighing 220–250 g, were provided by Pasteur Institute, Tehran, Iran. The rats were housed two per cage in an animal house, kept at 22 ± 2°C and a 12 hour dark/light cycle, and were given free access to food and water.

Rats were anesthetized by intraperitoneal (i.p.) injection of 10% ketamine (50 mg/kg) and 2% xylazine (5 mg/kg) (Struck et al., 2011) and all efforts were made to minimize the pain and distress of experimental animals. All procedures for the treatment of animals were reviewed and approved by the Research and Ethics Committee of the Biology School, University of Arak, Iran and performed according to the National Institute of Health Guidelines for the Care and Use of Laboratory Animals.


All rats were equally and randomly divided into five groups. In the control group, rats daily received i.c.v. (10 μL for each lateral ventricle) and i.p. (10 mL/kg) injections of normal saline. In the STZ group, rats received injection of STZ (3 mg/kg, i.c.v., 10 μL on each side, on first and third days) under the stereotaxic surgery and normal saline (10 mL/kg, i.p.). In the STZ + 5 mg/kg myricetin and STZ + 10 mg/kg myricetin groups, rats received injection of STZ (3 mg/kg, i.c.v.) and myricetin (5 and 10 mg/kg respectively, i.p.). In the saline + myricetin group, rats received injection of normal saline (10 μL for each lateral ventricle, i.c.v.) and myricetin (10 mg/kg, i.p.). Myricetin/saline i.p. administration started 1 day before stereotactic surgery and was performed in the morning between 9:00 and 12:00 over 21 days. After 21 days, the passive avoidance test (the shuttle box test) was performed on the 22nd day. Immediately after that, rat brains were removed and stained with hematoxylin-eosin to examine the effects of myricetin on hippocampal CA3 pyramidal neurons.


The drugs used in the study were STZ (Sigma-Aldrich, St. Louis, MO, USA) and myricetin (Sigma-Aldrich). They were dissolved in sterile 0.9% saline just before the experiment. STZ was administered into the lateral ventricle, and myricetin or saline was i.p. injected.

Stereotaxic surgery

After anesthesia induction, the animal's head was shaved and then placed into a stereotaxic instrument (Stoelting, Chicago, IL, USA). 10 μL of STZ (ICV) was injected into each lateral ventricle via a Hamilton syringe. The stereotaxic coordinates were chosen based on the rat brain  Atlas More Details of Paxinos and Watson (1998): anteriorposterior = –0.8 mm; mediolateral = ± 1.4 mm; dorso-ventral = –3.5 mm from bregma.

Behavioral test

At the end of the treatment, the passive avoidance test (the shuttle box test) was performed. It consisted of two equally-sized compartments, a bright room (white compartment, 20 cm × 20 cm × 30 cm), and a dark one (black compartment, 20 cm × 20 cm × 30 cm). The chambers were separated by a guillotine-type door.

Prior to the experiment, all animals were placed into the apparatus for approximately 30 minutes (habituation stage). Afterward, each rat was individually placed in the bright chamber and the guillotine door was opened. As soon as the rat entered the dark chamber, the door was closed, and an electric shock was delivered by an isolated stimulator (1Hz, 3 seconds, 1/5 MA) through the grid floor. Twenty-four hours later, each rat was placed in the bright chamber for the retention test. The step-through latency (STL) and the total time spent in the dark chamber (TDC) were measured.

Tissue preparation and hematoxylin-eosin staining

Rats were deeply anesthetized with 3.5% chloral hydrate (35 mg/100 g, i.p.), and vessels were perfusion fixed by intracardiac infusion with phosphate buffer solution (0.1 M, pH 7.4) followed by 200 mL of 4% paraformaldehyde fixative in phosphate buffer solution (0.1 M, pH 7.4) for 15 minutes. Rat brains were removed, isolated, post fixed in 4% para formaldehyde (24 hours), and embedded in paraffin. Coronal sections, 10 μm in thickness, were taken from the dorsal hippocampus and stained with hematoxylin and eosin. Finally, the numbers of damaged and intact neurons in the hippocampal CA3 pyramidal layer were counted (Koike et al., 2008) using a light microscope (BX40, Olympus, New York, USA) connected to a camera (Olympus, DP12), and quantitatively analyzed by ImageJ software (Neuroscience Center of Shahid Beheshti University, Iran).

Statistical analysis

All results are expressed as the mean ± SEM. For the behavioral test, STL and TDC were analyzed by one-way analysis of variance (ANOVA) and Tukey's post-hoc test. Statistical results were analyzed using SPSS 16.0 software (SPSS, Chicago, IL, USA). Differences between groups in the average number of intact and damaged neurons in the hippocampal CA3 pyramidal layer were analyzed using GraphPad Prism Software (version 5.00) (GraphPad Software Inc., San Diego, CA, USA). A value of P < 0.05 was considered statistically significant.

  Results Top

Effect of myricetin on cognitive function of rats with Alzheimer's disease

Passive avoidance test results showed that STL was decreased and TDC was increased in the STZ group, indicating memory impairment, than in the control group (P < 0.05). STL was significantly increased and TDC was significantly decreased in the STZ + 10 mg/kg myricetin group than in the STZ group (P < 0.01). There were no significant differences in STL and TDC between STZ + 5 mg/kg myricetin and STZ groups (P > 0.05). STL was increased and TDC was decreased in the saline + 10 mg/kg myricetin group than in the STZ group ([Figure 1]).
Figure 1: Effect of myricetin (5 and 10 mg/kg) on learning and memory of Alzheimer's disease rats measured by passive avoidance test (the shuttle box test).
(A, B) Step-through latency (A) and total time spent in the dark chamber (B) in passive avoidance test were measured after intracerebroventricular injection of STZ followed by 21-day treatment of myricetin. Values are expressed as the mean ± SEM with 10 rats in each group. *P < 0.05, **P < 0.01, vs. STZ group (one-way analysis of variance followed by Tukey's post-hoc test). I–V: STZ (intracerebroventricular injection of STZ + intraperitoneal injection of normal saline), control (intracerebroventricular and intraperitoneal injections of normal saline), STZ + 5 mg/kg myricetin (intracerebroventricular injection of STZ + intraperitoneal injection of 5 mg/kg myricetin), STZ +10 mg/kg myricetin (intracerebroventricular injection of STZ + intraperitoneal injection of 10 mg/kg myricetin), saline + 10 mg/kg myricetin (intracerebroventricular injection of normal saline + intraperitoneal injection of 10 mg/kg myricetin) groups, respectively. STZ: Streptozotocin.

Click here to view

Effect of myricetin on hippocampal CA3 pyramidal neuron density in rats with Alzheimer's disease

Histological studies revealed striking changes in neuron morphology in each group. The number of intact neurons in the hippocampal CA3 pyramidal layer was markedly decreased in the STZ group, and there were some irregularities in the layer; however, the number of intact neurons was significantly increased in the control group and saline + myricetin group. Despite the fact that STZ greatly damaged neurons, myricetin (10 mg/kg/d, i.p.) significantly increased the number of intact neurons containing large, round, and regular neurons ([Figure 2]A,[Figure 2]B,[Figure 2]C,[Figure 2]D,[Figure 2]E).
Figure 2: Effect of myricetin (5 and 10 mg/kg) on morphology of hippocampal CA3 pyramidal neurons of rats with Alzheimer's disease (hematoxylin-eosin staining, original magnification ×40).
(A) Control group (natural and intact neurons with arranged CA3 layer); (B) STZ group (significant neural loss and an irregular layer); (C) STZ + 5 mg/kg myricetin (most of the cells were damaged; however, there were some intact neurons); (D) STZ + 10 mg/kg myricetin (neurons were neatly arranged with a lot of intact and round cells); (E) saline +10 mg/kg myricetin (regular layer and significant increases in intact neuron). Black arrows indicate intact neurons and red arrows represent damaged neurons (F) The average number of intact neurons in hippocampal CA3 pyramidal layer. All data are represented as the mean ± SEM. *P < 0.05, ***P < 0.001, vs. STZ group (one-way analysis of variance followed by Tukey's post-hoc test). I–V: STZ (intracerebroventricular injection of STZ + intraperitoneal injection of normal saline), control (intracerebroventricular and intraperitoneal injections of normal saline), STZ + 5 mg/kg myricetin (intracerebroventricular injection of STZ + intraperitoneal injection of 5 mg/kg myricetin), STZ +10 mg/kg myricetin (intracerebroventricular injection of STZ + intraperitoneal injection of 10 mg/kg myricetin), saline + 10 mg/kg myricetin (intracerebroventricular injection of normal saline + intraperitoneal injection of 10 mg/kg myricetin) groups, respectively. STZ: Streptozotocin.

Click here to view

Although i.c.v. injection of STZ resulted in severe hippocampal CA3 pyramidal neuronal damage, saline did not lead to any severe neuronal damage in this area in control rats; the number of damaged neurons in the STZ group was significantly increased than that in the control group (P < 0.05). However, the number of damaged neurons was significantly decreased in the STZ + 10 mg/kg myricetin group than in the STZ group (P < 0.01) ([Figure 2]F). These results suggest that myricetin (10 mg/kg/d) exhibited significant protective effects on STZ-induced neuronal damage.

  Discussion Top

The hippocampus plays a vital role in learning and memory. Moreover, hippocampal CA3 pyramidal neurons are significantly vulnerable to the negative effects of STZ. Therefore, hippocampal CA3 neurons located near the DG were the target of the current study. Hematoxylin-eosin staining showed that the number of intact neurons was greatly decreased in the STZ group; however, myricetin (10 mg/kg) alleviated neuronal damage in hippocampal CA3 region of rats receiving i.p. injection of STZ. This result indicates that myricetin at 10 mg/kg/d can promote neuronal recovery and at the same time improve neurogenesis in the hippocampus. i.c.v. injection of STZ in rats lead to learning, memory and cognitive impairments and worsened inflammatory response in the central nervous system (Baluchnejadmojarad., 2009; Khalili et al., 2010). The underlying mechanism remains unclear; however, it is likely attributed to the peripheral performance in the body (Grunblatt et al., 2007).

STZ in rat brain promoted inflammatory response after 3 weeks (Chu et al., 2005; Lester-Coll et al., 2006). Following 3 weeks of i.c.v. injection of STZ, great changes were observed in the rat brain (Agrawal et al., 2009). Free radicals induce neurotoxicity. Moreover, they lead to the symptoms of Alzheimer's disease (Khalili et al., 2010). There is evidence that STZ injections into the brain induce insulin resistance and lead to an increase in amyloid precursor protein processing to produce beta-amyloid and tau pathology (Kamat, 2015). Tau protein and Aβ are the most important pathological properties of AD. They are responsible for upcoming pathological events that result in a lack of cognitive performance, neuropsychiatric alterations, and eventually lead to neuronal death (Kamat, 2015).

Flavonoids can reportedly affect different kinds of synaptic plasticity, regulate receptor activation, signaling pathways and gene expression, and promote long-term potentiation (Rendeiro et al., 2012). In spite of many studies reporting flavonoid-mediated neuroprotection, there is no enough information regarding the interaction of flavonoids or their circulating metabolites with the blood-brain barrier (Youdim et al., 2004). Yao et al. (2014) demonstrated that myricetin is a lipophilic compound with low water solubility but high solubility in organic solvents or with solubilizers. It can pass through biological membranes such as the blood-brain barrier. Moreover, they show strong neuroprotective effects under in vivo conditions (Das et al., 2008; Hamaguchi et al., 2009), and their metabolites have been found in the brain tissue of rodents after oral administration (Paulke et al., 2006). These results display their ability to cross the blood-brain barrier (Paulke et al., 2006; Franco et al., 2010). In some age-related diseases, oxidative stress may contribute to the breakdown of blood-brain barrier, so flavonoids can enter the brain more easily than under the healthy state (Youdim et al., 2004).

It is strongly believed that Alzheimer's disease and other neurodegenerative disorders are triggered by multifactorial processes, including neuroinflammation, glutamatergic excitotoxicity, increases in iron, and/or the depletion of endogenous antioxidants (Jellinger, 2001). Flavonoids can inhibit apoptosis and other damage in neurons through neurotoxic species, but not directly. They modulate a number of protein kinase and lipid kinase signaling cascades, like PI3 kinase (PI3K)/Akt, tyrosine kinase, protein kinase C (PKC), and MAPK signaling pathways (Spencer, 2009). Spencer (2009) reported that flavonoids induce angiogenesis and new nerve cell growth in the hippocampus. Under the destructive effects of STZ, microglia and astrocytes produce cytokines (interleukin-1β, tumor necrosis factor-α) and nitric oxide (NO•) that lead to glial-induced neuronal death. Flavonoids play a truly significant role in the inhibition of NO•, interleukin-1β, and TNF-α in activated microglial cells (Spencer, 2009). Flavones have been shown to significantly inhibit 6-hydroxydopamine-induced JNK activation and neuronal cell death, and they may suppress JNK activity and apoptosis induced by hydrogen peroxide, 4-hydroxy-2-nonenal, and tumor necrosis factor-α (Kobuchi et al., 1999).

The present study clearly demonstrated that myricetin (10 mg/kg/d; i.p.) significantly inhibited cognitive impairments caused by i.c.v. injection of STZ. It can also increase the survival of hippocampal CA3 pyramidal neurons. The present findings add evidence to treatment of Alzheimer's disease using myricetin as a flavonoid.[47]

  References Top

Agrawal R, Tyagi E, Shukla R, Nath C (2009) A study of brain insulin receptors, AChE activity and oxidative stress in rat model of ICV STZ induced dementia. Neuropharmacology 56:779-787.  Back to cited text no. 1
Ashrafpour M, Parsaei S, Sepehri H (2015) Quercetin improved spatial memory dysfunctions in rat model of intracerebroventricular streptozotocin-induced sporadic Alzheimer's disease. Natl J Physiol 5:411-415.  Back to cited text no. 2
Baluchnejadmojarad T (2009) The effect of genistein on intracerebroventricular streptozotocin-induced cognitive deficits in male rat. Basic Clin Neurosci 1:17-21.  Back to cited text no. 3
Bruel-Jungerman E, Rampon C, Laroche S (2007) Adult hippocampal neurogenesis, synaptic plasticity and memory: facts and hypotheses. Rev Neurosci 18:93-114.  Back to cited text no. 4
Choi GN, Kim JH, Kwak JH, Jeong CH, Jeong HR, Lee U, Heo HJ (2012) Effect of quercetin on learning and memory performance in ICR mice under neurotoxic trimethyltin exposure. Food Chem 132:1019-1024.   Back to cited text no. 5
Chu WZ, Qian CY (2005) Expressions of Abeta1-40, Abeta1-42, tau202, tau396 and tau404 after intracerebroventricular injection of streptozotocin in rats. Di Yi Jun Yi Da Xue Xue Bao 25:168-170.  Back to cited text no. 6
Das S, Mandal AK, Ghosh A, Panda S, Das N, Sarkar S (2008) Nanoparticulated quercetin in combating age related cerebral oxidative injury. Curr Aging Sci 1:169-174.  Back to cited text no. 7
Dong H, Csernansky CA, Goico B, Csernansky JG (2003) Hippocampal neurogenesis follows kainic acid-induced apoptosis in neonatal rats. J Neurosci 23:1742-1749.  Back to cited text no. 8
Eriksson PS, Perfilieva E, Björk-Eriksson T, Alborn AM, Nordborg C, Peterson DA, Gage FH (1998) Neurogenesis in the adult human hippocampus. Nat Med 4:1313-1317.  Back to cited text no. 9
Francoa JL, Posser T, Missau F, Pizzolatti MG, Santos A, Souza DO, Aschner M, Rocha JBT, Dafre AL, Farina M (2010) Structure-activity relationship of flavonoids derived from medicinal plants in preventing methylmercury-induced mitochondrial dysfunction. Environ Toxicol Pharmacol 30:272-278.  Back to cited text no. 10
Grunblatt E, Salkovic-Petrisic M, Osmanovic J, Riederer P, Hoyer S (2007) Brain insulin system dysfunction in streptozotocin intracerebroventricularly treated rats generates hyperphosphorylated tau protein. J Neurochem 101:757-770.  Back to cited text no. 11
Hamaguchi T, Ono K, Murase A, Yamada M (2009) Phenolic compounds prevent Alzheimer's pathology through different effects on the amyloid-beta aggregation pathway. Am J Pathol 175:2557-2565.  Back to cited text no. 12
Huang JJ, Liu X, Wang XQ, Yang LH, Qi DS, Yao RQ (2012) Effects of quercetin on the learning and memory ability of neonatal rats with hypoxic-ischemic brain damage. Zhongguo Dang Dai Er Ke Za Zhi 14:454-457.  Back to cited text no. 13
Jellinger KA (2001) Cell death mechanisms in neurodegeneration. J Cell Mol Med 5:1-17.  Back to cited text no. 14
Jung WY, Park SJ, Park DH, Kim JM, Kim DH, Ryu JH (2010) Quercetin impairs learning and memory in normal mice via suppression of hippocampal phosphorylated cyclic AMP response element-binding protein expression. Toxicol Lett 197:97-105.  Back to cited text no. 15
Kamat PK (2015) Streptozotocin induced Alzheimer's disease like changes and the underlying neural degeneration and regeneration mechanism. Neural Regen Res 10:1050-1052.  Back to cited text no. 16
Kang KA, Wang ZH, Zhang R, Piao MJ, Kim KC, Kang SS, Kim YW, Lee J, Park D, Hyun JW (2010) Myricetin protects cells against oxidative stress-induced apoptosis via regulation of PI3K/Akt and MAPK signaling pathways. Int J Mol Sci 11:4348-4360.   Back to cited text no. 17
Khalili M, Hamzeh F (2010) Effects of active constituents of Crocus sativus L., crocin on streptozocin-induced model of sporadic Alzheimer's disease in male rats. Iran Biomed J 14:59-65.   Back to cited text no. 18
Kim JK, Choi SJ, Cho HY, Hwang HJ, Kim YJ, Lim ST, Kim CJ, Kim HK, Peterson S, Shin DH (2010) Protective effects of kaempferol (3,4′,5,7-tetrahydroxyflavone) against amyloid beta peptide (Aβ)-induced neurotoxicity in ICR mice. Biosci Biotechnol Biochem 74:397-401.  Back to cited text no. 19
Kobuchi H, Roy S, Sen CK, Nguyen HG, Packer L (1999) Quercetin inhibits inducible ICAM-1 expression in human endothelial cells through the JNK pathway. Am J Physiol 277:403-411.  Back to cited text no. 20
Koike M, Shibata M, Tadakoshi M, Gotoh K, Komatsu M, Waguri S, Kawahara N, Kuida K, Nagata S, Kominami E, Tanaka K, Uchiyama Y (2008) Inhibition of autophagy prevents hippocampal pyramidal neuron death after hypoxic-ischemic injury. Am J Pathol 172:454-469.  Back to cited text no. 21
Krishnaveni M (2012) Flavonoid in enhancing memory function. J Pharm Res 5:3870-3874.  Back to cited text no. 22
Kumar S, Pandey AK (2013) Chemistry and biological activities of flavonoids: an overview. ScientificWorldJournal 2013:162750.  Back to cited text no. 23
Lee JH, Lee SR (2012) The effect of Baicalein on hippocampal neuronal damage and metalloproteinase activity following transient global cerebral ischaemia. Phytother Res 26:1614-1619.  Back to cited text no. 24
Lester-Coll N, Rivera EJ, Soscia SJ, Doiron K, Wands JR, de la Monte SM (2006) Intracerebroventricular streptozotocin model of type 3 diabetes relevance to sporadic Alzheimer's disease. J Alzheimers Dis 9:13-33.  Back to cited text no. 25
Liu JX, Pinnock SB, Herbert J (2011) Novel control by the CA3 region of the hippocampus on neurogenesis in the dentate gyrus of the adult rat. PLoS One 6:1-8.  Back to cited text no. 26
Ma Z, Wang G, Cui L, Wang Q (2015) Myricetin attenuates depressant-like behavior in mice subjected to repeated restraint stress. Int J Mol Sci 16:28377-28385.   Back to cited text no. 27
Machado S, Cunha M, Minc D, Portella CE, Velasques B, Basile LF, Cagy M, Piedade R, Ribeiro P (2009) Alzheimer's disease and implicit memory. Arq Neuropsiquiatr 67(2-A):334-342.  Back to cited text no. 28
Macready AL, Kennedy OB, Ellis JA, Williams CM, Spencer JP, Butler LT (2009) Flavonoids and cognitive function: a review of human randomized controlled trial studies and recommendations for future studies. Genes Nutr 4:227-242.   Back to cited text no. 29
Mu Y, Gage FH (2011) Adult hippocampal neurogenesis and its role in Alzheimer's disease. Mol Neurodegener 6:85.   Back to cited text no. 30
Newman M, Musgrave IF, Lardelli M (2007) Alzheimer disease: amyloidogenesis, the presenilins and animal models. Biochim Biophys Acta 1772:285-297.  Back to cited text no. 31
Oberbauer E, Urmann C, Steffenhagen C, Bieler L, Brunner D, Furtner T, Humpel C, Bäumer B, Bandtlow C, Couillard-Despres S, Rivera FJ, Riepl H, Aigner L (2013) Chroman-like cyclic prenylflavonoids promote neuronal differentiation and neurite outgrowth and are neuroprotective. J Nutr Biochem 24:1953-1962.   Back to cited text no. 32
Paulke A, Schubert-Zsilavecz M, Wurglics M (2006) Determination of St. John's wort flavonoid-metabolites in rat brain through high performance liquid chromatography coupled with fluorescence detection. J Chromatogr B Analyt Technol Biomed Life Sci 832:109-113.  Back to cited text no. 33
Paxinos G, Watson C (1998) The rat brain in stereotaxic coordinates. 4th edition. San Diego: Academic Press.   Back to cited text no. 34
Rendeiro C, Rhodes JS, Spencer JP (2015) The mechanisms of action of flavonoids in the brain: Direct versus indirect effects. Neurochem Int 89:126-139.   Back to cited text no. 35
Rendeiro C, Guerreiro JD, Williams CM, Spencer JP (2012) Flavonoids as modulators of memory and learning: molecular interactions resulting in behavioural effects. Proc Nutr Soc 71:246-262.  Back to cited text no. 36
Rendeiro C, Spencer JP, Vauzour D, Butler LT, Ellis JA, Williams CM (2009) The impact of flavonoids on spatial memory in rodents: from behaviour to underlying hippocampal mechanisms. Genes Nutr 4:251-270.  Back to cited text no. 37
Song J, Hur BE, Bokara KK, Yang W, Cho HJ, Park KA, Lee WT, Lee KM, Lee JE (2014) Agmatine improves cognitive dysfunction and prevents cell death in a streptozotocin-induced Alzheimer rat model. Yonsei Med J 55:689-699.  Back to cited text no. 38
Spencer JP (2009) Flavonoids and brain health: multiple effects underpinned by common mechanisms. Genes Nutr 4:243-250.  Back to cited text no. 39
Spencer JP (2007) The interactions of flavonoids within neuronal signalling pathways. Genes Nutr 2:257-273.  Back to cited text no. 40
Struck MB, Andrutis KA, Ramirez HE, Battles AH (2011) Effect of a short-term fast on ketamine-xylazine anesthesia in rats. J Am Assoc Lab Anim Sci 50:344-348.  Back to cited text no. 41
Tongjaroenbuangam W, Ruksee N, Chantiratikul P, Pakdeenarong N, Kongbuntad W, Govitrapong P (2011) Neuroprotective effects of quercetin, rutin and okra (Abelmoschus esculentus Linn.) in dexamethasone-treated mice. Neurochem Int 59:677-685.  Back to cited text no. 42
Vauzour D (2014) Effect of flavonoids on learning, memory and neurocognitive performance: relevance and potential implications for Alzheimer's disease pathophysiology. J Sci Food Agric 94:1042-1056.  Back to cited text no. 43
Vauzour D, Vafeiadou K, Rodriguez-Mateos A, Rendeiro C, Spencer JP (2008) The neuroprotective potential of flavonoids: a multiplicity of effects. Genes Nutr 3:115-126.  Back to cited text no. 44
Wang H, Wang H, Cheng H, Che Z (2016) Ameliorating effect of luteolin on memory impairment in an Alzheimer's disease model. Mol Med Rep 13:4215-4220.  Back to cited text no. 45
Yao Y, Lin G, Xie Y, Ma P, Li G, Meng Q, Wu T (2014) Preformulation studies of myricetin: a natural antioxidant flavonoid. Pharmazie 69:19-26.  Back to cited text no. 46
Youdim KA, Shukitt-Hale B, Joseph JA (2004) Flavonoids and the brain: interactions at the blood-brain barrier and their physiological effects on the central nervous system. Free Radic Biol Med 37:1683-1693.  Back to cited text no. 47

Author contributions: All authors contributed to conception of this study, participated in data analysis and paper writing and approved the final version of this paper for publication. ND supervised the study.
Conflicts of interest: None declared.
Plagiarism check: This paper was screened twice using CrossCheck to verify originality before publication.
Peer review: This paper was double-blinded and stringently reviewed by international expert reviewers.


  [Figure 1], [Figure 2]

This article has been cited by
1 Mechanistic new insights of flavonols on neurodegenerative diseases
Muhammad Shoaib Tahir,Maged Almezgagi,Yu Zhang,Adnan Bashir,Hasnat Mazhar Abdullah,Mohammed Gamah,Xiaozhou Wang,Qinfang Zhu,Xiangqun Shen,Qianqian Ma,Muhammad Ali,Zeeshan Ahmed Solangi,Waseem Sami Malik,Wei Zhang
Biomedicine & Pharmacotherapy. 2021; 137: 111253
[Pubmed] | [DOI]
2 Neuroprotective Potential of Mung Bean (Vigna radiata L.) Polyphenols in Alzheimer’s Disease: A Review
Hui Xu,Qian Zhou,Bin Liu,Ka-Wing Cheng,Feng Chen,Mingfu Wang
Journal of Agricultural and Food Chemistry. 2021; 69(39): 11554
[Pubmed] | [DOI]
3 Polyphenols and neurodegenerative diseases: focus on neuronal regeneration
Seyed Zachariah Moradi,Faramarz Jalili,Negin Farhadian,Tanuj Joshi,Mingfu Wang,Liang Zou,Hui Cao,Mohammad Hosein Farzaei,Jianbo Xiao
Critical Reviews in Food Science and Nutrition. 2021; : 1
[Pubmed] | [DOI]
4 Role of Natural Plant Products Against Alzheimer’s Disease
Himanshi Varshney, Yasir Hasan Siddique
CNS & Neurological Disorders - Drug Targets. 2021; 20
[Pubmed] | [DOI]
5 Critical Review of the Alzheimer’s Disease Non-Transgenic Models: Can They Contribute to Disease Treatment?
Julio A. Flores-Cuadra, Alanna Madrid, Patricia L. Fernández, Ambar R. Pérez-Lao, Diana C. Oviedo, Gabrielle B. Britton, Maria B. Carreira, K.S. Jagannatha Rao, Gabrielle B. Britton, Luisa Lilia Rocha Arrieta, Norberto Garcia-Cairasco, Alberto Lazarowski, Adrián Palacios, Antoni Camins Espuny, Ricardo B. Maccioni
Journal of Alzheimer's Disease. 2021; 82(s1): S227
[Pubmed] | [DOI]
6 Pharmacological Actions of Myricetin in the Nervous System: A Comprehensive Review of Preclinical Studies in Animals and Cell Models
Jie Li, Haitao Xiang, Chao Huang, Jiashu Lu
Frontiers in Pharmacology. 2021; 12
[Pubmed] | [DOI]
7 Anti-Oxidative, Anti-Inflammatory and Anti-Apoptotic Effects of Flavonols: Targeting Nrf2, NF-?B and p53 Pathways in Neurodegeneration
Maja Jazvinšcak Jembrek, Nada Oršolic, Lucija Mandic, Anja Sadžak, Suzana Šegota
Antioxidants. 2021; 10(10): 1628
[Pubmed] | [DOI]
8 Therapeutic Potential of Phytoconstituents in Management of Alzheimer’s Disease
Anurag Kumar Singh,Sachchida Nand Rai,Anand Maurya,Gaurav Mishra,Rajendra Awasthi,Anshul Shakya,Dinesh Kumar Chellappan,Kamal Dua,Emanuel Vamanu,Sushil Kumar Chaudhary,M. P. Singh,Adolfo Andrade-Cetto
Evidence-Based Complementary and Alternative Medicine. 2021; 2021: 1
[Pubmed] | [DOI]
9 Myricetin bioactive effects: moving from preclinical evidence to potential clinical applications
Yasaman Taheri,Hafiz Ansar Rasul Suleria,Natália Martins,Oksana Sytar,Ahmet Beyatli,Balakyz Yeskaliyeva,Gulnaz Seitimova,Bahare Salehi,Prabhakar Semwal,Sakshi Painuli,Anuj Kumar,Elena Azzini,Miquel Martorell,William N. Setzer,Alfred Maroyi,Javad Sharifi-Rad
BMC Complementary Medicine and Therapies. 2020; 20(1)
[Pubmed] | [DOI]
10 Inhibitory Effects of Myricetin on Lipopolysaccharide-Induced Neuroinflammation
Jung-Hee Jang,Seung Hoon Lee,Kyungsook Jung,Horyong Yoo,Gunhyuk Park
Brain Sciences. 2020; 10(1): 32
[Pubmed] | [DOI]
11 Protective effects of isoquercitrin on streptozotocin-induced neurotoxicity
Lei Chen,Peimin Feng,Anjiao Peng,Xiangmiao Qiu,Wanling Lai,Lin Zhang,Wanling Li
Journal of Cellular and Molecular Medicine. 2020;
[Pubmed] | [DOI]
12 Current Pharmacological Trends on Myricetin
Gudiya Gupta,Mohd Aftab Siddiqui,Mohd Muazzam Khan,Mohd Ajmal,Rabiya Ahsan,Md Azizur Rahaman,Md Afroz Ahmad,Md Arshad,Mohammad Khushtar
Drug Research. 2020;
[Pubmed] | [DOI]
13 Myrtus communis subsp. communis improved cognitive functions in ovariectomized diabetic rats
Beril Kadioglu Yaman,Özge Çevik,Kübra Yalman,Büsra Ertas,Ali Sen,Göksel Sener
Gene. 2020; : 144616
[Pubmed] | [DOI]
14 Myricetin against myocardial injury in rat heat stroke model
Xiaojing Lin,Cheng-Hsien Lin,Ruoxu Liu,Chenyi Li,Shuxin Jiao,Xueqing Yi,M.J. Walker,Xiao-Ming Xu,Tingbao Zhao,Po-Chang Huang,Gang Sun
Biomedicine & Pharmacotherapy. 2020; 127: 110194
[Pubmed] | [DOI]
15 Phytochemicals and cognitive health: Are flavonoids doing the trick?
Ioannis Bakoyiannis,Afrodite Daskalopoulou,Vasilios Pergialiotis,Despina Perrea
Biomedicine & Pharmacotherapy. 2019; 109: 1488
[Pubmed] | [DOI]
16 The ameliorative effects of myricetin on neurobehavioral activity, electrophysiology, and biochemical changes in an animal model of traumatic brain injury
Mohammad Ali Mirshekar,Mohammadreza Shahraki,Reza Najafi,Sahreh Shabani
Learning and Motivation. 2019; 68: 101597
[Pubmed] | [DOI]
17 The effect of Zataria multiflora hydroalcoholic extract on memory and lung changes induced by rats that inhaled paraquat
Mahrokh Heydari,Amin Mokhtari-Zaer,Fatemeh Amin,Arghavan Memarzia,Saeideh Saadat,Mahmoud Hosseini,Mohammad Hossein Boskabady
Nutritional Neuroscience. 2019; : 1
[Pubmed] | [DOI]
18 Natural Compounds for Alzheimer’s Disease Therapy: A Systematic Review of Preclinical and Clinical Studies
Stephanie Andrade,Maria João Ramalho,Joana Angélica Loureiro,Maria do Carmo Pereira
International Journal of Molecular Sciences. 2019; 20(9): 2313
[Pubmed] | [DOI]
19 Kaempferol attenuates cognitive deficit via regulating oxidative stress and neuroinflammation in an ovariectomized rat model of sporadic dementia
Somayeh Kouhestani,Adele Jafari,Parvin Babaei
Neural Regeneration Research. 2018; 13(10): 1827
[Pubmed] | [DOI]
20 Flavonoids Fraction of Mespilus Germanica Alleviates Insulin Resistance in Metabolic Syndrome Model of Ovariectomized Rats via Reduction in Tumor Necrosis Factor-a
Somayeh Kouhestani,Samad Zare,Parvin Babaei
Journal of Menopausal Medicine. 2018; 24(3): 169
[Pubmed] | [DOI]
21 Calycosin improves cognitive function in a transgenic mouse model of Alzheimeræs disease by activating the protein kinase C pathway
Lei Song,Xiaoping Li,Xiao-xue Bai,Jian Gao,Chun-yan Wang
Neural Regeneration Research. 2017; 12(11): 1870
[Pubmed] | [DOI]


Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
Access Statistics
Email Alert *
Add to My List *
* Registration required (free)

  In this article
Materials and Me...
Article Figures

 Article Access Statistics
    PDF Downloaded479    
    Comments [Add]    
    Cited by others 21    

Recommend this journal