Quercetin Modulates Behavioural and Biochemical Alterations in Stressed Mice

Abstract

Disruption of the active phase of sleep alters the physiological homeostasis of the body and results in oxidative breakdown which may trigger a wide array of defects. The central nervous system and the metabolic system are some of the most affected systems as described in several literatures. Some plant based compounds with antioxidant property have been previously described in the abrogation of the deleterious effects of active sleep disruption. One of such compounds is quercetin. This study was premeditated to expatiate on the probable neuroprotective effect of quercetin on mice exposed to 72hr active sleep disruption. Mice were allotted into five treatment groups (n = 6): group 1 served as control, group 2 received 10 mL/kg vehicle, groups 3 and 4 received 25 and 50 mg/kg quercetin respectively, and group 5 received 50 mg/kg astaxanthin. Treatment lasted for 7 days while groups 2-5 were exposed to the sleep deprivation protocol starting from day 4. Behavioural tests followed by biochemical assays and histopathological changes in the prefrontal cortex were evaluated. Data were analysed by ANOVA set at p<0.05 significance. The results revealed that quercetin, in both doses, significantly amplified memory performance, attenuated depression-like behaviour, replenished catalase and superoxide dismutase, attenuated nitric oxide levels in brain and liver of mice when compared to control group and protected against loss of prefrontal cortex neurons. In conclusion, quercetin possesses protective effects against sleep deprivation-induced brain damage.

Full text

BIOSCIENCES BIOTECHNOLOGY RESEARCH ASIA, December 2021. Vol. 18(4), p. 681-689
Published by Oriental Scientific Publishing Company © 2021
This is an Open Access article licensed under a Creative Commons license: Attribution 4.0 International (CC-BY).
*Corresponding author E-mail:
Quercetin Modulates Behavioural and Biochemical
Alterations in Stressed Mice
Anthony Taghogho Eduviere1, Emuesiri Goodies Moke1,
Adrian Itivere Omogbiya1, Lily Oghenevovwero Otomewo1*,
Juliet Nnenda Olayinka2, Faith Eninidiere Aboyewa1 and Atare Peace Ijeje1
1Department of Pharmacology, Delta State University, Abraka, Nigeria.
2Department of Pharmacology, AfeBabalola University, Ado-Ekiti, Nigeria.
*Corresponding Author E-mail: ejirukomaotomewo@gmail.com
http://dx.doi.org/10.13005/bbra/2951
(Received: 27 October 2021; accepted: 30 November 2021)
Disruption of the active phase of sleep alters the physiological homeostasis of the
body and results in oxidative breakdown which may trigger a wide array of defects. The central
nervous system and the metabolic system are some of the most affected systems as described
in several literatures. Some plant based compounds with antioxidant property have been
previously described in the abrogation of the deleterious effects of active sleep disruption. One
of such compounds is quercetin. This study was premeditated to expatiate on the probable
neuroprotective effect of quercetin on mice exposed to 72hr active sleep disruption. Mice were
allotted into five treatment groups (n = 6): group 1 served as control, group 2 received 10 mL/kg
vehicle, groups 3 and 4 received 25 and 50 mg/kg quercetin respectively, and group 5 received
50 mg/kg astaxanthin. Treatment lasted for 7 days while groups 2-5 were exposed to the sleep
deprivation protocol starting from day 4. Behavioural tests followed by biochemical assays
and histopathological changes in the prefrontal cortex were evaluated. Data were analysed by
ANOVA set at p<0.05 significance. The results revealed that quercetin, in both doses, significantly
amplified memory performance, attenuated depression-like behaviour, replenished catalase and
superoxide dismutase, attenuated nitric oxide levels in brain and liver of mice when compared
to control group and protected against loss of prefrontal cortex neurons. In conclusion, quercetin
possesses protective effects against sleep deprivation-induced brain damage.
Keywords: Antioxidants; Hepatoprotective; Liver; Neuroprotective; Oxidative stress; Quercetin.
 Acutestresssuchasinsucientsleepis
aninfamouschallengeinmodernsociety,aecting
asignicantnumberofpeopleatvariouspointsin
theirlives.Althoughoccasionalsleepdisruptions
are usually no more than a nuisance, persistent
lack of sleep can lead to various alterations in
bodilyfunctionsthatmayalterthequalityoflife1.
Meanwhile, there are reports that acute stress
increase oxidations and diminishes antioxidant
protectionparticularlyintheliver2.Asimilarripple
eecthadpreviouslybeennotedinthebraindue
totherelationshipbetweenthefunctionalstatusof
theliverandthebrain3.
 Ontheotherhand,thereisliteraryevidence
ontheneuroprotectiveeectofquercetin4.Several
scienticliteratureshaveshownthatquercetincan
bestowneuroprotectionandantagonizeoxidative
stress-mediated disorders in vivo. For example,

682 EduviErE et al., Biosci., Biotech. Res. Asia, vol. 18(4), 681-689 (2021)
oralquercetin was revealed toprotectlaboratory
animals from oxidative stress and neurotoxicity
which were induced by various insults5,6.Also,
Bona et al.7, reported that quercetin reversed
theincrease in serum levelsof liver enzymes in
rats caused by inhaled chloroform, supporting
the belief that quercetin possesses antioxidant,
hepatoprotective and neuroprotective ability.
However,there is paucity of information on the
role of quercetin in sleep deprivation-induced
stress.Therefore,this study is justiedin that it
contributestothebodyofliteratureontheprobable
modulatoryeectofquercetinonbehaviouraland
biochemical alterations in the brain and liver of
sleepdeprivedmice.
MATERIAL AND METHODS
Animals and Housing
 MaleAlbinoSwissmice(n=30;22.0±2.0
g) used in this study were procured from the
centralanimalfacility,FacultyofBMS,DeltaState
University,Abraka.Mice were housed inplastic
cagesingroupsofsixandmaintainedunderroom
temperaturewitha12hlight–darkcycle(lightson
from 07:00 to 19:00 hours). They were allowed
accesstowaterandrodentchow ad libitum.Note
thatmicewere acclimatized for about oneweek
beforetheexperiment.Theexperimentalprotocols
were performed according to the NIH guideline
forlaboratoryanimalswithdueapprovalfromthe
ethicalcommitteeoftheinstitution(REF/FBMS/
DELSU/21/105).
Drugs and Chemicals
 Quercetin,astaxanthinandDTNBwere
obtainedfromAldrich,Germany.Aceticacidwas
gottenfromSigma-Aldrich,Inc.,StLouis,USA.
TCAwas obtained from Burgoyne Burbidge’s&
Co.,Mumbai,India.TBAandDMSOwereobtained
from Guanghua Chemical Factory Co. Ltd.,
China.Tris-buer was obtained from Hopkins&
Williams Company, USA. NaHCO3,NaH2PO4.
H2O, K2HPO4, K2Cr2O7, KCl and Na2HPO4.H2O
wereobtainedfrom BDH Chemicals Ltd, Poole,
England. Sodium Carbonate was obtained from
Fisons,LoughboroughLeics,England.NaOHwas
obtainedfrom J.TBaker ChemicalsCo.,Phillips
burg,N.J.,USA.
Drug Preparation and Treatment Groups
 Theconcentrationsofquercetinused in
thisstudywereobtainedfollowingaserialdilution
of 100 mg quercetin in 20 mL of 0.5% DMSO.
The mice were indiscriminately distributed into
ve(5)treatmentgroups(n=6)basedonthedrug
theyreceived:group1 received vehicle (10 mL/
kg0.5%DMSO,p.o),group2receivedvehiclein
addition to being sleep-deprived, while group 3
receivedlow-dosequercetinandgroup4received
high-dosequercetin(25mg/kgand50mg/kgp.o,
respectively)inadditiontobeingsleep-deprived,
group 5 received astaxanthin (50 mg/kg) in
additionto being sleep-deprived.Totaltreatment
durationwasseven(7)days.Fromthefourthday,
miceingroups2-5weresubjectedto72hrsleep
deprivation.
Experimental Design
 Deprivation of the active stage of
sleep was carried out in line with the method
of Shinomiya and colleagues8 with moderate
modications.
 Attheendofthe72hrsleepdeprivation
duration, 1 hr after the last treatment, the eect
ofactivesleepdeprivationonbehaviour,hepatic/
brainoxidativestressparametersandlipidprole
wasassessed.Also,animals were euthanized on
the seventh day.Liver and brain tissues were
harvestedandspecictissueswerekeptasidefor
histopathologicalevaluation.
Behavioural Tests
Open eld test (OFT)
 The OFT was used to determine the
spontaneous motor activity (SMA) of mice
following the method described9,10. Number of
squarelinescrossedanddurationofambulationof
eachmousewasrecordedwithina10minperiod.
Tail suspension test(TST)
 TheTST was carried out in accordance
withtheproceduredescribed11withslightchanges.
Amousewasadjudgedtobenon-mobileifitmade
nomovementswithitsheadabovewaterlevel.
Novel object recognition test
 Thenovelobjectrecognitionmemorytest
explores the animal’spreference for novelty. In
thisstudy,themethoddescribed12 was followed.
Thepercentagepreference,whichwasusedasan
index of recognition memory,was calculated as
thetotaltimespentbyamousein exploring the
novel object divided by the summation of total
timespent exploring both thefamiliarandnovel
objectsmultipliedby100%.

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Assessment of lipid prole
Serum triglyceride levels
 Serumtriglyceridelevelinmouseserum
wasdeterminedbyenzymaticcolorimetricmethod
according to the protocol earlier described13.
Concentrationoftriglyceride(mg/dL)inthesample
wasobtainedfromtheequation:
CX=[K(AX-Ab)+Cb]xIF
Where:
Cx=Concentrationofsample
K=Concentrationfactor
Ax=MeanofabsorbanceofSample
Ab=Meanofabsorbanceofblank
Cb=concentrationofblank
IF=instrumentfactor(ordilutioncorrection)
High-density lipoproteins
 High-density lipoproteins (HDL)level
was determined in mouse serum by enzymatic
colorimetric method according to the protocol
described13.ConcentrationofHDL(mg/dL)inthe
sampleisobtainedfromtheequation:
CX=[K(AX-Ab)+Cb]xIF
Where:
Cx=Concentrationofsample
K=Concentrationfactor
Ax=MeanofabsorbanceofSample
Ab=Meanofabsorbanceofblank
Cb=concentrationofblank
IF=instrumentfactor(ordilutioncorrection)
Biochemical Assays
Superoxide dismutase (SOD) activity
approximation
 ThelevelofSODactivityinthebrainand
liverwasapproximatedaccording to the method
modiedbyUmukoroandhiscolleagues14 which
involvestheuse of adrenaline. This activity was
expressed in units of adrenaline consumed per
minutepermgprotein.
Estimation of catalase (CAT) activity
 Brain and liver catalase activity was
determined according to the Hadwan method15.
Thecatalaseactivitywasexpressedinµmol.
Estimation of nitric oxide
 Brainandlivernitriteconcentrationwas
estimatedfollowingthemethodofGreenetal.16,
whichinvolvestheuseofGreissreagent.
Statistical Analysis
 Data sets were presented as Mean ±
S.E.M.The resultswereanalysedusingthe one-
wayANOVA technique, and a specic post hoc
test(Student’sNewman–Keuls)wascarriedoutto
determinethecriterionofsignicanceusingGraph
PadBiostatisticssoftware.Signicanceforalltests
wasthenestablishedatp<0.05.
RESULTS AND DISCUSSION
 This study was undertaken to assess
the eect of active sleep deprivation alone and
#depictssignicance(p<0.05)comparedtononsleep-deprivedgroup.
*depictssignicance(p<0.05)comparedtovehicle+SDgroup.
VEH:Vehicle.AXT:Astaxanthin.QCT:Quercetin.SD:Sleepdeprivation.
Fig. 1. Eectofquercetinonrecognitionmemoryinsleepdeprivedmice

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SlideA:Non-sleepdeprivedgroup,VEH10mL/kg.
SlideB:Sleepdeprivedgroup,VEH10mL/kg+SD.
SlideC:Low-dosequercetingroup,QCT25mg/kg+SD.
SlideD:High-dosequercetingroup,QCT50mg/kg+SD.
SlideE:Astaxanthingroup,AXT50mg/kg+SD.
Blackarrows:Normalneuronalcells.
Redarrows:Neuronalcellsundergoingnecrosis.
VEH:Vehicle.AXT:Astaxanthin.QCT:Quercetin.SD:Sleepdeprivation.
Fig. 2.Photomicrographoftheprefrontalcortexofsleepdeprivedmice

685 EduviErE et al., Biosci., Biotech. Res. Asia, vol. 18(4), 681-689 (2021)
#depictssignicance(p<0.05)comparedtononsleep-deprivedgroup.
*depictssignicance(p<0.05)comparedtovehicle+SDgroup.
VEH:Vehicle.AXT:Astaxanthin.QCT:Quercetin.SD:Sleepdeprivation.
Fig. 3. Eectofquercetinonviableprefrontalcortexneuronsinsleep-deprivedmice
Table 1. Eectofquercetinonbrainoxidativestressparametersinsleepdeprivedmice
Treatment CAT SOD NO(µM)
 (units/mgprotein) (units/mgprotein)
VEH10mL/kg 33.47+1.93 16.91+0.62 47.37+4.55
VEH10mL/kg+SD 15.87+1.94# 10.32+0.95# 76.59+6.37#
QCT25mg/kg+SD 28.88+3.81* 16.93+0.86* 51.65+3.01*
QCT50mg/kg+SD 32.60+3.71* 20.67+0.94* 39.77+4.45*
AXT50mg/kg+SD 27.10+1.88* 15.61+1.07* 42.34+5.14*
#depictssignicance(p<0.05)comparedtononsleep-deprivedgroup.
*depictssignicance(p<0.05)comparedtovehicle+SDgroup.
VEH:Vehicle.AXT:Astaxanthin.QCT:Quercetin.SD:Sleepdeprivation.
in combination with quercetin supplementation
on brain and liver oxidative stress status and
behaviouralphenotypesinmice.Therearemany
mechanisms via which sleep deprivation can
be responsible for oxidative consequences and
liver toxicity,but these eects are probably not
attributabletoasinglenightofsleepdeprivation.
Inthisstudy,wemeasuredtheeectsof72hrsleep
deprivation on lipid prole parameters, hepatic
and brain oxidative stress biomarkers, anxiety-
like symptoms, depression-like behaviour and
recognitionmemoryconsolidationinmice.
 The results of this study showed that
sleep deprivation significantly diminished
recognitionmemory,asitdecreasedthepercentage
preferenceforthefamiliarobjectinmice(Figure
1). Recognition memory was impaired in the
sleepdeprivedgroupwithasignicantreduction
in percentage preference in the novel object
recognitionparadigmwhencomparedtothenon-
sleep-deprivedgroup.Traditionally,theusefulness
ofthistestinmemoryassessmentisbasedonthe
innateinclinationofanimals(particularlyrodents)
for unfamiliar objects12. The preference of mice
fora novel object as compared toafamiliarone
indicatesthe existence oftheobject’sfamiliarity
in the animals’memory. Thus, the duration of
exploration depends on the degree of residual
memory of the object. In this test, quercetin
increasedthedurationofexplorationofthenovel
object,whichsuggestsmemoryimprovement12.
 Quercetin also protects neuronal
cells. This was substantiated in this study by
histomorphometricanalysisoftheprefrontalcortex

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Table 2. Eectofquercetinonspontaneousmotoractivityinsleepdeprivedmice
Treatment Numberoflinescrossed Ambulation(min)
VEH10mL/kg 143.70±8.19 3.52±0.36
VEH10mL/kg+SD 213.50±10.22# 6.88±0.39#
QCT25mg/kg+SD 175.50±13.18* 4.80±0.38*
QCT50mg/kg+SD 165.70±7.66* 4.34±0.46*
AXT50mg/kg+SD 185.50±4.87* 5.09±0.28*
#depictssignicance(p<0.05)comparedtononsleep-deprivedgroup.
*depictssignicance(p<0.05)comparedtovehicle+SDgroup.
VEH:Vehicle.AXT:Astaxanthin.QCT:Quercetin.SD:Sleepdeprivation.
#depictssignicance(p<0.05)comparedtononsleep-deprivedgroup.
*depictssignicance(p<0.05)comparedtovehicle+SDgroup.
VEH:Vehicle.AXT:Astaxanthin.QCT:Quercetin.SD:Sleepdeprivation.
Fig. 4. Eectofquercetinondepression-likebehaviourinsleep-deprivedmice
of mice17. The data revealed that sleep deprived
micehadsignicantnecrosisofbraincells(slide
B) when compared with the non-sleep deprived
group(slideA).Thiswassimilartotheobserved
changes in neuronal densitities of the prefrontal
cortexof miceinallgroups18.Thiswasreversed
by quercetin supplementation (slides C and D;
Figure2and3)aseectivelyasastaxanthin(slide
E). This could also play a role in the memory
impairmentobservedsince a study by Umukoro
andEduviere19hadimplicatedtheprefrontalcortex
asoneofthenotablebrain regionswitharolein
recognition memory.Although more preclinical
studiesarenecessarybeforecommentingonhow
quercetinimproves memory in mice, the present
data suggest modulatory eect of quercetin on
sleep deprivation-induced recognition memory
impairment.
 Alsofromthisstudy,recognitionmemory
impairment caused by sleep deprivation was
accompaniedbyincreasedbrainoxidativestress,as
indicatedbyelevatedlevelsofnitriteanddecreased
antioxidantdefencesystemsinthebrain(Table1).
Inthebraintissueofthesleepdeprivedgroup,SOD
andCATactivityweresignicantly(p<0.05)lower,
whereasnitritelevelswassignicantlyincreased(p
<0.05)whencomparedtothecontrolgroup.This
eectwas however attenuatedby quercetin pre-

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Table 3. Eectofquercetinontriglycerideandhigh-densitylipoprotein
levelsinsleepdeprivedmice
Treatment HDL(mg/dL) Triglycerides(mg/dL)
VEH10mL/kg 118.3+2.10 110.0+2.68
VEH10mL/kg+SD 88.00+4.02# 166.3+5.76#
QCT25mg/kg+SD 106.8+2.48* 141.4+6.41*
QCT50mg/kg+SD 113.3+3.45* 134.9+3.42*
AXT50mg/kg+SD 104.0+2.36* 149.9+3.40*
#depictssignicance(p<0.05)comparedtononsleep-deprivedgroup.
*depictssignicance(p<0.05)comparedtovehicle+SDgroup.
VEH:Vehicle.AXT:Astaxanthin.QCT:Quercetin.SD:Sleepdeprivation
Table 4. Eectofquercetinonliveroxidativestressparametersinsleepdeprivedmice
Treatment CAT SOD NO
 (units/mgprotein) (units/mgprotein) (µM)
VEH10mL/kg 65.80+5.15 58.14+3.71 34.62+5.71
VEH10mL/kg+SD 26.28+3.21# 27.64+2.91# 81.13+4.85#
QCT25mg/kg+SD 49.60+5.49* 43.10+4.70* 51.81+6.87*
QCT50mg/kg+SD 58.03+5.42* 52.44+3.62* 40.28+3.00*
AXT50mg/kg+SD 48.23+4.31* 45.35+3.90* 49.41+5.15*
#depictssignicance(p<0.05)comparedtononsleep-deprivedgroup.
*depictssignicance(p<0.05)comparedtovehicle+SDgroup.
VEH:Vehicle.AXT:Astaxanthin.QCT:Quercetin.SD:Sleepdeprivation.
treatmentaseectivelyasastaxanthin.Thisis in
linewithpreviousstudies19,20.Thus,thecapability
ofquercetintoreversesleepdeprivation-induced
memory impairment in mice suggests an action
thatmayinvolvetheinhibitionofcentraloxidative
stress.Thisactionpossiblyresultedfromitsability
toreplenishantioxidantdefencesystems(SODand
catalase)anddecreaseNOlevels..
 Furthermore, other mood-related
behaviours(depressionandanxiety)wereassessed
in this study.Sleep deprived mice were more
activeintheopen eld test (Table2),signalling
anxiety;andincreaseddurationofimmobilestate
intheTST(Figure4),signallingdepression.Sleep
deprivationsignicantly(p<0.05)diminishedthe
motoractivity of mice as shown in less number
oflines crossed and duration of ambulation and
signicantly (p<0.05) increased the immobility
time of mice in the TST whencompared to the
non-sleep deprived group. However, quercetin-
treatedgroupsexhibitedimprovedmoodrecorded
asincreased numberoflines crossedintheopen
eldtestanddecreaseddurationofimmobilityin
theTST.Thisagreeswithpreviousstudieswhich
haveoutlinedthe benecial role of quercetinon
anxiety-anddepressive-likesymptoms22.
 Alsointhisstudy,triglyceridelevelwas
signicantly(p<0.05)elevatedwhilehigh-density
lipoproteinwassignicantly(p<0.05)diminished
in the sleep deprived group (Table 3). Literary
evidence has associated sleep disorders with
seriouscomplicationsliketype2diabetesmellitus23
andglucoseintoleranceorinsulinresistance24.The
liverwhichisthesiteofmetabolismisparticularly
vulnerabletooxidativestressthuspredisposingthe
organismtofurtherdamage25,26.Resultsfromthis
studyalsosupportthisevidencewithsleepdeprived
miceshowing a signicant (p<0.05) elevationin
nitrite levels and decrease in antioxidant levels
(Table4). The administration of quercetin in
sleep deprived mice was able to attenuate these
deleteriouseectsofsleepdeprivation.

688 EduviErE et al., Biosci., Biotech. Res. Asia, vol. 18(4), 681-689 (2021)
CONCLUSIONS
 Basedon the antioxidantandprotective
eectsofquercetinonthebrainandliverofmice
inthisstudy,webelievethatthiscompoundstands
achanceofbeingapotentialtherapeuticagentfor
thetreatment of neuronal degeneration resulting
from sleep deprivation. Nevertheless, more
reliable methods such as immunocytochemistry
arerecommendedforfurther investigationofthe
neuroprotectiveeectofquercetin.
ACKNOWLEDGEMENT
 Weappreciatethetechnicalsupportofthe
laboratorypersonnelofPharmacologydepartment.
Also,wegivespecialgratitudetoMr.Adedamola
Fafureforthehistology.
Conict of Interest
 The authors declare the absence of
conictsofinterest
Funding support
 Theauthorsreceivednoexternalfunding
for this research
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