Neuroprotective effects of sesamol against LPS-induced spatial learning and memory deficits are mediated via anti-inflammatory and antioxidant activities in the rat brain

Document Type : Original Research Article


Department of Physiology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran


Objective: Sesamol is a phenolic lignan extracted from sesame seeds, and it possesses anti-inflammatory and antioxidant activities. Lipopolysaccharide (LPS) is known to produce neuroinflammatory responses and memory impairment. The current study aimed to investigate the protective influence of sesamol against LPS-mediated neuroinflammation and memory impairment.
Materials and Methods: Sesamol (10 and 50 mg/kg) was injected to Wistar rats for two weeks. Then, animals received LPS injection (1 mg/kg) for five days, while treatment with sesamol was performed 30 min before LPS injection. Spatial learning and memory were assessed by the Morris water maze (MWM), two hours after LPS injection on days 15-19. Biochemical assessments were performed after the end of behavioral experiments.
Results: LPS-administered rats showed spatial learning and memory deficits, since they spent more time in the MWM to find the hidden platform and less time in the target quadrant. Besides these behavioral changes, tumor necrosis factor-α (TNF-α) and lipid peroxidation levels were increased, while total thiol level was decreased in the hippocampus and/or cerebral cortex. In addition, sesamol treatment (50 mg/kg) for three weeks decreased the escape latency and increased the time on probe trial. Sesamol also reduced lipid peroxidation and TNF-α level, while enhanced total thiol level in the brain of LPS-exposed rats.
Conclusion: Supplementation of sesamol attenuated learning and memory impairments in LPS-treated rats via antioxidative and anti-inflammatory activities in the rat brain. 


Adetuyi BO, Farombi EO. 2021. 6-Gingerol,
an active constituent of ginger, attenuates
lipopolysaccharide-induced oxidation,
inflammation, cognitive deficits,
neuroplasticity, and amyloidogenesis in rat.
J Food Biochem, 45: e13660.
Akiyama H, Barger S, Barnum S, Bradt B,
Bauer J, Cole GM, Cooper NR,
Eikelenboom P, Emmerling M, Fiebich
BL, Finch CE, Frautschy S, Griffin
WS, Hampel H, Hull M, Landreth G, Lue
L, Mrak R, Mackenzie IR, McGeer
PL, O'Banion MK, Pachter J, Pasinetti
G, Plata-Salaman C, Rogers J, Rydel
R, Shen Y, Streit W, Strohmeyer
R, Tooyoma I, Van Muiswinkel
FL, Veerhuis R, Walker D, Webster
S, Wegrzyniak B, Wenk G, Wyss-Coray T.
2000. Inflammation and Alzheimer's
disease. Neurobiol Aging, 21: 383-421.
Ammari M, Othman H, Hajri A, Sakly M,
Abdelmelek H. 2018. Pistacia lentiscus oil
attenuates memory dysfunction and
decreases levels of biomarkers of oxidative
stress induced by lipopolysaccharide in
rats. Brain Res Bull, 140: 140-147.
Amooheydari Z, Rajaei Z, Alaei H, Esmaeil N.
2022. Supplementation of carvacrol
attenuates hippocampal tumor necrosis
factor‑alpha level, oxidative stress, and
learning and memory dysfunction in
lipopolysaccharide‑exposed rats. Adv
Biomed Res, 11: 33.
Amraie I, Pouraboli I, Rajaei Z. 2020.
Neuroprotective effects of Levisticum
officinale on LPS-induced spatial learning
and memory impairments through
neurotrophic, anti-inflammatory, and
antioxidant properties. Food Funct, 11:
Azmand MJ, Rajaei Z. 2021. Effects of crocin
on spatial or aversive learning and memory
impairments induced by lipopolysaccharide
in rats. Avicenna J Phytomed, 11: 79-90.
Barnham KJ, Masters CL, Bush AI. 2004.
Neurodegenerative diseases and oxidative
stress. Nat Rev Drug Discov, 3: 205-214.
Batista CRA, Gomes GF, Candelario-Jalil E,
Fiebich BL, de Oliveira ACP. 2019.
neuroinflammation as a bridge to
understand neurodegeneration. Int J Mol
Sci, 20: 2293.
Bosebabu B, Cheruku SP, Chamallamudi MR,
Nampoothiri M, Shenoy RR, Nandakumar
K, Parihar VK, Kumar N. 2020. An
appraisal of current pharmacological
perspectives of sesamol: a review. Mini
Rev Med Chem, 20: 988-1000.
Brown GC. 2019.The endotoxin hypothesis of
neurodegeneration. J Neuroinflammation,
16: 180.
Bryant CE, Spring DR, Gangloff M, Gay NJ.
2010. The molecular basis of the host
response to lipopolysaccharide. Nat Rev
Microbiol, 8: 8-14.
Cai B, Seong KJ, Bae SW, Kook MS, Chun C,
Lee JH, Choi WS, Jung JY, Kim WJ. 2019.
Water-soluble arginyl-diosgenin analog
attenuates hippocampal neurogenesis
impairment through blocking microglial
Beheshtimanesh et al.
AJP, Vol. 13, No. 2, Mar-Apr 2023 220
activation underlying NF-κB and JNK
MAPK signaling in adult mice challenged
by LPS. Mol Neurobiol, 56: 6218-6238.
Campos PB, Paulsen BS, Rehen SK. 2014.
Accelerating neuronal aging in vitro model
brain disorders: a focus on reactive oxygen
species. Front Aging Neurosci, 6: 292.
Chidambaram SB, Pandian A, Sekar
S, Haridass S, Vijayan R, Thiyagarajan
LK, Ravindran J, Raghavendran
HRB, Kamarul T. 2016. Sesame indicum, a
nutritional supplement, elicits antiamnesic
effect via cholinergic pathway in
scopolamine intoxicated mice. Environ
Toxicol, 31: 1955-1963.
Chu PY, Hsu DZ, Hsu PY, Liu My. 2010.
Sesamol down-regulates the
lipopolysaccharide-induced inflammatory
response by inhibiting nuclear factor-kappa
B activation. Innate Immun, 16: 333-339.
Czerniawski J, Guzowski JF. 2014. Acute
neuroinflammation impairs context
discrimination memory and disrupts pattern
separation processes in hippocampus. J
Neurosci, 34: 12470-12480.
Daroi PA, Dhage SN, Juvekar AR. 2022. pCoumaric acid mitigates lipopolysaccharide
induced brain damage via alleviating
oxidative stress, inflammation and
apoptosis. J Pharm Pharmacol, 74: 556-
Dementia. WHO Newsletter; 2 September
Ozdamar Unal G, Asci H, Erzurumlu Y, Ilhan
I, Hasseyid N, Ozmen O. 2022.
Dexpanthenol may protect the brain against
lipopolysaccharide induced
neuroinflammation via anti-oxidant action
and regulating CREB/BDNF signaling.
Immunopharmacol Immunotoxicol, 44:
Ganguly U, Kaur U, Chakrabarti SS, Sharma
P, Agrawal BK, Saso L, Chakrabarti S.
2021. Oxidative stress, neuroinflammation,
and NADPH oxidase: implications in the
pathogenesis and treatment of Alzheimer’s
disease. Oxid Med Cell Longev, 2021:
Gao XJ, Xie GN, Liu L, Fu ZJ, Zhang ZW,
Teng LZ. 2017. Sesamol attenuates
oxidative stress, apoptosis and
inflammation in focal cerebral
ischemia/reperfusion injury. Exp Ther Med,
14: 841-847.
Gardner LE, White JD, Eimerbrink MJ,
Boehm GW, Chumley MJ. 2016. Imatinib
methanesulfonate reduces
hyperphosphorylation of tau following
repeated peripheral exposure to
lipopolysaccharide. Neuroscience, 331: 72-
Houdek HM, Larson J, Watt JA, Rosenberger
TA. 2014. Bacterial lipopolysaccharide
induces a dose-dependent activation of
neuroglia and loss of basal forebrain
cholinergic cells in the rat brain. Inflamm
Cell Signal, 1: e47.
Hsu DZ, Chen KT, Li YH, Chuang YC, Liu
MY. 2006. Sesamol delays mortality and
attenuates hepatic injury after cecal ligation
and puncture in rats: role of oxidative
stress. Shock, 25: 528-532.
John J, Nampoothiri M, Kumar N, Mudgal J,
Nampurath GK, Chamallamudi MR. 2015.
Sesamol, a lipid lowering agent,
ameliorates aluminium chloride induced
behavioral and biochemical alterations in
rats. Pharmacogn Mag, 11: 327-336.
Joshi R, Kumar MS, Satyamoorthy K,
Unnikrishnan MK, Mukherjee T. 2005.
Free radical reactions and antioxidant
activities of sesamol: Pulse radiolytic and
biochemical studies. J Agric Food Chem,
53: 2696-2703.
Kumar CM, Singh SA. 2015. Bioactive
lignans from sesame (Sesamum indicum
L.): evaluation of their antioxidant and
antibacterial effects for food applications. J
Food Sci Technol, 52: 2934-2941.
Khan MS, Ali T, Kim MW, Jo MH, Jo MG,
Badshah H. 2016. Anthocyanins protect
against LPS-induced oxidative stress
mediated neuroinflammation and
neurodegeneration in the adult mouse
cortex. Neurochem Int, 100: 1-10.
Kuhad A, Chopra K. 2008. Effect of sesamol
on diabetes-associated cognitive decline in
rats. Exp Brain Res, 185: 411-420.
Liu Z, Chen Y, Qiao Q, Sun Y, Liu Q, Ren B,
Liu X. 2017. Sesamol supplementation
prevents systemic inflammation-induced
memory impairment and amyloidogenesis
via inhibition of nuclear factor kappaB.
Mol Nutr Food Res, 61.
Majdalawieh AF, Mansour ZR. 2019.
Sesamol, a major lignan in sesame seeds
(Sesamum indicum): Anti-cancer properties
and mechanisms of action. Eur J
Pharmacol, 855: 75-89.
Millington C, Sonego S, Karunaweera N,
Sesamol and LPS-induced memory deficits
AJP, Vol. 13, No. 2, Mar-Apr 2023 221
Rangel A, Aldrich-Wright JR, Campbell
IL, Gyengesi E, Münch G. 2014. Chronic
Neuroinflammation in Alzheimer’s disease:
new perspectives on animal models and
promising candidate drugs. BioMed Res
Int, 2014: 309129.
Monje ML, Toda H, Palmer TD. 2003.
Inflammatory blockade restores adult
hippocampal neurogenesis. Science, 302:
Morris MC, Gilliam EA, Li L. 2015. Innate
immune programing by endotoxin and its
pathological consequences. Front Immunol,
5: 680.
Nizri E, Hamra-Amitay Y, Sicsic C, Lavon I,
Brenner T. 2006. Anti-inflammatory
properties of cholinergic up-regulation: a
new role for acetylcholinesterase inhibitors.
Neuropharmacology, 50: 540-547.
Parajuli B, Sonobe Y, Kawanokuchi J, Doi Y,
Noda M, Takeuchi H, Mizuno T, Suzumura
A. 2012. GM-CSF increases LPS-induced
production of proinflammatory mediators
via upregulation of TLR4 and CD14 in
murine microglia. J Neuroinflammation, 9:
Park BS, Lee JO. 2013. Recognition of
lipopolysaccharide pattern by TLR4
complexes. Exp Mol Med, 45: e66.
Perl DP. Neuropathology of Alzheimer's
disease. 2010. Mt Sinai J Med, 77: 32-42.
Rajaei Z, Hadjzadeh MA, Nemati H, Hosseini
M, Ahmadi M, Shafiee S. 2013.
Antihyperglycemic and antioxidant activity
of crocin in streptozotocin‑induced diabetic
rats. J Med Food, 16: 206‑210.
Rather MA, Khan A, Alshahrani S, Rashid H,
Qadri M, Rashid S, Alsaffar RM, Kamal
MA, Rehman MU. 2021.Inflammation and
Alzheimer's disease: mechanisms and
therapeutic implications by natural
products. Mediators Inflamm, 2021:
Ren B, Yuan T, Diao Z, Zhang C, Liu Z, Liu
X. 2018. Protective effects of sesamol on
systemic oxidative stress-induced cognitive
impairments via regulation of Nrf2/Keap1
pathway. Food Function, 9: 5912-5924.
Ren B, Yuan T, Zhang X, Wang L, Pan J, Liu
Y, Zhao B, Zhao W, Liu Z, Liu X. 2020.
Protective effects of sesamol on systemic
inflammation and cognitive impairment in
aging mice. J Agric Food Chem, 68: 3099-
Sachdeva AK, Misra S, Kaur IP, Chopra K.
2015. Neuroprotective potential of sesamol
and its loaded solid lipid nanoparticles in
ICV-STZ-induced cognitive deficits:
behavioral and biochemical evidence. Eur J
Pharmacol, 747: 132-140.
Shahidani S, Rajaei Z, Alaei H,
Mohammadzadeh S. 2022. The impact of
sesamol and exercise on striatal TNF-α
level, behavioral deficits and oxidative
stress status in the rat model of Parkinson’s
disease. Physiol Pharmacol, 26: 30-38.
Siriwarin B, Weerapreeyakul N. 2016.
Sesamol induced apoptotic effect in lung
adenocarcinoma cells through both intrinsic
and extrinsic pathways. Chem Biol Interact,
254: 109-116.
Topal M. 2019. The inhibition profile of
sesamol against α-glycosidase and
acetylcholinesterase enzymes. Int J Food
Properties, 22: 1527-1535.
Tyagi E, Agrawal R, Nath C, Shukla R. 2010.
Effect of melatonin on neuroinflammation
and acetylcholinesterase activity induced
by LPS in rat brain. Eur J Pharmacol, 640:
Uttara B, Singh AV, Zamboni P, Mahajan RT.
2009. Oxidative stress and
neurodegenerative diseases: a review of
upstream and downstream antioxidant
therapeutic options. Curr Neuropharmacol,
7: 65-74.
Valero J, Mastrella G, Neiva I, Sanchez S,
Malva JO. 2014. Long term effects of an
acute and systemic administration of LPS
on adult neurogenesis and spatial memory.
Front Neurosci, 8: 83.
Varnum MM, Ikezu T. 2012. The
classification of microglial activation
phenotypes on neurodegeneration and
regeneration in Alzheimer’s disease brain.
Arch Immunol Ther Exp (Warsz), 60: 251-
Voet S, Srinivasan S, Lamkanfi M, van Loo G.
2019. Inflammasomes in
neuroinflammatory and neurodegenerative
diseases. EMBO Mol Med, 11.
Winkler J, Thal LJ, Gage FH, Fisher LJ. 1998.
Cholinergic strategies for Alzheimer's
disease. J Mol Med (Berl), 76: 555-567.
Wu Xl, Liou CJ, Li ZY, Lai XY, Fang LW,
Huang WC. 2015. Sesamol suppresses the
inflammatory response by inhibiting NFκB/MAPK activation and upregulating
AMP kinase signaling in RAW 264.7
macrophages. Inflamm Res, 64: 577-588.
Beheshtimanesh et al.
AJP, Vol. 13, No. 2, Mar-Apr 2023 222
Wyss-Coray T. 2006. Inflammation in
Alzheimer disease: driving force, bystander
or beneficial response? Nat Med, 12: 1005-
Zakaria R, Wan Yaacob WM, Othman Z,
Long I, Ahmad AH, Al-Rahbi B. 2017.
Lipopolysaccharide-induced memory
impairment in rats: a model of Alzheimer’s
disease. Physiol Res, 66: 553-565.
Zhan X, Stamova B, Sharp FR. 2018.
Lipopolysaccharide associates with
amyloid plaques, neurons and
oligodendrocytes in Alzheimer’s disease
brain: a review. Front Aging Neurosci, 10:
Zhu L, Yuan Q, Zeng Z, Zhou R, Luo R,
Zhang J, Tsang CK, Bi W. 2021.
Rifampicin suppresses amyloid-beta
accumulation through enhancing autophagy
in the hippocampus of a
lipopolysaccharide-induced mouse model
of cognitive decline. J Alzheimers Dis, 79: