Abdullaev F. 2002. Cancer chemopreventive
and tumoricidal properties of saffron
Crocin and LPS-induced memory impairment
AJP, Vol. 11, No. 1, Jan-Feb 2021 87
(Crocus sativus L.). Exp Biol Med, 227:20-
25.
Abe K, Saito H. 2000. Effects of saffron extract
and its constituent crocin on learning
behaviour and long-term potentiation.
Phytother Res, 14:149-152.
Ahmadi M, Rajaei Z, Hadjzadeh MA, Nemati
H, Hosseini M. 2017. Crocin improves
spatial learning and memory deficits in the
Morris water maze via attenuating cortical
oxidative damage in diabetic rats. Neurosci
Lett, 642:1–6.
Ali MRA, Abo-Youssef AMH, Messiha BAS,
Khattab MM. 2016. Tempol and perindopril
protect against lipopolysaccharide induced
cognition impairment and amyloidogenesis
by modulating brain-derived neurotropic
factor, neuroinflammation and oxidonitrosative stress. Naunyn-Schmiedeberg's
Arch Pharmacol, 389:637–656.
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.
Amraie E, Pouraboli I, Rajaei Z. 2020. The
effects of Levisticum officinale on LPSinduced spatial learning and memory
impairments through neurotrophic, antiinflammatory, and antioxidant properties.
Food Funct, 11:6608-6621.
Asadi F, Jamshidi AH, Khodagholi F, Yans A,
Azimi L, Faizi M, Vali L, Abdollahi M,
Ghahremani MH, Sharifzadeh M. 2015.
Reversal effects of crocin on amyloid βinduced memory deficit: modification of
autophagy or apoptosis markers. Pharmacol
Biochem Behav, 139: 47–58.
Assimopoulou AN, Sinakos Z, Papageorgiou
VP. 2005. Radical scavenging activity of
Crocus sativus L. extract and its bioactive
constituents. Phytother Res, 19: 997–1000.
Behravanfar N, Abnous K, Razavi BM,
Hosseinzadeh H. 2017. Effects of crocin on
spatial memory impairment induced by
hyoscine and its effects on BDNF, CREB,
and p-CREB protein and mRNA levels in rat
hippocampus. Jundishapur J Nat Pharm
Prod, 12: e64315.
Bossu P, Cutuli D, Palladino I, Caporali P,
Angelucci F, Laricchiuta D, Gelfo F, De
Bartolo P, Caltagirone C, Petrosini L. 2012.
A single intraperitoneal injection of
endotoxin in rats induces long-lasting
modifications in behavior and brain protein
levels of TNF-α and IL-18. J Neuroinflamm,
9:101.
Chang CY, Kuan YH, Li JR, Chen WY, Ou YC,
Pan HC, Liao SL, Raung SL, Chang CJ,
Chen CJ. 2013. Docosahexaenoic acid
reduces cellular inflammatory response
following permanent focal cerebral
ischemia in rats. J Nutr Biochem, 24:2127-
2137.
Chen Y, Zhang H, Tian X, Zhao C, Cai L, Liu
Y, Jia L, Yin HX, Chen C. 2008.
Antioxidant potential of crocins and ethanol
extracts of Gardenia jasminoides Ellis and
Crocus sativus L: a relationship
investigation between antioxidant activity
and crocin contents. Food Chem, 109:484–
492.
Cunningham C, Wilcockson DC, Campion S,
Lunnon K, Perry VH. 2005. Central and
systemic endotoxin challenges exacerbate
the local inflammatory response and
increase neuronal death during chronic
neurodegeneration. J Neurosci, 25:9275–
9284.
Czerniawski J, Miyashita T, Lewandowski G,
Guzowski JF. 2015. Systemic
lipopolysaccharide administration impairs
retrieval of context-object discrimination,
but not spatial, memory: Evidence for
selective disruption of specific
hippocampus-dependent memory functions
during acute neuroinflammation. Brain
Behav Immun, 44:159–166.
Daulatzai MA. 2016. Fundamental role of paninflammation andoxidative-nitrosative
pathways in neuropathogenesis of
Alzheimer’s disease in focal cerebral
ischemic rats. Am J Neurodegener Dis,
5:102-130.
Dinel AL, Andre C, Aubert A, Ferreira G, Laye
S, Castanon N. 2011. Cognitive and
emotional alterations are related to
hippocampal inflammation in a mouse
model of metabolic syndrome. PloS one,
6:e24325.
Geromichalos GD, Lamari FN, Papandreou
MA, Trafalis DT, Margarity M,
Papageorgiou A, Sinakos Z. 2012. Saffron
as a source of novel acetylcholinesterase
inhibitors: molecular docking and in vitro
enzymatic studies. J Agric Food Chem,
60:6131–6138.
Ghahghaei A, Bathaie Z, Kheirkhah H,
Bahraminejad E. 2013. The protective effect
Azmand and Rajaei
AJP, Vol. 11, No. 1, Jan-Feb 2021 88
of crocin on the amyloid fibril formation of
Aβ42 peptide in vitro. Cell Mol Biol Lett,
18:328-339.
Gholami M, Rajaei Z, Malek M. 2019. Effects
of carvacrol on spatial learning
performances, hippocampal interleukin-1ß
level and oxidative stress markers in
lipopolysaccharide-treated rats. Physiol
Pharmacol, 23:286-295.
Götz J, Ittner LM. 2008. Animal models of
Alzheimer's disease and frontotemporal
dementia, Nat Rev Neurosci, 9:532–544.
Hauss-Wegryzniak B, Dobrzankski P, Stoehr
JD, Wenk GL. 1998. Chronic
neuroinflammation in rats reproduces
components of neurobiology of Alzheimer’s
disease. Brain Res, 780:294–303.
Hauss-Wegrzyniak B, Vraniak PD, Wenk GL.
2000. LPS-induced neuroinflammatory
effects do not recover with time.
Neuroreport, 11:1759-1763.
Hennigan A, Trotter C, Kelly AM. 2007.
Lipopolysaccharide impairs long-term
potentiation and recognition memory and
increases p75NTR expression in the rat
dentate gyrus. Brain Res, 1130:158-166.
Henry CJ, Huang Y, Wynne AM, Godbout JP.
2009. Peripheral lipopolysaccharide (LPS)
challenge promotes microglial hyperactivity
in aged mice that is associated with
exaggerated induction of both proinflammatory IL-1b and anti-inflammatory
IL-10 cytokines. Brain Behav Immun,
23:309–317.
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.
Hritcu L, Ciobica A, Stefan M, Mihasan M,
Palamiuc L, Nabeshima T. 2011. Spatial
memory deficits and oxidative stress
damage following exposure to
lipopolysaccharide in a rodent model of
Parkinson’s disease. Neurosci Res, 71:35–
43.
Hou Y, Xie G, Miao F, Ding L, Mou Y, Wang
L, Su G, Chen G, Yang J, Wu C. 2014.
Pterostilbene attenuates lipopolysaccharideinduced learning and memory impairment
possibly via inhibiting microglia activation
and protecting neuronal injury in mice. Prog
Neuro-Psychopharmacol Biol Psychiatry,
54:92–102.
Kim JJ, Diamond DM. 2002. The stressed
hippocampus, synaptic plasticity and lost
memories. Nat Rev Neurosci, 3:453–462.
Kranjac D, McLinden KA, Deodati LE, Papini
MR, Chumley MJ, Boehm GW. 2012.
Peripheral bacterial endotoxin
administration triggers both memory
consolidation and reconsolidation deficits in
mice. Brain Behav Immun, 26:109–121.
Lee B, Shim I, Lee H. 2018. Gypenosides
attenuate lipopolysaccharide-induced
neuroinflammation and memory impairment
in rats. Evid Based Complement Alternat
Med, 2018:4183670.
Lee JW, Lee YK, Yuk DY, Choi DY, Ban SB,
Oh KW, Hong JT. 2008. Neuroinflammation induced by
lipopolysaccharide causes cognitive
impairment through enhancement of betaamyloid generation. J Neuroinflam, 29:5-37.
Li X, Jiang C, Zhu W. 2017. Crocin reduces the
inflammation response in rheumatoid
arthritis. Biosci Biotechnol Biochem,
81:891–898.
Lobo V, Patil A, Phatak A, Chandra N. 2010.
Free radicals, antioxidants and functional
foods: Impact on human health.
Pharmacogn Rev, 4:118.
Lv B, Huo F, Zhu Z, Xu Z, Dang X, Chen T,
Zhang T, Yang X. 2016. Crocin upregulates
CX3CR1 expression by suppressing NFκB/YY1 signaling and inhibiting
lipopolysaccharide-induced microglial
activation. Neurochem Res, 41:1949-1957.
Mohammadzadeh L, Abnous K, Razavi BM,
Hosseinzadeh H. 2020. Crocin-protected
malathion-induced spatial memory deficits
by inhibiting TAU protein
hyperphosphorylation and antiapoptotic
effects. Nutr Neurosci, 23:221-236.
Monje ML, Toda H, Palmer TD. 2003.
Inflammatory blockade restores adult
hippocampal neurogenesis. Science,
302:1760–1765.
Montine TJ, Neely MD, Quinn JF, Beal MF,
Markesbery WR, Roberts LJ, Morrow JD.
2002. Lipid peroxidation in aging brain and
Alzheimer’s disease. Free Radic Biol Med,
33:620-626.
Moreira PI, Santos MS, Oliveira CR, Shenk JC,
Nunomura A, Smith MA, Zhu X, Perry G.
2008. Alzheimer disease and the role of free
radicals in the pathogenesis of the disease.
CNS Neurol Disord Drug Targets, 7:3–10.
Mozaffari S, RamezanyYasuj S, Motaghinejad
Crocin and LPS-induced memory impairment
AJP, Vol. 11, No. 1, Jan-Feb 2021 89
M, Motevalian M, Kheiri R. 2019. Crocin
acting as a neuroprotective agent against
methamphetamine-induced
neurodegeneration via CREB-BDNF
signaling pathway. Iran J Pharm Res, 18:
745-758.
Nam KN, Park YM, Jung HJ, Lee JY, Min BD,
Park SU, Jung WS, Cho KH, Park JH, Kang
I, Hong JW, Lee EH. 2010. Antiinflammatory effects of crocin and crocetin
in rat brain microglial cells. Eur J
Pharmacol, 648:110–116.
Noh H, Jeon J, Seo H. 2014. Systemic injection
of LPS induces region-specific
neuroinflammation and mitochondrial
dysfunction in normal mouse brain.
Neurochem Int, 69:35-40.
Ochiai T, Ohno S, Soeda S, Tanaka H,
Shoyama Y, Shimeno H. 2004. Crocin
prevents the death of rat pheochromyctoma
(PC-12) cells by its antioxidant effects
stronger than those of alpha-tocopherol.
Neurosci Lett, 362:61–64.
Pitsikas N, Zisopoulou S, Tarantilis PA,
Kanakis CD, Polissiou MG, Sakellaridis N.
2007. Effects of the active constituents of
Crocus sativus L., crocins on recognition
and spatial rats’ memory. Behav Brain Res,
183:141–146.
Qi Y, Chen L, Zhang L, Liu WB, Chen XY,
Yang XG. 2013. Crocin prevents retinal
ischaemia/reperfusion injury-induced
apoptosis in retinal ganglion cells through
the PI3K/AKT signalling pathway. Exp Eye
Res, 107:44–51.
Qin L, Wu X, Block ML, Liu X, Breese GR,
Hong JS, Knapp DJ, Crews FT. 2007.
Systemic LPS causes chronic
neuroinflammation and progressive
neurodegeneration. Glia, 55:453-462.
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.
Rajaei Z, Hosseini M, Alaei H. 2016. Effects of
crocin on brain oxidative damage and
aversive memory in a 6-OHDA model of
Parkinson’s disease. Arq Neuropsiquiatr,
74;723-239.
Sandra A, Puentes F, Baker D, Van Der Valk P.
2010. Inflammation in neurodegenerative
diseases. Immunology, 129:154-169.
Semmler A, Frisch C, Debeir T, Ramanathan
M, Okulla T, Klockgether T, Heneka MT.
2007. Long-term cognitive impairment,
neuronal loss and reduced cortical
cholinergic innervation after recovery from
sepsis in a rodent model. Exp Neurol,
204:733–740.
Shahidani S, Rajaei Z, Alaei H. 2019.
Pretreatment with crocin along with
treadmill exercise ameliorates motor and
memory deficits in hemiparkinsonian rats by
anti-inflammatory and antioxidant
mechanisms. Metab Brain Dis, 34:459–468.
Shaw KN, Commins S, O’Mara SM. 2001.
Lipopolysaccharide causes deficits in spatial
learning in the water maze but not in BDNF
expression in the rat dentate gyrus. Behav
Brain Res, 124:47–54.
Terrando N, Rei Fidalgo A, Vizcaychipi M,
Cibelli M, Ma D, Monaco C, Feldmann
M, Maze M. 2010. The impact of IL-1
modulation on the development of
lipopolysaccharide-inducedcognitive
dysfunction. Crit Care, 14:R88.
Theobaldo MC, Barbeiro HV, Barbeiro DF,
Petroni R, Soriano FG. 2012. Hypertonic
saline solution reduces the inflammatory
response in endotoxemic rats. Clinics (Sao
Paulo), 67:1463-1468.
Thomson LM, Sutherland RJ. 2005. Systemic
administration of lipopolysaccharide and
interleukin-1β have different effects on
memory consolidation. Brain Res Bull,
67:24-29.
Tseng YT, Hsu YY, Shih YT, Lo YC. 2012.
Paeonol attenuates microglia-mediated
inflammation and oxidative stress induced
neurotoxicity in rat primary microglia and
cortical neurons. Shock, 37:312-318.
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, 640:206–
210.
Valero J, Mastrella G, Neiva I, Sánchez 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.
Vasconcelos AR, Yshii LM, Viel TA, Buck HS,
Mattson MP, Scavone C, Kawamoto EM.
2014. Intermittent fasting attenuates
lipopolysaccharide-induced
neuroinflammation and memory
impairment. J Neuroinflammation, 11:85.
Wang T, Qin L, Liu B, Liu Y, Wilson B, Eling
TE, Langenbach R, Taniura S, Hong JS.
Azmand and Rajaei
AJP, Vol. 11, No. 1, Jan-Feb 2021 90
2004. Role of reactive oxygen species in
LPS-induced production of prostaglandin
E2 in microglia. J Neurochem, 88:939–947.
Wang G, Wang W, Zhao J, Ni Y, Zhou X,
Zhang W. 2011. Ghrelin prevents neuronal
apoptosis and cognitive impairments in
sepsis-associated encephalopathy.
Neuroreport, 22:959–964.
Willard LB, Hauss-Wegrzyniak B, Wenk GL.
1999. Pathological and biochemical
consequences of acute and chronic
neuroinflammation within the basal
forebrain cholinergic system of rats.
Neuroscience, 88:193–200.
Yang L, Dong X. 2017. Inhibition of
inflammatory response by crocin attenuates
hemorrhagic shock-induced organ damages
in rats. J Interferon Cytokine Res, 37:295–
302.
Yirmiya R, Goshen I. 2011. Immune
modulation of learning, memory, neural
plasticity and neurogenesis. Brain Behav
Immun, 25:181–213.
Zarifkar A, Choopani S, Ghasemi R, Naghdi N,
Maghsoudi AH, Maghsoudi N, Rastegar
K, Moosavi M. 2010. Agmatine prevents
LPS-induced spatial memory impairment
and hippocampal apoptosis. Eur J
Pharmacol, 634:84-88.
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, 10:42.
Zhang XY, Cao JB, Zhang LM, Li YF, Mi WD.
2015. Deferoxamine attenuates
lipopolysaccharide-induced
neuroinflammation and memory impairment
in mice. J Neuroinflammation, 12:20.
Zhu B, Wang ZG, Ding J, Liu N, Wang DM,
Ding LC, Yang C. 2014. Chronic
lipopolysaccharide exposure induces
cognitive dysfunction without affecting
BDNF expression in the rat hippocampus.
Exp Ther Med,7:750–754.
)