The Protective Effect of Celecoxib on CA1 Hippocampal Neurons and Oxidative Stress in a Rat Model of Parkinson’s Disease

  • Maryam Sarbishegi Cellular and Molecular Research Center, Zahedan University of Medical Sciences, Zahedan, Iran. AND Department of Anatomy, School of Medicine, Zahedan University of Medical Sciences, Zahedan, Iran.
  • Hamidreza Mahmoudzadeh-Sagheb Infectious Diseases and Tropical Medicine Research Center, Zahedan University of Medical Sciences, Zahedan, Iran. AND Department of Histology, School of Medicine, Zahedan University of Medical Sciences, Zahedan, Iran.
  • Zahra Heidari Infectious Diseases and Tropical Medicine Research Center, Zahedan University of Medical Sciences, Zahedan, Iran. AND Department of Histology, School of Medicine, Zahedan University of Medical Sciences, Zahedan, Iran.
  • Farzaneh Baharvand Mail Department of Anatomy, School of Medicine, Zahedan University of Medical Sciences, Zahedan, Iran.
Celecoxib, Parkinson’s disease, Hippocampus, Memory


Several studies point to an important role of neuroinflammation in Parkinson's disease (PD). Cognitive and memory impairments have been known in the early stages of PD. In the present study, we examined the effects of celecoxib (CLX), a selective inhibitor of cyclooxygenase-2 (COX-2), on hippocampus cell loss, passive avoidance memory and antioxidant status in a rat model of PD. We used the subcutaneous injection of 2.5 mg/kg/48h rotenone (ROT) for 4 weeks for induction of PD in a male Wistar rat. Animals were randomized to 4 groups (n=12): Control, sham, PD and PD+CLX group that receive celecoxib (20 mg/kg/day) for 4 weeks. Passive avoidance memory evaluated. We also determined the protective effect of CLX on a number of CA1 neurons in Nissl and TUNEL staining. Total antioxidant capacity (TAC) and malondialdehyde (MDA) a marker of lipid peroxidation in hippocampus assessed. Our findings indicated administration of CLX increase the passive avoidance memory (P<0.05), and by a decrease in apoptosis caused an increase in viable pyramidal neurons in CA1 hippocampus (P<0.01). On the other hand, CLX markedly reduced MDA level and increased TAC in the hippocampus of the PD model animal (P<0.05). It seems CLX with anti-inflammatory and antiapoptotic effect could prevent neurons loss and memory impairment which induced in PD.


Halliday GM, McCann H. The progression of pathology in Parkinson's disease. Ann NY Acad Sci. 2010;1184(1):188-95.

Good M. Spatial memory and hippocampal function: where are we now? Psicológica. 2002;23(1).

Laakso M, Partanen K, Riekkinen P, Lehtovirta M, Helkala E-L, Hallikainen M, et al. Hippocampal volumes in Alzheimer's disease, Parkinson's disease with and without dementia, and in vascular dementia An MRI study. Neurology. 1996;46(3):678-81.

Bird CM, Burgess N. The hippocampus and memory: insights from spatial processing. Nat Rev Neurosci. 2008;9(3):182-94.

Camicioli R, Moore MM, Kinney A, Corbridge E, Glassberg K, Kaye JA. Parkinson's disease is associated with hippocampal atrophy. Movement Disord. 2003;18(7):784-90.

Kaur K, Gill JS, Bansal PK, Deshmukh R. Neuroinflammation-A major cause for striatal dopaminergic degeneration in Parkinson's disease. J neurol sci. 2017;381:308-14.

Yang J, Song S, Li J, Liang T. Neuroprotective effect of curcumin on hippocampal injury in 6-OHDA-induced Parkinson's disease rat. Pathol Res Pract. 2014;210(6):357-62.

Breder CD, Dewitt D, Kraig RP. Characterization of inducible cyclooxygenase in rat brain. J Comp Neurol. 1995;355(2):296-315.

Teismann P, Tieu K, Choi D-K, Wu D-C, Naini A, Hunot S, et al. Cyclooxygenase-2 is instrumental in Parkinson's disease neurodegeneration. Proceed Nat Acad Sci. 2003;100(9):5473-8.

Cowley T, Fahey B, O’Mara S. COX‐2, but not COX‐1, activity is necessary for the induction of perforant path long‐term potentiation and spatial learning in vivo. Euro J Neurosci. 2008;27(11):2999-3008.

Feng Z-H, Wang T-G, Li D-D, Fung P, Wilson B, Liu B, et al. Cyclooxygenase-2-deficient mice are resistant to 1-methyl-4-phenyl1, 2, 3, 6-tetrahydropyridine-induced damage of dopaminergic neurons in the substantia nigra. Neurosci lett. 2002;329(3):354-8.

Yu L, Yang B, Wang J, Zhao L, Luo W, Jiang Q, et al. Time course change of COX2-PGI 2/TXA 2 following global cerebral ischemia reperfusion injury in rat hippocampus. Behav Brain Funct. 2014;10(1):42.

Smith CE, Soti S, Jones TA, Nakagawa A, Xue D, Yin H. Non-steroidal anti-inflammatory drugs are caspase inhibitors. Cell Chem Biol. 2017;24(3):281-92.

Kurhe Y, Mahesh R, Gupta D. Effect of a selective cyclooxygenase type 2 inhibitor celecoxib on depression associated with obesity in mice: an approach using behavioral tests. Neurochem Res. 2014;39(7):1395-402.

Reksidler AB, Lima MM, Zanata SM, Machado HB, da Cunha C, Andreatini R, et al. The COX-2 inhibitor parecoxib produces neuroprotective effects in MPTP-lesioned rats. Eur J Pharmacol. 2007;560(2):163-75.

Tapias V, Cannon JR, Greenamyre JT. Melatonin treatment potentiates neurodegeneration in a rat rotenone Parkinson's disease model. J Neurosci Res. 2010;88(2):420-7.

Javed H, Azimullah S, Khair SBA, Ojha S, Haque ME. Neuroprotective effect of nerolidol against neuroinflammation and oxidative stress induced by rotenone. BMC neurosci. 2016;17(1):58.

Rahimmi A, Khosrobakhsh F, Izadpanah E, Moloudi MR, Hassanzadeh K. N-acetylcysteine prevents rotenone-induced Parkinson's disease in rat: An investigation into the interaction of parkin and Drp1 proteins. Brain Res Bull. 2015;113:34-40.

Tamburella A, Micale V, Mazzola C, Salomone S, Drago F. The selective norepinephrine reuptake inhibitor atomoxetine counteracts behavioral impairments in trimethyltin-intoxicated rats. Eur J Pharmacol. 2012;683(1):148-54.

Paxinos G, Watson C. The rat brain in stereotaxic coordinates: Elsevier Academic Press. San Diego. 2005.

Sarbishegi M, Heidari Z, Mahmoudzadeh-Sagheb H, Valizadeh M, Doostkami M. Neuroprotective effects of Withania coagulans root extract on CA1 hippocamus following cerebral ischemia in rats. Avicenna J Phytomed. 2016:1-11.

Bradford MM. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976;72(1):248-54.

Ohkawa H, Ohishi N, Yagi K. Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem. 1979;95(2):351-8.

Benzie IF, Strain JJ. The ferric reducing ability of plasma (FRAP) as a measure of “antioxidant power”: the FRAP assay. Anal Biochem. 1996;239(1):70-6.

Choi AY, Choi JH, Lee JY, Yoon K-S, Choe W, Ha J, et al. Apigenin protects HT22 murine hippocampal neuronal cells against endoplasmic reticulum stress-induced apoptosis. Neurochem Int. 2010;57(2):143-52.

Carlesimo G, Piras F, Assogna F, Pontieri F, Caltagirone C, Spalletta G. Hippocampal abnormalities and memory deficits in Parkinson disease A multimodal imaging study. Neurology. 2012;78(24):1939-45.

den Heijer T, Vermeer S, Van Dijk E, Prins N, Koudstaal PJ, Hofman A, et al. Type 2 diabetes and atrophy of medial temporal lobe structures on brain MRI. Diabetologia. 2003;46(12):1604-10.

Kim M, Cho K-H, Shin M-S, Lee J-M, Cho H-S, Kim C-J, et al. Berberine prevents nigrostriatal dopaminergic neuronal loss and suppresses hippocampal apoptosis in mice with Parkinson's disease. Int J Mol Med. 2014;33(4):870-8.

Gupta A, Kumar A, Kulkarni S. Targeting oxidative stress, mitochondrial dysfunction and neuroinflammatory signaling by selective cyclooxygenase (COX)-2 inhibitors mitigates MPTP-induced neurotoxicity in mice. Prog Neuro-Psychopha. 2011;35(4):974-81.

Yang Y, Gao L. Celecoxib Alleviates Memory Deficits by Downregulation of COX-2 Expression and Upregulation of the BDNF-TrkB Signaling Pathway in a Diabetic Rat Model. J Mol Neurosci. 2017;62(2):188-98.

Minghetti L. Cyclooxygenase-2 (COX-2) in inflammatory and degenerative brain diseases. J Neuropath Exp Neur. 2004;63(9):901-10.

Ho L, Purohit D, Haroutunian V, Luterman JD, Willis F, Naslund J, et al. Neuronal cyclooxygenase 2 expression in the hippocampal formation as a function of the clinical progression of Alzheimer disease. Arch Neurol. 2001;58(3):487-92.

Small GW, Siddarth P, Silverman DH, Ercoli LM, Miller KJ, Lavretsky H, et al. Cognitive and cerebral metabolic effects of celecoxib versus placebo in people with age-related memory loss: randomized controlled study. Am J Geriat Psychiat. 2008;16(12):999-1009.

Jun-Qing Y, Bei-Zhong L, Bai-Cheng H, Qi-Qin Z. Protective effects of meloxicam on aluminum overload-induced cerebral damage in mice. Eur J Pharmacol. 2006;547(1):52-8.

Li Z-G, Zhang W, Grunberger G, Sima AA. Hippocampal neuronal apoptosis in type 1 diabetes. Brain Res. 2002;946(2):221-31.

Kalalian-Moghaddam H, Baluchnejadmojarad T, Roghani M, Goshadrou F, Ronaghi A. Hippocampal synaptic plasticity restoration and anti-apoptotic effect underlie berberine improvement of learning and memory in streptozotocin-diabetic rats. Eur J Pharmacol. 2013;698(1):259-66.

Ye L, Wang F, Yang R-H. Diabetes impairs learning performance and affects the mitochondrial function of hippocampal pyramidal neurons. Brain Res. 2011;1411:57-64.

Chung DW, Yoo K-Y, Hwang IK, Kim DW, Chung JY, Lee CH, et al. Systemic administration of lipopolysaccharide induces cyclooxygenase-2 immunoreactivity in endothelium and increases microglia in the mouse hippocampus. Cell Mol Neurobiol. 2010;30(4):531-41.

Abdel-Salam OM, Omara EA, El-Shamarka ME-S, Hussein JS. Nigrostriatal damage after systemic rotenone and/or lipopolysaccharide and the effect of cannabis. Comp Clin Pathol. 2014;23(5):1343-58.

De Simone R, Ajmone-Cat MA, Minghetti L. Atypical antiinflammatory activation of microglia induced by apoptotic neurons. Mol Neurobiol. 2004;29(2):197.

Sarbishegi M, Gorgich EAC, Khajavi O, Komeili G, Salimi S. The neuroprotective effects of hydro-alcoholic extract of olive (Olea europaea L.) leaf on rotenone-induced Parkinson’s disease in rat. Metab Brain Dis. 2017:1-10.

Sriraksa N, Wattanathorn J, Muchimapura S, Tiamkao S, Brown K, Chaisiwamongkol K. Cognitive-enhancing effect of quercetin in a rat model of Parkinson's disease induced by 6-hydroxydopamine. Evidence-Based Complementary and Alternative Medicine. 2012;2012.

Sarrafchi A, Bahmani M, Shirzad H, Rafieian-Kopaei M. Oxidative stress and Parkinson’s disease: new hopes in treatment with herbal antioxidants. Curr Pharm Design. 2016;22(2):238-46.

Martinez TN, Greenamyre JT. Toxin models of mitochondrial dysfunction in Parkinson's disease. Antioxid Redox Sign. 2012;16(9):920-34.

Swanson L. The projections of the ventral tegmental area and adjacent regions: a combined fluorescent retrograde tracer and immunofluorescence study in the rat. Brain Res Bull. 1982;9(1):321-53.

Bartels AL, Leenders KL. Cyclooxygenase and neuroinflammation in Parkinson's disease neurodegeneration. Curr Neuropharmacol. 2010;8(1):62-8.

Santiago RM, Barbiero J, Martynhak BJ, Boschen SL, da Silva LM, Werner MF, et al. Antidepressant-like effect of celecoxib piroxicam in rat models of depression. J Neural Transm. 2014;121(6):671-82.

How to Cite
Sarbishegi M, Mahmoudzadeh-Sagheb H, Heidari Z, Baharvand F. The Protective Effect of Celecoxib on CA1 Hippocampal Neurons and Oxidative Stress in a Rat Model of Parkinson’s Disease. Acta Med Iran. 57(2):94-102.