Effect of Jujuboside A on Brain Ischemia / Reperfusion Injury Via Expression of Antiapoptotic Gene

  • Alieh Karimi Department of Cellular and Molecular, Science and Research Branch, Islamic Azad University, Tehran, Iran
  • Akram Eydi Department of Animal Biology, Science and Research Branch, Islamic Azad University, Tehran, Iran
  • Zahra Nadia Sharifi Department of Anatomical Sciences and Cognitive Neuroscience, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
  • Shabnam Movassaghi Department of Anatomical Sciences and Cognitive Neuroscience, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
Keywords: Hippocampus, Ischemia, Jujuboside A, Antiapoptotic, Reperfioen, Brain-derived Neurotrophic Factor


Background: Some studies highlighted the role of Jujuboside A as a potent antioxidant on ischemic neurons. However, the definitive effect of this substance on the change in the expression of the neuroprotective genes has not been clearly identified. Therefore, this study aimed to investigate the effects of Jujuboside A on the expression of proliferation-inducing genes and cell count enhancement in the hippocampus after the induction of transient global ischemia/reperfusion. Materials and Methods: This experimental study was performed on 24 male Wistar rats in four groups control, ischemia, vehicle, and Jujuboside A. Three days after induction of ischemia, the hippocampus of animals was removed and isolated from brain tissue. In order to investigate the results of the intervention, the expression of nuclear factor-κB (NF-κB), nerve growth factor (NGF), and Brain-derived neurotrophic factor (BDNF) genes were determined using real-time polymerase chain reaction. Results: The results showed that NGF expression was significantly higher in the Jujuboside A group than in the ischemic group (P<0.05). Moreover, the expression of BDNF in the Jujuboside A group was increased compared to the ischemic group. However, the expression of NFκB in the Jujuboside A group was lower than that of the ischemic and control groups, but these changes were not significant (P>0.05). Conclusion: Jujuboside A can increase the expression of NGF by promoting a protective effect on the hippocampus after transient global ischemia/reperfusion.


Abbasi Gamasaee N, Radmansouri M, Ghiasvand S, Shahriari F, Zare Marzouni H, Aryan H, et al. Hypericin Induces Apoptosis in MDA-MB-175-VII Cells in Lower Dose Compared to MDA-MB-231. Arch Iran Med. 2018;21(9):387-92.

Kooti W, Servatyari K, Behzadifar M, Asadi-Samani M, Sadeghi F, Nouri B, Zare Marzouni H. Effective Medicinal Plant in Cancer Treatment, Part 2: Review Study. J Evid Based Complementary Altern Med. 2017;22(4):982-95.


PMid:28359161 PMCid:PMC5871268

Rafiee S, Nekouyian N, Hosseini S, Sarabandi F, Chavoshi-Nejad M, Mohsenikia M, et al. Effect of topical linum usitatissimum on full thickness excisional skin wounds. Trauma Mon. 2017;22(6):e64930.


Jeong EJ, Lee HK, Lee KY, Jeon BJ, Kim DH, Park JH, et al. The effects of lignan-riched extract of Shisandra chinensis on amyloid-β-induced cognitive impairment and neurotoxicity in the cortex and hippocampus of mouse. J Ethnopharmacol. 2013;146(1):347-54.



You ZL, Xia Q, Liang FR, Tang YJ, Xu CL, Huang J, et al. Effects on the expression of GABAA receptor subunits by jujuboside a treatment in rat hippocampal neurons. J Ethnopharmacol. 2010;128(2):419-23.



Chen CJ LM, Wang XL, Fang FF, Ling CQ. Effect of Sour Date (Semen ziziphi spinosae) Seed Extract on Treating Insomnia and Anxiety. In: Nuts and Seeds in Health and Disease Prevention. Academic Press; 2011. p. 1037-43.



Huang YS, Pan YY, Jia YH. A study of anti-apoptosis effect and mechanism of Jujuboside A in hydrogen peroxide damaged myocardial cell. Liaoning Journal of Traditional Chinese Medicine. 2011;38(3):454-5.

Marzouni HZ, Bagherabad MB, Sharaf S, Zarrinkamar M, Shaban S, Aryan H, et al. Thioredoxin Reductase Activity and Its Tissue Distribution in the Pathologic Specimens of Patients with Laryngeal Squamous Cell Carcinoma. GMJ. 2016;5(3):153-59.


Zare Marzouni H, Lavasani Z, Shalilian M, Najibpour R, Saadat Fakhr M, Nazarzadeh R, et al. Women's Awareness and Attitude Toward Breast Self-Examination in Dezful City, Iran, 2013. Iran Red Crescent Med J. 2014;17(1):e17829.


PMid:25763260 PMCid:PMC4341502

Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman M, et al. Heart disease and stroke statistics-2016 update a report from the American Heart Association. Circulation. 2016;133(4):e38-360.

Zhang S, Qi Y, Xu Y, Han X, Peng J, Liu K, Sun CK. Protective effect of flavonoid-rich extract from Rosa laevigata Michx on cerebral ischemia-reperfusion injury through suppression of apoptosis and inflammation. Neurochem Int. 2013;63(5):522-32.



Dekeyzer S, De Kock I, Nikoubashman O, Vanden Bossche S, Van Eetvelde R, De Groote J, et al. "Unforgettable" - a pictorial essay on anatomy and pathology of the hippocampus. Insights Imaging. 2017;8(2):199-12.


PMid:28108955 PMCid:PMC5359145

Morioka T, Kalehua A, Streit W. Progressive expression of immunomolecules on microglial cells in rat dorsal hippocampus following transient forebrain ischemia. Acta Neuropathol. 1992;83(2):149-57.



Lakhan SE, Kirchgessner A, Hofer M. Inflammatory mechanisms in ischemic stroke: therapeutic approaches. J Transl Med. 2009;7(1):97.


PMid:19919699 PMCid:PMC2780998

Shenoda B. The role of Na+/Ca2+ exchanger subtypes in neuronal ischemic injury. Transl Stroke Res. 2015;6(3):181-90.



Liu Z, Zhao X, Liu B, Liu A-j, Li H, Mao X, et al. Jujuboside A, a neuroprotective agent from semen Ziziphi Spinosae ameliorates behavioral disorders of the dementia mouse model induced by Aβ1-42. Eur J Pharmacol. 2014;738:206-13.



Yoo KY, Li H, Hwang IK, Choi JH, Lee CH, Kwon DY, et al. Zizyphus attenuates ischemic damage in the gerbil hippocampus via its antioxidant effect. J Med Food. 2010;13(3):557-63.



Han D, Wan C, Liu F, Xu X, Jiang L, Xu J. Jujuboside A Protects H9C2 Cells from Isoproterenol-Induced Injury via Activating PI3K/Akt/mTOR Signaling Pathway. Evid Based Complement Alternat Med. 2016; 2016:1-8.




PMid:26989428 PMCid:PMC4771918

Menzies FM, Ince PG, Shaw PJ. Mitochondrial involvement in amyotrophic lateral sclerosis. Neurochem Int. 2002;40(6):543-51.



Belousova MA, Korsakova EA, Gorodetskaia EA, Kalenikova EI, Medvedev OS. New antioxidants as neuroprotective agents for the treatment of ischemic brain injury and neurodegenerative diseases. Eksp Klin Farmakol. 2014;77(11):36-44.

Jangholi E, Sharifi ZN, Hoseinian M, Zarrindast MR, Rahimi HR, Mowla A, et al. Verapamil inhibits mitochondria-induced reactive oxygen species and dependent apoptosis pathways in cerebral transient global ischemia/reperfusion. Oxid Med Cell Longev. 2020;2020:5872645.


PMid:33133347 PMCid:PMC7591985

Marzouni HZ, Tarkhan F, Aidun A, Shahzamani K, Tigh HRJ, Malekshahian S, et al. Cytotoxic Effects of Coated Gold Nanoparticles on PC12 Cancer Cell. GMJ. 2018;7:e1110.


Shahzamani K, Zare Marzouni H, Tarkhan F, Lashgarian H. A Study of Mechanism and Rate of PC12 Cancer Cell Destruction Induced by Lysine-Coated Gold Nanoparticle. Journal of Babol University of Medical Sciences. 2016;18(8):41-7.

Olmez I, Zhang Y, Manigat L, Benamar M, Brenneman B, Nakano I, et al. Combined c-met/Trk inhibition overcomes resistance to CDK4/6 inhibitors in glioblastoma. Cancer Res. 2018;78(15):4360-9.


PMid:29844123 PMCid:PMC6072607

Caviedes A, Lafourcade C, Soto C, Wyneken U. BDNF/NF-κB signaling in the neurobiology of depression. Curr Pharm Des. 2017;23(21):3154-63.



Wang C, You ZL, Xia Q, Xiong T, Xia Y, Yao DZ. Upregulation of Mark3 and Rpgrip1 mRNA expression by jujuboside A in mouse hippocampus. Acta Pharmacol Sin. 2007;28(3):334-8.



Freeman RS, Burch RL, Crowder RJ, Lomb DJ, Schoell MC, Straub JA, et al. NGF deprivation-induced gene expression: after ten years, where do we stand? Prog Brain Re. 2004;146:111-26.



Brunet A, Datta SR, Greenberg ME. Transcription-dependent and-independent control of neuronal survival by the PI3K-Akt signaling pathway. Curr Opin Neurobiol. 2001;11(3):297-305.



Levi-Montalcini R. The nerve growth factor and the neuroscience chess board. Prog Brain Res. 2004;146:523-7.


Hubbard SR. Autoinhibitory mechanisms in receptor tyrosine kinases. Front Biosci. 2002;7:d330-40.



Patapoutian A, Reichardt LF. Trk receptors: mediators of neurotrophin action. Curr Opin Neurobiol. 2001;11(3):272-80.



Meloche S, Pouysségur J. The ERK1/2 mitogen-activated protein kinase pathway as a master regulator of the G1-to S-phase transition. Oncogene. 2007;26(22):3227.



Crowder RJ, Freeman RS. Phosphatidylinositol 3-kinase and Akt protein kinase are necessary and sufficient for the survival of nerve growth factor-dependent sympathetic neurons. J Neurosci. 1998;18(8):2933-43.


PMid:9526010 PMCid:PMC6792598

Lee R, Kermani P, Teng KK, Hempstead BL. Regulation of cell survival by secreted proneurotrophins. Science. 2001;294(5548):1945-8.



Li Q, Verma IM. NF-κB regulation in the immune system. Nat Rev Immunol. 2002;2(10):725-34.



Rabinovich G, Alonso C, Sotomayor C, Durand S, Bocco J, Riera C. Molecular mechanisms implicated in galectin-1-induced apoptosis: activation of the AP-1 transcription factor and downregulation of Bcl-2. Cell Death Differ. 2000;7(8):747-53.



How to Cite
Karimi, A., Eydi, A., Sharifi , Z. N., & Movassaghi , S. (2022). Effect of Jujuboside A on Brain Ischemia / Reperfusion Injury Via Expression of Antiapoptotic Gene. Galen Medical Journal, 11, e1620. https://doi.org/10.31661/gmj.v11i.1620
Original Article