Effect of berberine chloride on caspase-3 dependent apoptosis and antioxidant capacity in the hippocampus of the chronic cerebral hypoperfusion rat model

Document Type : Original Article


1 Neurobiomedical Research Center, School of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran

2 Deptartment of Anatomy and Cell Biology, School of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran

3 Department of Biochemistry, School of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran

4 Neuroscience Research Center, Iran University of Medical Sciences, Tehran, Iran


Objective(s): The main goal of the current research was to examine the effects of Berberine (BBR) on apoptotic signaling and hippocampal oxidative stress induced by common carotid artery occlusion.
Materials and Methods: Chronic cerebral hypoperfusion (CCH) model was created by occluding the two common carotid arteries (two-vessel occlusion [2VO]) permanently. BBR (50 and 100 mg/kg/daily) was intra-gastrically administered to ischemic rats. Neuronal survival was evaluated by Nissl staining. The levels of malondialdehyde (MDA) and antioxidant enzymes, including catalase (CAT) and superoxide dismutase (SOD), along with the activities of caspase 3 were estimated in the hippocampus 2 month after treating the rats with 2VO.
Results: According to findings of the present research, the BBR therapy inhibited the neuro-degeneration of hippocampus. BBR also significantly decreased the amount of MDA and activity of caspase 3 in the hippocampus. Furthermore, the administration of BBR alleviated the lowered activities of SOD and CAT after 2VO surgery.
Conclusion: The antioxidant and antiapoptotic properties of BBR might play important roles in improving functional outcomes and might have significant neuroprotective effects on the CCH damage.


Main Subjects

1. Harukuni I, Bhardwaj A. Mechanisms of brain injury after global cerebral ischemia. Neurologic clinics 2006; 24:1-21.
2. Gheibi S, Aboutaleb N, Khaksari M, Kalalian-Moghaddam H, Vakili A, Asadi Y, et al. Hydrogen sulfide protects the brain against ischemic reperfusion injury in a transient model of focal cerebral ischemia. J Mol Neurosci 2014; 54:264-270.
3. Farkas E, Luiten PG, Bari F. Permanent, bilateral common carotid artery occlusion in the rat: a model for chronic cerebral hypoperfusion-related neurodegenerative diseases. Brain Res Rev 2007; 54:162-180.
4. Lee JS, Im DS, An Y-S, Hong JM, Gwag BJ, Joo IS. Chronic cerebral hypoperfusion in a mouse model of Alzheimer’s disease: an additional contributing factor of cognitive impairment. Neurosci Lett 2011; 489:84-88.
5. Anand KS, Dhikav V. Hippocampus in health and disease: An overview. Ann Indian Acad Neurol 2012; 15:239-246.
6. Cobley JN, Fiorello ML, Bailey DM. 13 reasons why the brain is susceptible to oxidative stress. Redox Biology 2018; 15:490-503.
7. Mehrjerdi FZ, Aboutaleb N, Habibey R, Ajami M, Soleimani M, Arabian M, et al. Increased phosphorylation of mTOR is involved in remote ischemic preconditioning of hippocampus in mice. Brain Res 2013; 1526:94-101.
8. Barnham KJ, Masters CL, Bush AI. Neurodegenerative diseases and oxidative stress. Nat Rev Drug Discov 2004; 3:205-214.
9. Muche A, Arendt T, Schliebs R. Oxidative stress affects processing of amyloid precursor protein in vascular endothelial cells. PloS one 2017; 12:e0178127.
10. Rahbardar MG, Amin B, Mehri S, Mirnajafi-Zadeh SJ, Hosseinzadeh H. Rosmarinic acid attenuates development and existing pain in a rat model of neuropathic pain: an evidence of anti-oxidative and anti-inflammatory effects. Phytomedicine 2018; 40:59-67.
11. Ye M, Fu S, Pi R, He F. Neuropharmacological and pharmacokinetic properties of berberine: a review of recent research. J Pharm Pharm Sci 2009; 61:831-837.
12. Gao F, Gao Y, Liu Y-f, Wang L, Li Y-j. Berberine exerts an anticonvulsant effect and ameliorates memory impairment and oxidative stress in a pilocarpine-induced epilepsy model in the rat. Neuropsychiatr Dis Treat 2014; 10:2139-2145.
13. Pires ENS, Frozza RL, Hoppe JB, de Melo Menezes B, Salbego CG. Berberine was neuroprotective against an in vitro model of brain ischemia: survival and apoptosis pathways involved. Brain Res 2014; 1557:26-33.
14. Moghaddam HK, Baluchnejadmojarad T, Roghani M, Khaksari M, Norouzi P, Ahooie M, et al. Berberine ameliorate oxidative stress and astrogliosis in the hippocampus of STZ-induced diabetic rats. Mol Neurobiol 2014; 49:820-826.
15. Cechetti F, Worm PV, Pereira L, Siqueira IR, A Netto C. The modified 2VO ischemia protocol causes cognitive impairment similar to that induced by the standard method, but with a better survival rate. Braz J Med Biol Res 2010; 43:1178-1183.
16. Aski ML, Rezvani ME, Khaksari M, Hafizi Z, Pirmoradi Z, Niknazar S, et al. Neuroprotective effect of berberine chloride on cognitive impairment and hippocampal damage in experimental model of vascular dementia. Iran J Basic Med Sci 2018; 21:53-58.
17. Mehrjerdi FZ, Aboutaleb N, Pazoki-Toroudi H, Soleimani M, Ajami M, Khaksari M, et al. The protective effect of remote renal preconditioning against hippocampal ischemia reperfusion injury: role of KATP channels. J Mol Neurosci 2015; 57:554-560.
18. Chen W, Wei S, Yu Y, Xue H, Yao F, Zhang M, et al. Pretreatment of rats with increased bioavailable berberine attenuates cerebral ischemia-reperfusion injury via down regulation of adenosine-5′ monophosphate kinase activity. Eur J Pharmacol 2016; 779:80-90.
19. 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; 72:248-254.
20. Gülçin İ. Antioxidant activity of caffeic acid (3, 4-dihydroxycinnamic acid). Toxicology 2006; 217:213-220.
21. Scott KR, Barrett AM. Dementia syndromes: evaluation and treatment. Expert Rev Neurother 2007; 7:407-422.
22. Atlasi MA, Naderian H, Noureddini M, Fakharian E, Azami A. Morphology of Rat Hippocampal CA1 neurons following modified two and four-vessels global ischemia models. Arch Trauma Res 2013; 2:124-128.
23. Zhang G-L, Deng J-P, Wang B-H, Zhao Z-W, Li J, Gao L, et al. Gypenosides improve cognitive impairment induced by chronic cerebral hypoperfusion in rats by suppressing oxidative stress and astrocytic activation. Behav Pharmacol 2011; 22:633-644.
24. Rahal A, Kumar A, Singh V, Yadav B, Tiwari R, Chakraborty S, et al. Oxidative stress, prooxidants, and antioxidants: the interplay. BioMed Research International 2014; 2014; 761264-761283.
25. Dong S, Yasui N, Negishb H, Kishimoto A, Sun J, Ikeda K. Increased oxidative stress in cultured 3T3-L1 cells was attenuated by berberine treatment. Nat Prod Commun 2015; 10:895-897.
26. Smith JA, Park S, Krause JS, Banik NL. Oxidative stress, DNA damage, and the telomeric complex as therapeutic targets in acute neurodegeneration. Neurochem Int 2013; 62:764-775.