Neuroprotective effect of berberine chloride on cognitive impairment and hippocampal damage in experimental model of vascular dementia

Document Type: Original Article


1 International Campuse, Shahid Sadoughi University of Medical Sciences, Yazd, Iran

2 Neurobiomedical Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran

3 Addiction Research Center, Shahroud University of Medical Sciences, Shahroud, Iran

4 Hearing Disorders Research Center, Loghman Hakim Medical Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran


Objective(s):The major objective of the present study was to investigate the potential neuroprotective effect of berberine chloride on vascular dementia. Berberine, as an ancient medicine in China and India, is the main active component derived from the Berberis sp. Several studies have revealed the beneficial effects of berberine in various neurodegenerative disorders.
Materials and Methods: To induce vascular dementia, chronic bilateral common carotid artery occlusion was performed on male Wistar rats. After surgery, the rats were treated daily by oral administration of berberine chloride (50 mg/kg) for two months. The cognition function of treated rats, were evaluated by Morris Water Maze (MWM) test. In addition, Nissl and TUNEL staining were chosen to assess neuronal damage within the hippocampal CA1 area.
Results: It was obvious that chronic cerebral hypoperfusion (CCH), caused cognitive impairment and neuronal damages within CA1 hippocampal subregion. Berberine chloride was able to prevent cognitive deficits, (P<0.05) and reversed CCH-induced hippocampal neuronal loss and apoptosis, (P<0.05).
Conclusion: Berberine chloride may be considered as a potential treatment for cognitive deficits and neuronal injury caused by CCH in the hippocampal CA1 area.


Main Subjects

1.  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.

2. 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.

3. Liu H, Zhang J. Cerebral hypoperfusion and cognitive impairment: the pathogenic role of vascular oxidative stress.  Int J Neurosci 2012;122:494-499.

4. Pereira FM, Ferreira EDF, de Oliveira RMW, Milani H. Time-course of neurodegeneration and memory impairment following the 4-vessel occlusion/internal carotid artery model of chronic cerebral hypoperfusion in middle-aged rats. Behav Brain Res 2012;229:340-348.

5. Jian H, Yi-Fang W, Qi L, Xiao-Song H, Gui-Yun Z. Cerebral blood flow and metabolic changes in hippocampal regions of a modified rat model with chronic cerebral hypoperfusion. ActaNeurol Belg 2013; 113:313-317.

6. Shamsaei N, Khaksari M, Erfani S, Rajabi H, Aboutaleb N. Exercise preconditioning exhibits neuroprotective effects on hippocampal CA1 neuronal damage after cerebral ischemia.Neural Regen Res 2015; 10:1245-50.

7. Ye M, Fu S, Pi R, He F. Neuropharmacological and pharmacokinetic properties of berberine: a review of recent research. J Pharm Pharmacol 2009;61:831-837.

8. 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. MolNeurobiol 2014;49:820-826.

9. Ji H-F, Shen L. Berberine: a potential multipotent natural product to combat Alzheimer’s disease. Molecules 2011;16:6732-6740.

10. Kim SO, Kim HJ. Berberine ameliorates cold and mechanical allodynia in a rat model of diabetic neuropathy. J Med Food 2013;16:511-517.

11. 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;33:870-878.

12. 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.

13. 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.

14. 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  MolNeurosci 2015;57:554-560.

15. Khaksari M, Mehrjerdi FZ, Rezvani ME, Safari F, Mirgalili A, Niknazar S. The role of erythropoietin in remote renal preconditioning on hippocampus ischemia/reperfusion injury. J Physiol Sci 2016:1-9.

16. Ni J-W, Matsumoto K, Li H-B, Murakami Y, Watanabe H. Neuronal damage and decrease of central acetylcholine level following permanent occlusion of bilateral common carotid arteries in rat.  Brain Res 1995;673:290-296.

17. Román GC. Cholinergic dysfunction in vascular dementia. ‎Curr Psychiatry Rep 2005;7:18-26.

18. Giacobini E. Cholinergic receptors in human brain: effects of aging and Alzheimer disease. J  Neurosci  Res 1990;27:548-560.

19. Bhutada P, Mundhada Y, Bansod K, Tawari S, Patil S, Dixit P, et al. Protection of cholinergic and antioxidant system contributes to the effect of berberine ameliorating memory dysfunction in rat model of streptozotocin-induced diabetes. ‎Behav  Brain Res 2011; 220:30-41.

20. Huang L, Su T, Shan W, Luo Z, Sun Y, He F, et al. Inhibition of cholinesterase activity and amyloid aggregation by berberine-phenyl-benzoheterocyclic and tacrine-phenyl-benzoheterocyclic hybrids. Bioorganic Med  Chem 2012;20:3038-3048.

21. Oh SM, Betz AL. Interaction between free radicals and excitatory amino acids in the formation of ischemic brain edema in rats. Stroke 1991;22:915-921.

22. Matsuo Y, Kihara T, Ikeda M, Ninomiya M, Onodera H, Kogure K. Role of neutrophils in radical production during ischemia and reperfusion of the rat brain: effect of neutrophil depletion on extracellular ascorbyl radical formation. J Cereb Blood Flow Metab 1995;15:941-947.

23. Erfani S, Aboutaleb N, Oryan S, Shamsaei N, Khaksari M, Kalalian-Moghaddam H, et al. Visfatin inhibits apoptosis and necrosis of hippocampus CA3 cells following transient global ischemia/reperfusion in rats. Int J Pept Res Ther 2015;21:223-228.

24. Hur JM, Hyun MS, Lim SY, Lee WY, Kim D. The combination of berberine and irradiation enhances anti‐cancer effects via activation of p38 MAPK pathway and ROS generation in human hepatoma cells. J Cell  Biochem 2009;107:955-964.

25. Ahmed T, Abdollahi M, Daglia M, Nabavi SF, Nabavi SM. Berberine and neurodegeneration: A review of literature. Pharmacol Rep 2015;67:970-979.

26. Saxena AK, Majeed A, Saad S, Oothuman P, Mahmoud M, Al-Deen MI. Lipid peroxidation in chronic cerebral hypoperfusion-induced neurodegeneration in rats. Inter Med J Malaysia 2011;10:3-6.

27. Zhang J, Yang J-Q, He B-C, Zhou Q-X, Yu H-R, Tang Y, et al. Berberine and total base from rhizoma coptis chinensis attenuate brain injury in an aluminum-induced rat model of neurodegenerative disease. Saudi Med J 2009;30:760-766.

28. Tomimoto H, Ihara M, Wakita H, Ohtani R, Lin J-X, Akiguchi I, et al. Chronic cerebral hypoperfusion induces white matter lesions and loss of oligodendroglia with DNA fragmentation in the rat.Acta Neuropathol 2003;106:527-534.

29. Kim S, Choi JH, Kim JB, Nam SJ, Yang J-H, Kim J-H, et al. Berberine suppresses TNF-α-induced MMP-9 and cell invasion through inhibition of AP-1 activity in MDA-MB-231 human breast cancer cells. Molecules 2008;13:2975-2985.

30. Domitrović R, Cvijanović O, Pernjak-Pugel E, Škoda M, Mikelić L, Crnčević-Orlić Ž. Berberine exerts nephroprotective effect against cisplatin-induced kidney damage through inhibition of oxidative/nitrosative stress, inflammation, autophagy and apoptosis. Food Chem Toxicol 2013;62:397-406.