Berberine attenuates convulsing behavior and extracellular glutamate and aspartate changes in 4-aminopyridine treated rats

Authors

1 Neurocognitive Research Center, Mashhad University of Medical Sciences, Mashhad, Iran

2 Pharmacological Research Center of Medicinal Plants, Mashhad University of Medical Sciences, Mashhad, Iran

3 Pharmaceutical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran

Abstract

Objective(s): K+ channel blocker 4-aminopyridine (4-AP) stimulates the release of glutamate from nerve terminals and induces seizures. Berberine as a potential herbal drug exerts several pharmacological actions on the central nervous system including anxiolytic, anticonvulsant, and neuroprotective properties. The present study aimed to investigate the effect of berberine on seizure onset and time course of the extracellular levels of excitatory amino acids (EAA), glutamate and aspartate, changes produced by 4-AP in rat hippocampus.
Materials and Methods: The rats were given either saline or berberine (50, 100 and 200 mg/kg, IP) 40 min before administration of 4-AP (15 mg/kg, IP) and the onset of seizure was recorded. A group of rats also received diazepam (DZP, 15 mg/kg, IP) 20 min prior to 4-AP administration. Hippocampal extracellular levels of EAA were also measured using microdialysis assay. Analysis of the dialysate samples was performed by reversed-phase high performance liquid chromatography (HPLC) with precolumn derivatization with o-phthaldialdehyde and fluorescence detection.
Results: Our findings suggest that berberine significantly delayed the seizure onset following 4-AP injection. There was a considerable increase in the extracellular glutamate and aspartate levels in 4-AP treated rats and 4-AP-evoked release of EAA was sharply reduced (about 4-5 fold especially at 20 min after 4-AP administration) in berberine treatment groups.
Conclusion: The results of present study show that berberine attenuates 4-AP induced seizures by decreasing hippocampal aspartate and glutamate release in rats.

Keywords


1. Ayala GX, Tapia R. HSP70 expression protects against hippocampal neurodegeneration induced by endogenous glutamate in vivo. Neuropharmacology 2008; 55:1383-1390.

2. Segovia G, Porras A, Mora F. Effects of 4-aminopyridine on extracellular concentrations of glutamate in striatum of the freely moving rat. Neurochem Res 1997; 22:1491-1497.

3. Medina-Ceja L, Cordero-Romero A, Morales-Villagrán A. Antiepileptic effect of carbenoxolone on seizures induced by 4-aminopyridine: a study in the rat hippocampus and entorhinal cortex. Brain Res 2008; 1187:74-81.

4. Peña F, Tapia R. Relationships among seizures, extracellular amino acid changes, and neurodegeneration induced by 4‐aminopyridine in rat hippocampus: A microdialysis and electroencephalographic study. J Neurochem 1999; 72:2006-2014.

5. Imanshahidi M, Hosseinzadeh H. Pharmacological and therapeutic effects of Berberis vulgaris and its active constituent, berberine. Phytother Res 2008; 22:999-1012.

6. Yang J, Zhou Z, Xu J. Protective effect of berberine on cardiac hypertrophy induced by L-thyroxine in rats. Sichuan Da Xue Xue Bao Yi Xue Ban 2004; 35:223-225.

7. Zheng L, Zhou Z, Tao D, Lan T. Protective effect of berberine on cardiac myocyte injured by ischemia-reperfusion. Sichuan Da Xue Xue Bao Yi Xue Ban 2003; 34:452-454.

8. Lau CW, Yao XQ, Chen ZY, Ko WH, Huang Y. Cardiovascular actions of berberine. Cardiovasc Drug Rev 2001; 19:234-244.

9. Mantena SK, Sharma SD, Katiyar SK. Berberine, a natural product, induces G1-phase cell cycle arrest and caspase-3-dependent apoptosis in human prostate carcinoma cells. Mol Cancer Ther 2006; 5:296-308.

10. Barzegar E, Fouladdel S, Movahhed TK, Atashpour S, Ghahremani MH, Ostad SN, et al. Effects of berberine on proliferation, cell cycle distribution and apoptosis of human breast cancer T47D and MCF7 cell lines. Iran J Basic Med Sci 2015; 18:334-342.

11. Ahmadiankia N, Moghaddam HK, Mishan MA, Bahrami AR, Naderi-Meshkin H, Bidkhori HR, et al. Berberine suppresses migration of MCF-7 breast cancer cells through down-regulation of chemokine receptors. Iran J Basic Med Sci 2016; 19:125-131.

12. Wu M, Wang J, Liu LT. Advance of studies on anti-atherosclerosis mechanism of berberine. Chin J Integr Med 2010; 16:188-92.

13. Yang Q-h, Hu S-p, Zhang Y-p, Xie W-n, Li N, Ji G-y, et al. Effect of berberine on expressions of uncoupling protein-2 mRNA and protein in hepatic tissue of non-alcoholic fatty liver disease in rats. Chin J Integr Med 2011; 17:205-211.

14. Yin J, Xing H, Ye J. Efficacy of berberine in patients with type 2 diabetes mellitus. Metabolism 2008; 57:712-717.

15. Kulkarni SK, Dhir A. Possible involvement of L-arginine-nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) signaling pathway in the antidepressant activity of berberine chloride. Eur J Pharmacol 2007; 569:77-83.

16. Kuo C-L, Chi C-W, Liu T-Y. The anti-inflammatory potential of berberine in vitro and in vivo. Cancer Lett 2004; 203:127-137.

17. Ahmed T, Abdollahi M, Daglia M, Nabavi SF, Nabavi SM. Berberine and neurodegeneration: A review of literature. Pharmacol Rep 2015.

18. Cui H-S, Matsumoto K, Murakami Y, Hori H, Zhao Q, Obi R. Berberine exerts neuroprotective actions against in vitro ischemia-induced neuronal cell damage in organotypic hippocampal slice cultures: involvement of B-cell lymphoma 2 phosphorylation suppression. Biol Pharm Bull 2009; 32:79-85.

19. Han AM, Heo H, Kwon YK. Berberine promotes axonal regeneration in injured nerves of the peripheral nervous system. J Med Food 2012; 15:413-417.

20. Hong JS, Chu YK, Lee H, Ahn BH, Park JH, Kim MJ, et al. Effects of berberine on hippocampal neuronal damage and matrix metalloproteinase‐9 activity following transient global cerebral ischemia. J Neurosci Res 2012; 90:489-497.

21. 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; 698:259-266.

22. Moghaddam HK, Baluchnejadmojarad T, Roghani M, Goshadrou F, Ronaghi A. Berberine chloride improved synaptic plasticity in STZ induced diabetic rats. Metab Brain Dis 2013; 28:421-428.

23. Zhu F, Qian C. Berberine chloride can ameliorate the spatial memory impairment and increase the expression of interleukin-1beta and inducible nitric oxide synthase in the rat model of Alzheimer's disease. BMC Neurosci 2006; 7:78.

24. 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; 10:2139-45.

25. Mojarad TB, Roghani M. The anticonvulsant and antioxidant effects of berberine in kainate-induced temporal lobe epilepsy in rats. Basic Clin Neurosci 2014; 5:124-30.

26. Sedaghat R, Taab Y, Kiasalari Z, Afshin-Majd S, Baluchnejadmojarad T, Roghani M. Berberine ameliorates intrahippocampal kainate-induced status epilepticus and consequent epileptogenic process in the rat: Underlying mechanisms. Biomed Pharmacother 2017; 87:200-208.

27. Mojarad TB, Roghani M. The anticonvulsant and antioxidant effects of berberine in kainate-induced temporal lobe epilepsy in rats. Basic Clin Neurosci 2014; 5:124-30.

28. Bhutada P, Mundhada Y, Bansod K, Dixit P, Umathe S, Mundhada D. Anticonvulsant activity of berberine, an isoquinoline alkaloid in mice. Epilepsy Behavior 2010; 18:207-210.

29. Sadeghnia HR, Darbarpanah S, Hosseini SM. Effect of berberine on pentylenetetrazol-induced seizures in rats. Avicenna J Phytomed 2011; 1:78-82.

30. Hosseinzadeh H, Sadeghnia H. Protective effect of safranal on pentylenetetrazol-induced seizures in the rat: involvement of GABAergic and opioids systems. Phytomedicine 2007; 14:256-262.

31. Hosseinzadeh H, Sadeghnia HR, Rahimi A. Effect of safranal on extracellular hippocampal levels of glutamate and aspartate during kainic acid treatment in anesthetized rats. Planta Med 2008; 74:1441-1445.

32. 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.

33. Yu W, Smith AB, Pilitsis J, Shin DS. Isovaline attenuates epileptiform activity and seizure behavior in 4-aminopyridine treated rats. Epilepsy Res 2014; 108:331-335.

34. Kovács A, Mihály A, Komáromi Á, Gyengési E, Szente M, Weiczner R, et al. Seizure, neurotransmitter release, and gene expression are closely related in the striatum of 4-aminopyridine-treated rats. Epilepsy Res 2003; 55:117-129.

35. Lin T-Y, Lin Y-W, Lu C-W, Huang S-K, Wang S-J. Berberine inhibits the release of glutamate in nerve terminals from rat cerebral cortex. PLoS One 2013. 8:e67215

36. Meldrum BS. Glutamate as a neurotransmitter in the brain: review of physiology and pathology. J Nutr 2000; 130:1007S-1015S.

37. Mdzinarishvili A, Sambria RK, Lang D, Klein J. Ginkgo extract EGb761 confers neuroprotection by reduction of glutamate release in ischemic brain. J Pharm Pharm Sci 2012; 15:94-102.

38. Wang S-J, Wang K-Y, Wang W-C. Mechanisms underlying the riluzole inhibition of glutamate release from rat cerebral cortex nerve terminals (synaptosomes). Neuroscience 2004; 125:191-201.

39. Coyle JT, Puttfarcken P. Oxidative stress, glutamate, and neurodegenerative disorders. Science 1993; 262:689-695.

40. Wang X, Wang R, Xing D, Su H, Ma C, Ding Y, et al. Kinetic difference of berberine between hippocampus and plasma in rat after intravenous administration of Coptidis rhizoma extract. Life Sci 2005; 77:3058-3067.

41. Kulkarni SK, Dhir A. Berberine: a plant alkaloid with therapeutic potential for central nervous system disorders. Phytother Res 2010; 24:317-324.

42. Zhou X-Q, Zeng X-N, Kong H, Sun X-L. Neuroprotective effects of berberine on stroke models in vitro and in vivo. Neurosci Lett 2008; 447:31-36.

43. Wang J, Zhang Y, Du S, Zhang M. Protective effects of berberine against amyloid beta-induced toxicity in cultured rat cortical neurons. Neural Regen Res 2011; 6:183-187

44. Hsu Y-Y, Chen C-S, Wu S-N, Jong Y-J, Lo Y-C. Berberine activates Nrf2 nuclear translocation and protects against oxidative damage via a phosphati-dylinositol 3-kinase/Akt-dependent mechanism in NSC34 motor neuron-like cells. Eur J Pharm Sci 2012; 46:415-425.

45. Wang F, Zhao G, Cheng L, Zhou H-Y, Fu L-Y, Yao W-X. Effects of berberine on potassium currents in acutely isolated CA1 pyramidal neurons of rat hippocampus. Brain Res 2004; 999:91-97.

46. 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.

47. Bhutada P, Mundhada Y, Bansod K, Dixit P, Umathe S, Mundhada D. Anticonvulsant activity of berberine, an isoquinoline alkaloid in mice. Epilepsy Behav 2010; 18:207-210.

48. 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; 698:259-266.

49. Mülsch A, Busse R, Mordvintcev PI, Vanin AF, Nielsen EO, Scheel-Krüger J, et al. Nitric oxide promotes seizure activity in kainate-treated rats. Neuroreport 1994; 5:2325-2328.

50. Sarro G, Paola ED, Sarro A, Vidal M. Role of nitric oxide in the genesis of excitatory amino acid‐induced seizures from the deep prepiriform cortex. Fundam Clin Pharmacol 1991; 5:503-511.