Evaluation of the neuroprotective, anticonvulsant, and cognition-improvement effects of apigenin in temporal lobe epilepsy: Involvement of the mitochondrial apoptotic pathway

Document Type : Original Article

Authors

1 Department of Physiology, School of Medicine and Cellular and Molecular Research Centre, Iran University of Medical Sciences, Tehran, Iran

2 Physiology Research Centre, Iran University of Medical Sciences, Tehran, Iran

3 Cellular and Molecular Research Center, School of Medicine, Iran University of Medical Sciences, Tehran, Iran

Abstract

Objective(s): Cognitive deficit is a common problem in epilepsy. A major concern emergent from the use of antiepileptic drugs includes their side effects on learning and memory. Herbal medicine is considered a complementary and alternative therapy in epilepsy. Apigenin is a safe flavone with antioxidant properties. However, there is little information about the beneficial effect of apigenin on cognition in epilepsy.
Materials and Methods: For evaluating the anticonvulsant effect of apigenin in the kainite temporal epilepsy model, apigenin was orally administered at 50 mg/kg for six days. Reference and working memory were examined via the Morris water maze and Y-maze task spontaneously.
Results: Results showed that apigenin had significant anticonvulsant activity (P<0.01) and restored the memory-deficit induced by kainic acid (P<0.05). Furthermore, apigenin significantly increased the number of living neurons in the hilus (P<0.001). Immunohistochemical analysis showed that apigenin reduced the release of cytochrome c (P<0.01), suggesting an inhibitory role in the intrinsic apoptotic pathway.
Conclusion: These results suggest that apigenin restores memory impairment via anticonvulsant and neuroprotective activity.

Keywords

Main Subjects


1. Giblin KA, Blumenfeld H. Is epilepsy a preventable disorder? New evidence from animal models. Neuroscientist 2010; 16:253-275.
2. Kuruba R, Hattiangady B, Shetty AK. Hippocampal neurogenesis and neural stem cells in temporal lobe epilepsy. Epilepsy Behav. 2009; 14:65-73.
3. Pauli E, Hildebrandt M, Romstöck J, Stefan H, Blümcke I. Deficient memory acquisition in temporal lobe epilepsy is predicted by hippocampal granule cell loss. Neurology 2006; 67:1383-1389.
4. Lévesque M, Avoli M. The kainic acid model of temporal lobe epilepsy. Neurosci Biobehav Rev 2013; 37:2887-2899.
5. Helmstaedter C, Elger C. Chronic temporal lobe epilepsy: a neurodevelopmental or progressively dementing disease? Brain 2009; 132:2822-2830.
6. Höller Y, Trinka E. What do temporal lobe epilepsy and progressive mild cognitive impairment have in common? Front Syst Neurosci 2014; 8.
7. Kotloski R, Lynch M, Lauersdorf S, Sutula T. Repeated brief seizures induce progressive hippocampal neuron loss and memory deficits. Prog Brain Res 2002; 135:95-110.
8. Cock H. The role of mitochondria in status epilepticus. Epilepsia 2007; 48:24-27.
9. Dalic L, Cook MJ. Managing drug-resistant epilepsy: challenges and solutions. Neuropsychiatr Dis Treat 2016; 12:2605-2616.
10. Meador KJ. Cognitive and memory effects of the new antiepileptic drugs. Epilepsy Res 2006; 68:63-67.
11. Lasoń W, Leśkiewicz M. Effect of plant polyphenols on seizures–animal studies. Journal of Epileptology 2013; 21:79-87.
12. Tang D, Chen K, Huang L, Li J. Pharmacokinetic properties and drug interactions of apigenin, a natural flavone. Expert Opin Drug Metab Toxicol 2017; 13:323-330.
13. Ali F, Rahul, Naz F, Jyoti S, Siddique YH. Health functionality of apigenin: A review. International Journal of Food Properties 2017; 20:1197-1238.
14. Zhao L, Wang J-L, Liu R, Li X-X, Li J-F, Zhang L. Neuroprotective, anti-amyloidogenic and neurotrophic effects of apigenin in an Alzheimer’s disease mouse model. Molecules 2013; 18:9949-9965.
15. Zheng P-W, Chiang L-C, Lin C-C. Apigenin induced apoptosis through p53-dependent pathway in human cervical carcinoma cells. Life Sci 2005; 76:1367-1379.
16. Shukla S, Gupta S. Molecular targets for apigenin-induced cell cycle arrest and apoptosis in prostate cancer cell xenograft. Mol Cancer Ther. 2006; 5:843-852.
17. Way T-D, Kao M-C, Lin J-K. Apigenin induces apoptosis through proteasomal degradation of HER2/neu in HER2/neu-overexpressing breast cancer cells via the phosphatidylinositol 3-kinase/Akt-dependent pathway. J Biol Chem 2004; 279:4479-4489.
18. Hu J, Li Z, Xu L-t, Sun A-j, Fu X-y, Zhang L, et al. Protective effect of apigenin on ischemia/reperfusion injury of the isolated rat heart. Cardiovasc Toxicol 2015; 15:241-249.
19. Dang Y, Li Z, Luo B, Pan L, Wei Q, Zhang Y. Protective effects of apigenin against acrylonitrile-induced subchronic sperm injury in rats. Food Chem Toxicol 2017; 109:517-525.
20. Schmued LC, Hopkins KJ. Fluoro-Jade B: a high affinity fluorescent marker for the localization of neuronal degeneration. Brain Res 2000; 874:123-130.
21. Liang H, Sonego S, Gyengesi E, Rangel A, Niedermayer G, Karl T, et al. Anti-inflammatory and neuroprotective effect of apigenin: studies in the GFAP-IL6 mouse model of chronic neuroinflammation. Free Radic Biol Med 2017; 108:S10.
22. Taupin P. Apigenin and related compounds stimulate adult neurogenesis: Mars, Inc., the Salk Institute for Biological Studies: WO2008147483. Expert Opin Ther Pat 2009; 19:523-527.
23. Zhou JL, Shatskikh TN, Liu X, Holmes GL. Impaired single cell firing and long‐term potentiation parallels memory impairment following recurrent seizures. Eur J Neurosci 2007; 25:3667-3677.
24. Höller Y, Trinka E. What do temporal lobe epilepsy and progressive mild cognitive impairment have in common? Front Syst Neurosci 2014; 8:58.
25. Han J-Y, Ahn S-Y, Kim C-S, Yoo S-K, Kim S-K, Kim H-C, et al. Protection of apigenin against kainate-induced excitotoxicity by anti-oxidative effects. Biol Pharm Bull 2012; 35:1440-1446.
26. Gazola AC, Costa GM, Castellanos L, Ramos FA, Reginatto FH, Lima T, et al. Involvement of GABAergic pathway in the sedative activity of apigenin, the main flavonoid from Passiflora quadrangularis pericarp. Revista Brasileira de Farmacognosia 2015; 25:158-163.
27. Chang CY, Lin TY, Lu CW, Wang CC, Wang YC, Chou SSP, et al. Apigenin, a natural flavonoid, inhibits glutamate release in the rat hippocampus. Eur J Pharmacol 2015; 762:72-81.
28. Henshall DC, Simon RP. Epilepsy and apoptosis pathways. J Cereb Blood Flow Metab 2005; 25:1557-1572.
29. Aiyer RS, Nath JR. Mechanisms of memory deficit in temporal lobe epilepsy. Neropathology 2011; 22:6052-6061.
30. Balez R, Steiner N, Engel M, Muñoz SS, Lum JS, Wu Y, et al. Neuroprotective effects of apigenin against inflammation, neuronal excitability and apoptosis in an induced pluripotent stem cell model of Alzheimer’s disease.