Paeoniflorin has anti-inflammation and neurogenesis functions through nicotinic acetylcholine receptors in cerebral ischemia-reperfusion injury rats

Document Type: Original Article

Authors

1 Department of Chinese Medicine, China Medical University Hospital, Taichung 40447, Taiwan

2 Chinese Medicine Research Center, China Medical University, Taichung 40402, Taiwan

3 Graduate Institute of Acupuncture Science, College of Chinese Medicine, China Medical University, Taichung 40402, Taiwan

4 Graduate Institute of Integrated Medicine, College of Chinese Medicine, China Medical University, Taichung 40402, Taiwan

Abstract

Objective(s): Paeoniflorin (PF) has anti-oxidation, anti-inflammation, anti-apoptosis, and neuroprotection pharmacological effects against ischemic injury. The aim of the present study was to investigate the neuroprotection mechanisms of PF in cerebral ischemia-reperfusion injury rats.
Materials and Methods: We established an animal model of cerebral infarct by occlusion of the middle cerebral artery for 15 min, followed by reperfusion, and PF was administered 24 hr later (20 mg/kg, intraperitoneally for 6 days) after reperfusion
Results: Treatment with PF reduced the neurological deficit score, improved motor function, decreased cell counts of nicotinic acetylcholine receptor (nAChR) α4β2 immunoreactive cells, and increased cell counts of nAChR α7. Furthermore, PF administration suppressed neuronal apoptosis and promoted neurogenesis.
Conclusion: PF rescued neurological deficit and underlying mechanisms were inhibition of neurological apoptosis and inflammation by nAChRs.

Keywords

Main Subjects


1. Wang Q, Tang XN, Yenari MA. The inflammatory response in stroke. J Neuroimmunol 2007; 184:53-68.
2. Wu PF, Zhang Z, Wang F, Chen JG. Natural compounds from traditional medicinal herbs in the treatment of cerebral ischemia/reperfusion injury. Acta Pharmacol Sin 2010; 31:1523-1531.
3. Xiao L, Wang YZ, Liu J, Luo XT, Ye Y, Zhu XZ. Effects of paeoniflorin on the cerebral infarction, behavioral and cognitive impairments at the chronic stage of transient middle cerebral artery occlusion in rats. Life Sci 2005; 78:413-420.
4. Tang NY, Liu CH, Hsieh CT, Hsieh CL. The anti-inflammatory effect of paeoniflorin on cerebral infarction induced by ischemia-reperfusion injury in Sprague-Dawley rats. Am J Chin Med 2010; 38:51-64.
5. Liu DZ, Xie KQ, Ji XQ, Ye Y, Jiang CL, Zhu XZ. Neuroprotective effect of paeoniflorin on cerebral ischemic rat by activating adenosine A1 receptor in a manner different from its classical agonists. Br J Pharmacol 2005; 146:604-611.
6. Chen DM, Xiao L, Cai X, Zeng R, Zhu XZ. Involvement of multitargets in paeoniflorin-induced preconditioning. J Pharmacol Exp Ther 2006; 319:165-180.
7. Picciotto MR, Zoli M. Neuroprotection via nAChRs: the role of nAChRs in neurodegenerative disorders such as Alzheimer’s and Parkinson’s disease. Front Biosci 2008; 13:492-504.
8. Belluardo N, Mudo G, Blum M, Fuxe K. Central nicotinic receptors, neurotrophic factors and neuroprotection. Behav Brain Res 2000; 113:21-34.
9. de Jonge WJ, Ulloa L. The alpha7 nicotinic acetylcholine receptor as a pharmacological target for inflammation. Br J Pharmacol 2007; 151:915-929.
10. Mukhin AG, Gundisch D, Horti AG, Koren AO, Tamagnan G, Kimes AS, et al. 5-Iodo-A-85380, an alpha4beta2 subtype-selective ligand for nicotinic acetylcholine receptors. Mol Pharmacol 2000; 57:642-649.
11. Martin A, Szczupak B, Gomez-Vallejo V, Domercq M, Cano A, Padro D, et al. In vivo PET imaging of the alpha4beta2 nicotinic acetylcholine receptor as a marker for brain inflammation after cerebral ischemia. J Neurosci 2015; 35:5998-6009.
12. Yakel JL. Nicotinic ACh receptors in the hippocampal circuit; functional expression and role in synaptic plasticity. J Physiol 2014; 592:4147-4153.
13. Narla S, Klejbor I, Birkaya B, Lee YW, Morys J, Stachowiak EK, et al. Alpha7 nicotinic receptor agonist reactivates neurogenesis in adult brain. Biochem Pharmacol 2013; 86:1099-1104.
14. Kuo CT, Lin YW, Tang NY, Cheng CY, Hsieh CL. Electric stimulation of the ears ameliorated learning and memory impairment in rats with cerebral ischemia-reperfusion injury. Sci Rep 2016; 6:20381.
15. Zaleska MM, Mercado ML, Chavez J, Feuerstein GZ, Pangalos MN, Wood A. The development of stroke therapeutics: promising mechanisms and translational challenges. Neuropharmacology 2009; 56:329-341.
16. Neumann S, Shields NJ, Balle T, Chebib M, Clarkson AN. Innate Immunity and Inflammation Post-Stroke: An alpha7-Nicotinic Agonist Perspective. Int J Mol Sci 2015; 16:29029-29046.
17. Tracey KJ. The inflammatory reflex. Nature 2002; 420:853-859.
18. Meisel C, Schwab JM, Prass K, Meisel A, Dirnagl U. Central nervous system injury-induced immune deficiency syndrome. Nat Rev Neurosci 2005; 6:775-786.
19. Tracey KJ. Reflex control of immunity. Nat Rev Immunol 2009; 9:418-428.
20. Borovikova LV, Ivanova S, Zhang M, Yang H, Botchkina GI, Watkins LR, et al. Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature 2000; 405:458-462.
21. Cai PY, Bodhit A, Derequito R, Ansari S, Abukhalil F, Thenkabail S, et al. Vagus nerve stimulation in ischemic stroke: old wine in a new bottle. Front Neurol 2014; 5:107.
22. Krafft PR, Altay O, Rolland WB, Duris K, Lekic T, Tang J, et al. Alpha7 nicotinic acetylcholine receptor agonism confers neuroprotection through GSK-3beta inhibition in a mouse model of intracerebral hemorrhage. Stroke 2012; 43:844-850.
23. Dasgupta P, Rastogi S, Pillai S, Ordonez-Ercan D, Morris M, Haura E, et al. Nicotine induces cell proliferation by beta-arrestin-mediated activation of Src and Rb-Raf-1 pathways. J Clin Invest 2006; 116:2208-2217.