The anti-inflammatory effect of picroside II and the optimizing of therapeutic dose and time window in cerebral ischemic injury in rats

Li Zhao, Xiaodan Li, Tingting Wang, Yunliang Guo, Fangfang Pang, Cuicui Chang

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Institute of Cerebrovascular Diseases, Affiliated Hospital of Qingdao University Medical College, Qingdao, China.

DOI: 10.4236/mri.2013.23006                

Abstract

The aim is to optimize the anti-inflammatory effect and the therapeutic dose and time window of picrosede II by orthogonal test in cerebral ischemic injury in rats. The forebrain ischemia models were established by bilateral common carotid artery occlusion (BCCAO) methods in 30 Wistar rats. The successful models were randomly divided into sixteen groups according to orthogonal experimental design and treated by injecting picroside II intraperitoneally at different ischemic time with different dose. The concentrations of aquaporins 4 (AQP4), matrix metalloproteinases9 (MMP9) and cyclooxygenase 2 (COX2) in serum and brain tissue were determined by enzyme linked immunosorbent assay to evaluate the therapeutic effect of picroside II in cerebral ischemic injury. The best therapeutic time window and dose of picroside II in cerebral ischemic injury were 1) ischemia 2.0 h with 20 mg/kg and 1.5 h with 20 mg/kg body weight according to the concentration of AQP4 in serum and brain tissue; 2) ischemia 1.5 h with 20 mg/kg and ischemia 2.0 h with 20 mg/kg according to the concentrations of MMP9 in serum and brain tissue; and 3) ischemia 1.5 h with 10 mg/kg and ischemia 1.5 h with 20 mg/kg according to the concentrations of COX2 in serum and brain tissue respectively. According to the principle of the lowest therapeutic dose with the longest time window, the optimized therapeutic dose and time window were injecting picroside II intraperitoneally with 10 - 20 mg/kg body weight at ischemia 1.5 - 2.0 h in cerebral ischemic injury.

Keywords

Picroside II; Therapeutic Dose; Time Window; Cerebral Ischemia; AQP4; MMP9; COX-2; Rats

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1]	Zelenina, M. (2010) Regulation of brain aquaporins. Neurochemistry International, 57, 468-488. doi:10.1016/j.neuint.2010.03.022
[2]	Sun, W., Su, Z.Q., Liu, J.F., et al. (2009)The effect of Kir4.1 and AQP4 in focal cerebral ischemia reperfusion injury rats. Chinese Journal of Neuromedicine, 8, 484-487.
[3]	Li, Z., Xu, X.Y., Li, Q., et al. (2010) Protective mechanisms of picroside on AQP4 in rat model of MCAO/R. Neural Regeneration Research, 5, 411-416.
[4]	Tayebjee, M.H., Nadar, S., Blann, A.D., et al. (2004) Matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 in hypertension and their relationship to cardiovascular risk and treatment: A substudy of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT). American Journal of Hypertension, 17, 764-769. doi:10.1016/S0895-7061(04)00855-6
[5]	Gu, Z., Cui, J., Brown, S., et al. (2005) A highly specific inhibitor of matrix metalloproteinase-9 rescues laminin from proteolysis and neurons from apoptosis in transient focal cerebral ischemia. Journal of Neuroscience, 25, 6401-6408. doi:10.1523/JNEUROSCI.1563-05.2005
[6]	Asahi, M., Wang, X., Mori, T., et al. (2001) Effects of matrix metalloproteinase-9 gene knock-out on the proteolysis of blood-brain barrier and white matter components after cerebral ischemia. Journal of Neuroscience, 21, 7724-7732.
[7]	Yang, Y., Estrada, E.Y., Thompson, J.F., et al. (2007) Matrix metalloproteinase mediated disruption of tight junction proteins in cerebral vessels is reversed by synthetic matrix metalloproteinase inhibitor in focal ischemia in rat. Journal of Cerebral Blood Flow & Metabolism, 27, 697-709.
[8]	Xu, Q.Y., Liu, Y.M., Shen, Q., et al. (2011) The effect of Artificial musk in the expression of brain MMP-9 mRNA and protein in focal cerebral ischemic injury in rats. Journal of Tropical Medicine, 11, 875-878.
[9]	Zhu, M.Z., Xu, B., Liang, S.L., et al. (2011) The effect of Astragalus injection in the expression of MMP-9 and IL-1β in cerebral ischemic injury in rats. Zhejiang Journal of Traditional Chinese Medicine, 46, 207-208.
[10]	Li, X., Xu, X.Y., Li, Z., et al. (2010) Picroside II downregulates matrix metalloproteinase-9 expression following cerebral ischemia/reperfusion injury in rats. Neural Regeneration Research, 5, 1403-1407.
[11]	Li, J., Liang, X., Wang, Q., et al. (2008) Misoprostol, an anti-ulcer agent and PGE2 receptor agonist, protects against cerebral ischemia. Neuroscience Letters, 438, 210-215. doi:10.1016/j.neulet.2008.04.054
[12]	Kim, S.S., Kong, P.J., Kim, B.S., et al. (2004) Inhibitory action of minocycline on lipopolysaccharide-induced release of nitric oxide and prostaglandin E2 in BV2 microglial cells. Archives of Pharmacal Research, 27, 314-318. doi:10.1007/BF02980066
[13]	Breder, C.D., Dewitt, D. and Kraig, R.P. (1995) Characterization of inducible cyclooxygenase in rat brain. Journal of Comparative Neurology, 355, 296-315. doi:10.1002/cne.903550208
[14]	Candelario-Jalil, E. and Fiebich, B.L. (2008) Cyclooxygenase inhibition in ischemic brain injury. Current Pharmaceutical Design, 14, 1401-1418. doi:10.2174/138161208784480216
[15]	Guo, Y.L., Xu, X.Y., Li, Q., et al. (2010) Anti-inflammation effects of picrosideⅡ in cerebral ischemic injury rats. Behavioral Brain Function, 6, 43-53.
[16]	Li, Z., Li, Q., Shen, W., et al. (2010) Intervention effects of picrosideⅡ in NFκB and IκB in cerebral ischemic injury rats. Chinese Pharmacological Bulletin, 26, 52-55.
[17]	Li, Z., Li, Q., Guo, Y.L., et al. (2010) Intervention effects of picrosideⅡ in cerebral ischemic injury rats. Acta Anatomica Sinica, 41, 9-12.
[18]	Li, Q., Li, Z., Xu, X.Y., et al. (2010) Neuroprotective properties of picroside II in rat model of focal cerebral ischemia. International Journal of Molecular Sciences, 11, 4580-4590. doi:10.3390/ijms11114580
[19]	Pei, H.T., Su, X., Zhao, L., et al. (2012) Primary study for the therapeutic dose and time window of picroside II in treating cerebral ischemic injury in rats. International Journal of Molecular Sciences, 13, 2551-2562. doi:10.3390/ijms13032551
[20]	Márquez-Martín, A., Jiménez-Altayó, F., Dantas, A.P., et al. (2012) Middle cerebral artery alterations in a rat chronic hypoperfusion model. Journal of Applied Physiology, 112, 511-518. doi:10.1152/japplphysiol.00998.2011
[21]	Masato, Y. (2009) Regulation, structure and function of brain aquaporin. Rinsho Shinkeigaku, 49, 786-788. doi:10.5692/clinicalneurol.49.786
[22]	Yang, M., Gao, F., Liu, H., et al. (2011) Immunolocalization of aquaporins in rat brain. Anatomia, Histologia, Embryologia, 40, 299-306. doi:10.1111/j.1439-0264.2011.01070.x
[23]	Zhang, H. and Verkman, A.S. (2008) Aquaporin-4 independent Kir4.1 K+ channel function in brain glial cells. Molecular and Cellular Neuroscience, 37, 1-10. doi:10.1016/j.mcn.2007.08.007
[24]	Yasui, M. (2011) Aquaporin from basic to clinical medicine: roles in brain edema. No To Hattatsu, 43, 191-194.
[25]	Manley, G.T., Fujimura, M., Ma, T., et al. (2000) Aquaporin-4 deletion in mice reduces brain edema after acute water intoxication and ischemic stroke. Nature Medicine, 6, 159-163. doi:10.1038/72256
[26]	Shi, W.Z., Zhao, C.Z., Zhao, B., et al. (2012) Aquaporin-4 deficiency attenuates acute lesions but aggravates delayed lesions and microgliosis after cryoinjury to mouse brain. Neuroscience Bulletin, 28, 61-68. doi:10.1007/s12264-012-1063-7
[27]	Shi, W.Z., Qi, L.L., Fang, S.H., et al. (2012) Aggravated chronic brain injury after focal cerebral ischemia in aquaporin-4-deficient mice. Neurosci Letters, 520, 121-125. doi:10.1016/j.neulet.2012.05.052
[28]	Rosenberg, G.A., Cunningham, L.A., Wallace, J., et al. (2001) Immunohistochemistry of matrix metalloproteinases in reperfusion injury to rat brain: Activation of MMP-9 linked to stromelysin-1 and microglia in cell cultures. Brain Research, 893, 104-112. doi:10.1016/S0006-8993(00)03294-7
[29]	Liu, H.X., Zhang, J.J., Xiong, L., et al. (2010) The effect of oxidative stress in chronic ischemic cerebral white matter injury. Chinese Journal of Neuromedicine, 9, 240-244. doi:10.1002/cjoc.20020200307
[30]	Mehta, S.L., Manhas, N. and Raghubir, R. (2007) Molecular targets in cerebral ischemia for developing novel therapeutics. Brain Research Reviews, 54, 34-66. doi:10.1016/j.brainresrev.2006.11.003