DOI QR코드

DOI QR Code

The use of Stronger Neo-Minophagen C, a glycyrrhizin-containing preparation, in robust neuroprotection in the postischemic brain

  • Kim, Seung-Woo (Department of Anatomy, Center for Advanced Medical Education by BK21 Project, Inha University School of Medicine) ;
  • Lim, Chae-Moon (Jeju National University School of Medicine) ;
  • Lee, Hye-Kyung (Department of Anatomy, Center for Advanced Medical Education by BK21 Project, Inha University School of Medicine) ;
  • Lee, Ja-Kyeong (Department of Anatomy, Center for Advanced Medical Education by BK21 Project, Inha University School of Medicine)
  • Published : 2011.12.31

Abstract

Stronger Neo-Minophagen C (SNMC) is a glycyrrhizin-containing preparation that is approved in Japan for the treatment of chronic hepatic diseases and is marketed in Japan, China, Korea, Taiwan, and India. Glycyrrhizin, a triterpene present in the roots and rhizomes of licorice (Glycyrrhiza glabra) has been shown to have anti-inflammatory, anti-oxidative, and anti-viral eff ects. In the present study, we demonstrated the marked neuroprotective effects of SNMC in the postischemic rat brain aft er middle cerebral artery occlusion (MCAO). We used 1 ml/kg of SNMC, which is within the dose range used for the treatment of patients with chronic hepatic disease. The administration of SNMC intravenously at 30 minutes before or 30 minutes and 3 hours aft er MCAO (60 minutes) reduces mean infarct volumes to 27.0${\pm}$4.2%, 37.1${\pm}$12.4%, and 67.8${\pm}$5.8% of that of untreated controls, respectively. This neuroprotective effect is accompanied by improvements in motor impairment and neurological deficits. The administration of SNMC is shown to suppress microglia activation and neutrophil infiltration in the postischemic brain. In addition, SNMC suppresses lipopolysaccharide-induced nitrite production and proinflammatory cytokine induction in a microglia cell line, BV2. This indicates that the neuroprotective effect of SNMC might be due, at least in part, to an anti-inflammatiory effect. Interestingly, SNMC shows significantly higher neuroprotective potency compared to an equivalent dose of pure glycyrrhizin, in terms of reducing infarct volume and improving neurological defi cits. Together these results indicate that SNMC, a glycyrrhizin-containing preparation developed for chronic liver disease, has a marked neuroprotective function in the postischemic brain via its anti-inflammatory effects.

Keywords

References

  1. Lipton P. Ischemic cell death in brain neurons. Physiol Rev 1999;79:1431-568. https://doi.org/10.1152/physrev.1999.79.4.1431
  2. Graham SH, Chen J. Programmed cell death in cerebral ischemia. J Cereb Blood Flow Metab 2001;21:99-109. https://doi.org/10.1097/00004647-200102000-00001
  3. Kirino T. Delayed neuronal death in the gerbil hippocampus following ischemia. Brain Res 1982;239:57-69. https://doi.org/10.1016/0006-8993(82)90833-2
  4. Michaelis M, Geiler J, Naczk P, Sithisarn P, Leutz A, Doerr HW, Cinatl J Jr. Glycyrrhizin exerts antioxidative effects in H5N1 influenza A virus-infected cells and inhibits virus replication and pro-inflammatory gene expression. PLoS One 2011;6:e19705. https://doi.org/10.1371/journal.pone.0019705
  5. Orlent H, Hansen BE, Willems M, Brouwer JT, Huber R, Kullak- Ublick GA, Gerken G, Zeuzem S, Nevens F, Tielemans WC, Zondervan PE, Lagging M, Westin J, Schalm SW. Biochemical and histological effects of 26 weeks of glycyrrhizin treatment in chronic hepatitis C: a randomized phase II trial. J Hepatol 2006;45:539-46. https://doi.org/10.1016/j.jhep.2006.05.015
  6. Arase Y, Ikeda K, Murashima N, Chayama K, Tsubota A, Koida I, Suzuki Y, Saitoh S, Kobayashi M, Kumada H. The long term efficacy of glycyrrhizin in chronic hepatitis C patients. Cancer 1997;79:1494-500. https://doi.org/10.1002/(SICI)1097-0142(19970415)79:8<1494::AID-CNCR8>3.0.CO;2-B
  7. Finney RS, Somers GF. The antiinflammatory activity of glycyrrhetinic acid and derivatives. J Pharm Pharmacol 1958;10:613-20. https://doi.org/10.1111/j.2042-7158.1958.tb10349.x
  8. Iino S, Tango T, Matsushima T, Toda G, Miyake K, Hino K, Kumada H, Yasuda K, Kuroki T, Hirayama C, Suzuki H. Therapeutic effects of stronger neo-minophagen C at different doses on chronic hepatitis and liver cirrhosis. Hepatol Res 2001;19:31-40. https://doi.org/10.1016/S1386-6346(00)00079-6
  9. Yoshida T, Abe K, Ikeda T, Matsushita T, Wake K, Sato T, Inoue H. Inhibitory effect of glycyrrhizin on lipopolysaccharide and d-galactosamine-induced mouse liver injury. Eur J Pharmacol 2007;576:136-42. https://doi.org/10.1016/j.ejphar.2007.08.012
  10. Nagai T, Egashira T, Kudo Y, Yamanaka Y, Shimada T. Attenuation of dysfunction in the ischemia-reperfused liver by glycyrrhizin. Jpn J Pharmacol 1992;58:209-18. https://doi.org/10.1254/jjp.58.209
  11. Kim YJ, Lee CS. Glycyrrhizin attenuates MPTP neurotoxicity in mouse and MPP-induced cell death in PC12 Cells. Korean J Physiol Pharmacol 2008;12:65-71. https://doi.org/10.4196/kjpp.2008.12.2.65
  12. Hwang IK, Lim SS, Choi KH, Yoo KY, Shin HK, Kim EJ, Yoon-Park JH, Kang TC, Kim YS, Kwon DY, Kim DW, Moon WK, Won MH. Neuroprotective effects of roasted licorice, not raw form, on neuronal injury in gerbil hippocampus after transient forebrain ischemia. Acta Pharmacol Sin 2006;27:959-65. https://doi.org/10.1111/j.1745-7254.2006.00346.x
  13. Kim JB, Sig Choi J, Yu YM, Nam K, Piao CS, Kim SW, Lee MH, Han PL, Park JS, Lee JK. HMGB1, a novel cytokine-like mediator linking acute neuronal death and delayed neuroinflammation in the postischemic brain. J Neurosci 2006;26:6413-21. https://doi.org/10.1523/JNEUROSCI.3815-05.2006
  14. Chen J, Sanberg PR, Li Y, Wang L, Lu M, Willing AE, Sanchez- Ramos J, Chopp M. Intravenous administration of human umbilical cord blood reduces behavioral deficits after stroke in rats. Stroke 2001;32:2682-8. https://doi.org/10.1161/hs1101.098367
  15. Lee JK, Hwang WS, Lee YD, Han PL. Dynamic expression of SEK1 suggests multiple roles of the gene during embryogenesis and in adult brain of mice. Brain Res Mol Brain Res 1999;66:133-40. https://doi.org/10.1016/S0169-328X(99)00035-2
  16. Imai Y, Ibata I, Ito D, Ohsawa K, Kohsaka S. A novel gene iba1 in the major histocompatibility complex class III region encoding an EF hand protein expressed in a monocytic lineage. Biochem Biophys Res Commun 1996;224:855-62. https://doi.org/10.1006/bbrc.1996.1112
  17. Lalancette-Hebert M, Gowing G, Simard A, Weng YC, Kriz J. Selective ablation of proliferating microglial cells exacerbates ischemic injury in the brain. J Neurosci 2007;27:2596-605. https://doi.org/10.1523/JNEUROSCI.5360-06.2007
  18. Kumada H. Long-term treatment of chronic hepatitis C with glycyrrhizin [stronger neo-minophagen C (SNMC)] for preventing liver cirrhosis and hepatocellular carcinoma. Oncology 2002;62 Suppl 1:94-100.
  19. Nakamura T, Fujii T, Ichihara A. Enzyme leakage due to change of membrane permeability of primary cultured rat hepatocytes treated with various hepatotoxins and its prevention by glycyrrhizin. Cell Biol Toxicol 1985;1:285-95. https://doi.org/10.1007/BF00118193
  20. Shiki Y, Shirai K, Saito Y, Yoshida S, Mori Y, Wakashin M. Effect of glycyrrhizin on lysis of hepatocyte membranes induced by anti-liver cell membrane antibody. J Gastroenterol Hepatol 1992;7:12-6. https://doi.org/10.1111/j.1440-1746.1992.tb00927.x
  21. Park HY, Park SH, Yoon HK, Han MJ, Kim DH. Anti-allergic activity of 18beta-glycyrrhetinic acid-3-O-beta-D-glucuronide. Arch Pharm Res 2004;27:57-60. https://doi.org/10.1007/BF02980047
  22. Shibata S. A drug over the millennia: pharmacognosy, chemistry, and pharmacology of licorice. Yakugaku Zasshi 2000;120:849-62. https://doi.org/10.1248/yakushi1947.120.10_849
  23. Ohtsuki K, Abe Y, Shimoyama Y, Furuya T, Munakata H, Takasaki C. Separation of phospholipase A2 in Habu snake venom by glycyrrhizin (GL)-affinity column chromatography and identification of a GL-sensitive enzyme. Biol Pharm Bull 1998;21:574-8. https://doi.org/10.1248/bpb.21.574
  24. Kimura M, Inoue H, Hirabayashi K, Natsume H, Ogihara M. Glycyrrhizin and some analogues induce growth of primary cultured adult rat hepatocytes via epidermal growth factor receptors. Eur J Pharmacol 2001;431:151-61. https://doi.org/10.1016/S0014-2999(01)01424-8
  25. Yokozawa T, Liu ZW, Chen CP. Protective eff ects of Glycyrrhizae radix extract and its compounds in a renal hypoxia (ischemia)- reoxygenation (reperfusion) model. Phytomedicine 2000;6:439-45. https://doi.org/10.1016/S0944-7113(00)80072-0
  26. Monder C, Stewart PM, Lakshmi V, Valentino R, Burt D, Edwards CR. Licorice inhibits corticosteroid 11 beta-dehydrogenase of rat kidney and liver: in vivo and in vitro studies. Endocrinology 1989;125:1046-53. https://doi.org/10.1210/endo-125-2-1046
  27. Cherng JM, Lin HJ, Hung MS, Lin YR, Chan MH, Lin JC. Inhibition of nuclear factor kappaB is associated with neuroprotective effects of glycyrrhizic acid on glutamate-induced excitotoxicity in primary neurons. Eur J Pharmacol 2006;547:10-21. https://doi.org/10.1016/j.ejphar.2006.06.080
  28. Mollica L, De Marchis F, Spitaleri A, Dallacosta C, Pennacchini D, Zamai M, Agresti A, Trisciuoglio L, Musco G, Bianchi ME. Glycyrrhizin binds to high-mobility group box 1 protein and inhibits its cytokine activities. Chem Biol 2007;14:431-41. https://doi.org/10.1016/j.chembiol.2007.03.007
  29. Bianchi ME, Manfredi AA. High-mobility group box 1 (HMGB1) protein at the crossroads between innate and adaptive immunity. Immunol Rev 2007;220:35-46. https://doi.org/10.1111/j.1600-065X.2007.00574.x
  30. Qiu J, Nishimura M, Wang Y, Sims JR, Qiu S, Savitz SI, Salomone S, Moskowitz MA. Early release of HMGB-1 from neurons after the onset of brain ischemia. J Cereb Blood Flow Metab 2008;28:927-38. https://doi.org/10.1038/sj.jcbfm.9600582
  31. Ohnishi M, Katsuki H, Fukutomi C, Takahashi M, Motomura M, Fukunaga M, Matsuoka Y, Isohama Y, Izumi Y, Kume T, Inoue A, Akaike A. HMGB1 inhibitor glycyrrhizin attenuates intracerebral hemorrhage-induced injury in rats. Neuropharmacology 2011;61:975-80. https://doi.org/10.1016/j.neuropharm.2011.06.026
  32. Ogiku M, Kono H, Hara M, Tsuchiya M, Fujii H. Glycyrrhizin prevents liver injury by inhibition of high-mobility group box 1 production by Kupffer cells after ischemia-reperfusion in rats. J Pharmacol Exp Ther 2011;339:93-8. https://doi.org/10.1124/jpet.111.182592
  33. Kim SW, Jin YC, Shin JH, Kim ID, Park S, Han PL, Lee JK. Glycyrrhizic acid affords robust neuroprotection in the postischemic brain via anti-inflammatory effect by inhibiting HMGB1 phosphorylation and secretion. Neurobiol Dis (in press).
  34. Sakata M, Kawaguchi T, Taniguchi E, Abe M, Koga H, Sata M. Quick and simple method for increasing the reduced albumin fraction in human serum albumin preparations by using stronger neo-minophagen C. Hepatol Res 2011;41:1120-5. https://doi.org/10.1111/j.1872-034X.2011.00863.x

Cited by

  1. Blood-brain barrier permeability of Gualou Guizhi granules and neuroprotective effects in ischemia/reperfusion injury vol.12, pp.1, 2015, https://doi.org/10.3892/mmr.2015.3520
  2. Anti-Inflammation of Natural Components from Medicinal Plants at Low Concentrations in Brain via Inhibiting Neutrophil Infiltration after Stroke vol.2016, pp.None, 2011, https://doi.org/10.1155/2016/9537901
  3. Glycyrrhizin Ameliorate Ischemia Reperfusion Lung Injury through Downregulate TLR2 Signaling Cascade in Alveolar Macrophages vol.8, pp.None, 2011, https://doi.org/10.3389/fphar.2017.00389
  4. Preclinical Evidence for the Pharmacological Actions of Glycyrrhizic Acid: A Comprehensive Review vol.21, pp.None, 2011, https://doi.org/10.2174/1389200221666200620204914