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  • 1 Nanjing University of Chinese Medicine College of Pharmacy Nanjing PR China
  • 2 Nanjing University of Chinese Medicine College of Pharmacy 282 Hanzhong Road Nanjing 210029 PR China
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Berberine, a primary pharmacological active constitute of Coptidis Rhizoma, could inhibit neuronal apoptosis in cerebral ischemia. Here, we aimed to investigate whether and how HIF-1 is implicated in the anti-apoptosis effect of berberine on neurons under hypoxia/ischemia. Viability of PC12 cells treated with berberine prior to or following CoCl2-induced hypoxia was evaluated. Annexin V-PI staining was employed to analyse cell apoptosis ratio. HIF-1α and apoptosis-associated molecules were detected via Western blotting. TUNEL and immunohistochemistry were used to demonstrate apoptosis, HIF-1α and p53 levels in cerebral tissue of middle cerebral artery occlusion (MCAO) rats. Berberine pretreatment promoted PC12 cells survival and inhibited apoptosis under hypoxia condition. At the same time, it decreased cell viability and enhancement of apoptosis were observed with berberine treatment under hypoxia. Decreased HIF-1α, caspase 9, caspase 3 and increased Bcl-2/Bax ratio were responsible for the anti-apoptosis of berberine pretreatment. However, pro-apoptosis by berberine under hypoxia was indicated with opposing regulation of those molecules. Significant reduction of apoptosis, HIF-1α and p53 were found in cerebral tissue of MCAO rats treated with berberine. The present study suggests that berberine regulates neuronal apoptosis in cerebral ischemia, which might be dependent on the degree of cell injury. HIF-1 and the followed apoptotic pathway are involved in those effects of berberine.

  • Ardyanto TD, Osaki M, Tokuyasu N, Nagahama Y, Ito H: CoCl2-induced HIF-1alpha expression correlates with proliferation and apoptosis in MKN-1 cells: a possible role for the PI3K/Akt pathway. Int. J. Oncol. 29, 549–555 (2006)

    Ito H. , 'CoCl2-induced HIF-1alpha expression correlates with proliferation and apoptosis in MKN-1 cells: a possible role for the PI3K/Akt pathway ' (2006 ) 29 Int. J. Oncol. : 549 -555.

    • Search Google Scholar
  • Barone FC: Ischemic stroke intervention requires mixed cellular protection of the penumbra. Curr. Opin. Investig. Drugs 10, 220–223 (2009)

    Barone F.C. , 'Ischemic stroke intervention requires mixed cellular protection of the penumbra ' (2009 ) 10 Curr. Opin. Investig. Drugs : 220 -223.

    • Search Google Scholar
  • Boyd JM, Malstrom S, Subramanian T, Venkatesh LK, Schaeper U, Elangovan B, D’sa-Eipper C, Chinnadurai G: Adenovirus E1B 19 kDa and Bcl-2 proteins interact with a common set of cellular proteins. Cell 79, 341–351 (1994)

    Chinnadurai G. , 'Adenovirus E1B 19 kDa and Bcl-2 proteins interact with a common set of cellular proteins ' (1994 ) 79 Cell : 341 -351.

    • Search Google Scholar
  • Carrera E, Jones PS, Iglesias S, Guadagno JV, Warburton EA, Fryer TD, Aigbirhio FI, Baron JC: The vascular mean transit time: a surrogate for the penumbra flow threshold? J. Cereb. Blood Flow Metab. 31, 1027–1035 (2011)

    Baron J.C. , 'The vascular mean transit time: a surrogate for the penumbra flow threshold? ' (2011 ) 31 J. Cereb. Blood Flow Metab. : 1027 -1035.

    • Search Google Scholar
  • Chavez A, Miranda LF, Pichiule P, Chavez JC: Mitochondria and hypoxia-induced gene expression mediated by hypoxia-inducible factors. Ann. NY Acad. Sci. 1147, 312–320 (2008)

    Chavez J.C. , 'Mitochondria and hypoxia-induced gene expression mediated by hypoxia-inducible factors ' (2008 ) 1147 Ann. NY Acad. Sci. : 312 -320.

    • Search Google Scholar
  • Chen D, Li M, Luo J, Gu W: Direct interactions between HIF-1 alpha and Mdm2 modulate p53 function. J. Biol. Chem. 278, 13595–13598 (2003)

    Gu W. , 'Direct interactions between HIF-1 alpha and Mdm2 modulate p53 function ' (2003 ) 278 J. Biol. Chem. : 13595 -13598.

    • Search Google Scholar
  • Chen W, Jadhav V, Tang J, Zhang JH: HIF-1 alpha inhibition ameliorates neonatal brain damage after hypoxic-ischemic injury. Acta Neurochir. Suppl. 102, 395–399 (2008)

    Zhang J.H. , 'HIF-1 alpha inhibition ameliorates neonatal brain damage after hypoxic-ischemic injury ' (2008 ) 102 Acta Neurochir. Suppl. : 395 -399.

    • Search Google Scholar
  • Chen W, Ostrowski RP, Obenaus A, Zhang JH: Prodeath or prosurvival: two facets of hypoxia inducible factor-1 in perinatal brain injury. Exp. Neurol. 216, 7–15 (2009)

    Zhang J.H. , 'Prodeath or prosurvival: two facets of hypoxia inducible factor-1 in perinatal brain injury ' (2009 ) 216 Exp. Neurol. : 7 -15.

    • Search Google Scholar
  • Gulfraz M, Mehmood S, Ahmad A, Fatima N, Praveen Z, Williamson EM: Comparison of the antidiabetic activity of Berberis lyceum root extract and berberine in alloxan-induced diabetic rats. Phytother. Res. 22, 1208–1212 (2008)

    Williamson E.M. , 'Comparison of the antidiabetic activity of Berberis lyceum root extract and berberine in alloxan-induced diabetic rats ' (2008 ) 22 Phytother. Res. : 1208 -1212.

    • Search Google Scholar
  • Hayashi K, Minoda K, Nagaoka Y, Hayashi T, Uesato S: Antiviral activity of berberine and related compounds against human cytomegalovirus. Bioorg. Med. Chem. Lett. 17, 1562–1564 (2007)

    Uesato S. , 'Antiviral activity of berberine and related compounds against human cytomegalovirus ' (2007 ) 17 Bioorg. Med. Chem. Lett. : 1562 -1564.

    • Search Google Scholar
  • Huded V, Saraf R, Limaye U: Mechanical device the Penumbra system in the management of acute stroke: Report of five cases. Neurol. India 57, 310–312 (2009)

    Limaye U. , 'Mechanical device the Penumbra system in the management of acute stroke: Report of five cases ' (2009 ) 57 Neurol. India : 310 -312.

    • Search Google Scholar
  • Jung JY, Roh KH, Jeong YJ, Kim SH, Lee EJ, Kim MS, Oh WM, Oh HK, Kim WJ: Estradiol protects PC12 cells against CoCl2-induced apoptosis. Brain Res. Bull. 76, 579–585 (2008)

    Kim W.J. , 'Estradiol protects PC12 cells against CoCl2-induced apoptosis ' (2008 ) 76 Brain Res. Bull. : 579 -585.

    • Search Google Scholar
  • Kaelin WG: The von Hippel-Lindau tumour suppressor protein: O2 sensing and cancer. Nat. Rev. Cancer 8, 865–873 (2008)

    Kaelin W.G. , 'The von Hippel-Lindau tumour suppressor protein: O2 sensing and cancer ' (2008 ) 8 Nat. Rev. Cancer : 865 -873.

    • Search Google Scholar
  • Kaelin WG, Ratcliffe PJ: Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway. Mol. Cell 30, 393–402 (2008)

    Ratcliffe P.J. , 'Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway ' (2008 ) 30 Mol. Cell : 393 -402.

    • Search Google Scholar
  • Katiyar SK, Meeran SM, Katiyar N, Akhtar S: p53 cooperates berberine-induced growth inhibition and apoptosis of non-small cell human lung cancer cells in vitro and tumor xenograft growth in vivo. Mol. Carcinog. 48, 24–37 (2009)

    Akhtar S. , 'p53 cooperates berberine-induced growth inhibition and apoptosis of non-small cell human lung cancer cells in vitro and tumor xenograft growth in vivo ' (2009 ) 48 Mol. Carcinog. : 24 -37.

    • Search Google Scholar
  • Kim TS, Kang BY, Cho D, Kim SH: Induction of interleukin-12 production in mouse macrophages by berberine, a benzodioxoloquinolizine alkaloid, deviates CD4+ T cells from a Th2 to a Th1 response. Immunology 109, 407–414 (2003)

    Kim S.H. , 'Induction of interleukin-12 production in mouse macrophages by berberine, a benzodioxoloquinolizine alkaloid, deviates CD4+ T cells from a Th2 to a Th1 response ' (2003 ) 109 Immunology : 407 -414.

    • Search Google Scholar
  • Kothari S, Cizeau J, McMillan-Ward E, Israels SJ, Bailes M, Ens K, Kirshenbaum LA, Gibson SB: BNIP3 plays a role in hypoxic cell death in human epithelial cells that is inhibited by growth factors EGF and IGF. Oncogene 22, 4734–4744 (2003)

    Gibson S.B. , 'BNIP3 plays a role in hypoxic cell death in human epithelial cells that is inhibited by growth factors EGF and IGF ' (2003 ) 22 Oncogene : 4734 -4744.

    • Search Google Scholar
  • Kulkarni SK, Dhir A: Berberine: a plant alkaloid with therapeutic potential for central nervous system disorders. Phytother. Res. 24, 317–324 (2010)

    Dhir A. , 'Berberine: a plant alkaloid with therapeutic potential for central nervous system disorders ' (2010 ) 24 Phytother. Res. : 317 -324.

    • Search Google Scholar
  • Kumar G, Goyal MK, Sahota PK, Jain R: Penumbra, the basis of neuroimaging in acute stroke treatment: current evidence. J. Neurol. Sci. 288, 13–24 (2010)

    Jain R. , 'Penumbra, the basis of neuroimaging in acute stroke treatment: current evidence ' (2010 ) 288 J. Neurol. Sci. : 13 -24.

    • Search Google Scholar
  • Leonardo CC, Hall AA, Collier LA, Green SM, Willing AE, Pennypacker KR: Administration of a sigma receptor agonist delays MCAO-induced neurodegeneration and white matter injury. Transl. Stroke Res. 1, 135–145 (2010)

    Pennypacker K.R. , 'Administration of a sigma receptor agonist delays MCAO-induced neurodegeneration and white matter injury ' (2010 ) 1 Transl. Stroke Res. : 135 -145.

    • Search Google Scholar
  • Lin S, Tsai SC, Lee CC, Wang BW, Liou JY, Shyu KG: Berberine inhibits HIF-1alpha expression via enhanced proteolysis. Mol. Pharmacol. 66, 612–619 (2004)

    Shyu K.G. , 'Berberine inhibits HIF-1alpha expression via enhanced proteolysis ' (2004 ) 66 Mol. Pharmacol. : 612 -619.

    • Search Google Scholar
  • Schmid T, Zhou J, Brune B: HIF-1 and p53: communication of transcription factors under hypoxia. J. Cell Mol. Med. 8, 423–431 (2004)

    Brune B. , 'HIF-1 and p53: communication of transcription factors under hypoxia ' (2004 ) 8 J. Cell Mol. Med. : 423 -431.

    • Search Google Scholar
  • Taylor CT: Mitochondria and cellular oxygen sensing in the HIF pathway. Biochem. J. 409, 19–26 (2008)

    Taylor C.T. , 'Mitochondria and cellular oxygen sensing in the HIF pathway ' (2008 ) 409 Biochem. J. : 19 -26.

    • Search Google Scholar
  • Tokunaga E, Kimura Y, Oki E, Ueda N, Futatsugi M, Mashino K, Yamamoto M, Ikebe M, Kakeji Y, Baba H, Maehara Y: Akt is frequently activated in HER2/neu-positive breast cancers and associated with poor prognosis among hormone-treated patients. Int. J. Cancer 118, 284–289 (2006)

    Maehara Y. , 'Akt is frequently activated in HER2/neu-positive breast cancers and associated with poor prognosis among hormone-treated patients ' (2006 ) 118 Int. J. Cancer : 284 -289.

    • Search Google Scholar
  • Van Hoecke M, Prigent-Tessier AS, Garnier PE, Bertrand NM, Filomenko R, Bettaieb A, Marie C, Beley AG: Evidence of HIF-1 functional binding activity to caspase-3 promoter after photothrombotic cerebral ischemia. Mol. Cell Neurosci. 34, 40–47 (2007)

    Beley A.G. , 'Evidence of HIF-1 functional binding activity to caspase-3 promoter after photothrombotic cerebral ischemia ' (2007 ) 34 Mol. Cell Neurosci. : 40 -47.

    • Search Google Scholar
  • Wang F, Zhao G, Cheng L, Zhou HY, Fu LY, Yao WX: Effects of berberine on potassium currents in acutely isolated CA1 pyramidal neurons of rat hippocampus. Brain Res. 999, 91–97 (2004)

    Yao W.X. , 'Effects of berberine on potassium currents in acutely isolated CA1 pyramidal neurons of rat hippocampus ' (2004 ) 999 Brain Res. : 91 -97.

    • Search Google Scholar
  • Wu JF, Liu TP: Effects of berberine on platelet aggregation and plasma levels of TXB2 and 6-keto-PGF1 alpha in rats with reversible middle cerebral artery occlusion. Yao Xue Xue Bao. 30, 98–102 (1995)

    Liu T.P. , 'Effects of berberine on platelet aggregation and plasma levels of TXB2 and 6-keto-PGF1 alpha in rats with reversible middle cerebral artery occlusion ' (1995 ) 30 Yao Xue Xue Bao : 98 -102.

    • Search Google Scholar
  • Xu MG, Wang JM, Chen L, Wang Y, Yang Z, Tao J: Berberine-induced mobilization of circulating endothelial progenitor cells improves human small artery elasticity. J. Hum. Hypertens. 22, 389–393 (2008)

    Tao J. , 'Berberine-induced mobilization of circulating endothelial progenitor cells improves human small artery elasticity ' (2008 ) 22 J. Hum. Hypertens. : 389 -393.

    • Search Google Scholar
  • Yao H: Evolution of the ischemic penumbra in stroke-prone spontaneously hypertensive rats. Stroke 41, e197 (2010)

    Yao H. , 'Evolution of the ischemic penumbra in stroke-prone spontaneously hypertensive rats ' (2010 ) 41 Stroke : e197 -.

    • Search Google Scholar
  • Ye M, Fu S, Pi R, He F: Neuropharmacological and pharmacokinetic properties of berberine: a review of recent research. J. Pharm. Pharmacol. 61, 831–837 (2009)

    He F. , 'Neuropharmacological and pharmacokinetic properties of berberine: a review of recent research ' (2009 ) 61 J. Pharm. Pharmacol. : 831 -837.

    • Search Google Scholar
  • Yoo KY, Hwang IK, Kim JD, Kang IJ, Park J, Yi JS, Kim JK et al.: Antiinflammatory effect of the ethanol extract of Berberis koreana in a gerbil model of cerebral ischemia/reperfusion. Phytother. Res. 22, 1527–1532 (2008)

    Kim J.K. , 'Antiinflammatory effect of the ethanol extract of Berberis koreana in a gerbil model of cerebral ischemia/reperfusion ' (2008 ) 22 Phytother. Res. : 1527 -1532.

    • Search Google Scholar
  • Yoo KY, Hwang IK, Lim BO, Kang TC, Kim DW, Kim SM, Lee HY et al.: Berberry extract reduces neuronal damage and N-Methyl-D-aspartate receptor 1 immunoreactivity in the gerbil hippocampus after transient forebrain ischemia. Biol. Pharm. Bull. 29, 623–628 (2006)

    Lee H.Y. , 'Berberry extract reduces neuronal damage and N-Methyl-D-aspartate receptor 1 immunoreactivity in the gerbil hippocampus after transient forebrain ischemia ' (2006 ) 29 Biol. Pharm. Bull. : 623 -628.

    • Search Google Scholar
  • Zhou XQ, Zeng XN, Kong H, Sun XL: Neuroprotective effects of berberine on stroke models in vitro and in vivo. Neurosci. Lett. 447, 31–36 (2008)

    Sun X.L. , 'Neuroprotective effects of berberine on stroke models in vitro and in vivo ' (2008 ) 447 Neurosci. Lett. : 31 -36.

    • Search Google Scholar