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Higenamine reduces HMGB1 during hypoxia-induced brain injury by induction of heme oxygenase-1 through PI3K/Akt/Nrf-2 signal pathways

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Abstract

Growing lines of evidence suggests that high mobility group box-1 (HMGB1) plays an important role for promoting inflammation and apoptosis in brain ischemia. Previously, we demonstrated that inducers of heme oxygenase-1 (HO-1) significantly reduce HMGB1 release in inflammatory conditions in vitro and in vivo. Thus, we tested our hypothesis that higenamine protects brain injury by inhibition of middle cerebral artery occlusion (MCAO)-mediated HMGB1 release in vivo, and glucose/glucose oxidase (GOX)-induced apoptosis in C6 cells in vitro due to HO-1 induction. Higenamine increased HO-1 expression in C6 cells in both hypoxia and normoxia, in which the former was much more significant than the latter. Higenamine increased Nrf-2 luciferase activity, translocated Nrf-2 to nucleus, and increased phosphorylation of Akt in C6 cells. Consistent with this, LY 294002, a PI3K inhibitor, inhibited HO-1 induction by higenamine and apoptosis induced by glucose/GOX in C6 cells was prevented by higenamine, which effect was reversed by LY 294002. Importantly, administration of higenamine (i.p) significantly reduced brain infarct size, mortality rate, MPO activity and tissue expression of HMGB1 in MCAO rats. In addition, recombinant high mobility group box 1 induced apoptosis in C6 cells by increasing ratio of Bax/bcl-2 and cleaved caspase c, which was inhibited by higenamine, and all of these effects were reversed by co-treatment with ZnPPIX. Therefore, we conclude that higenamine, at least in part, protects brain cells against hypoxic damages by up-regulation of HO-1. Thus, higenamine may be beneficial for the use of ischemic injuries such as stroke.

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Abbreviations

ARE:

Antioxidant response element

GFAP:

Glial fibrillary acidic protein

HMGB1:

High mobility group box-1

HO-1:

Heme oxygenase-1

I/R:

Ischemia and reperfusion

LPS:

Lipopolysaccharide

MCAO:

Middle cerebral artery occlusion

MPO:

Myeloperoxidase

Nrf2:

Nuclear factor erythroid 2-related factor

PCNA:

Proliferating cell nuclear antigen

PI3K:

Phosphoinositol-3-kinase

PKA:

Protein kinase A

ROS:

Reactive oxygen species

TUNEL:

Terminal deoxynucleotidyl transferase dUTP-mediated nicked end labeling

ZnppIX:

Zinc protoporphyrin IX

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Acknowledgment

This work was supported by grant from NRF (03-2010-0298) and MRC program from MOST/KOSEF (R13-2005-012-01003-0).

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There is no report to declare the conflict of interest.

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Authors and Affiliations

  1. Department of Pharmacology, School of Medicine, Institute of Health Sciences, Gyeongsang National University, Jinju, 660-290, Republic of Korea

    Yu Mi Ha, Min Young Kim, Min Kyu Park, Young Soo Lee, Young Min Kim, Hye Jung Kim, Jae Heun Lee & Ki Churl Chang

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  1. Yu Mi Ha
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  2. Min Young Kim
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  3. Min Kyu Park
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Correspondence to Ki Churl Chang.

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Yu Mi Ha and Min Young Kim have contributed equally to this work.

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Ha, Y.M., Kim, M.Y., Park, M.K. et al. Higenamine reduces HMGB1 during hypoxia-induced brain injury by induction of heme oxygenase-1 through PI3K/Akt/Nrf-2 signal pathways. Apoptosis 17, 463–474 (2012). https://doi.org/10.1007/s10495-011-0688-8

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