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.