Shogaol but not gingerol has a neuroprotective effect on hemorrhagic brain injury: Contribution of the α, ß-unsaturated carbonyl to heme oxygenase-1 expression.

We investigated the effects of shogaol, which has an α, ß-unsaturated carbonyl group, and gingerol, which does not, on primary-cultured microglia to understand how the α, ß-unsaturated carbonyl interacts with Kelch-like ECH-associated protein (Keap)1. Shogaol (1 µM) but not the same concentration of gingerol significantly increased heme oxygenase (HO)-1 protein levels in cultured microglia without cytotoxicity. In addition, shogaol suppressed the release of the inflammation marker nitric oxide induced by 30 U/ml thrombin treatment. A docking simulation suggested that the α, ß-unsaturated carbonyl of shogaol but not gingerol interacts with Keap1. Nuclear import of nuclear factor E2-related factor 2 and increased binding of the HO-1 E2 enhancer support the docking-simulation prediction. The transcription inhibitor actinomycin D (0.1 µg/ml) markedly blocked the increase of HO-1 mRNA levels by shogaol. To evaluate whether the α, ß-unsaturated carbonyl can be used for intracerebral hemorrhage (ICH) therapy, we investigated the effect of shogaol on an in vivo mouse ICH model. Intracerebroventricular injection of 0.2 nmol shogaol increased striatal HO-1 protein levels and rescued ICH-induced neuron loss. Thus, the α, ß-unsaturated carbonyl is necessary for the interaction of compounds, such as shogaol, with Keap1, and these findings may be useful for screening novel ICH therapeutic agents that increase HO-1 expression.