Heptamethoxyflavone, a citrus flavonoid, enhances brain-derived neurotrophic factor production and neurogenesis in the hippocampus following cerebral global ischemia in mice

► HMF activated ERK1/2 and CREB phosphorylation in the hippocampus after ischemia. ► HMF increased BDNF synthesis in the hippocampus dentate gyrus. ► HMF increased doublecortin positive neuronal precursor cells in the dentate gyrus. ► HMF enhances BDNF production and neurogenesis in the cerebral ischemic brain. In the present study using a transient global ischemia mouse model, we showed that (1) a citrus flavonoid 3,5,6,7,8,3′,4′-heptamethoxyflavone (HMF) induced the phosphorylation of extracellular signal-regulated kinases 1/2 (ERK1/2) and cAMP response element-binding protein (CREB) in the hippocampus after ischemia; (2) HMF increased the expression of brain-derived neurotrophic factor (BDNF), a representative neurotrophic factor in the central nervous system, in the hippocampal dentate gyrus, and most BDNF-positive cells were also stained with anti-glial fibrillary acidic protein (one of the major intermediate filament proteins of mature astrocytes) and (3) HMF increased doublecortin positive neuronal precursor cells in the dentate gyrus subventricular zone or subgranular zone. These results suggest that HMF has the ability to induce BDNF production in astrocytes and enhance neurogenesis after brain ischemia, which may be mediated by activation of ERK1/2 and CREB.