Sulforaphane epigenetically enhances neuronal BDNF expression and TrkB signaling pathways

Scope Brain‐derived neurotrophic factor (BDNF) is a neurotrophin that supports the survival of existing neurons and encourages the growth and differentiation of new neurons and synapses. We investigated the effect of sulforaphane, a hydrolysis product of glucoraphanin present in Brassica vegetables, on neuronal BDNF expression and its synaptic signaling pathways. Methods and results Mouse primary cortical neurons and a triple‐transgenic mouse model of Alzheimer's disease (3 × Tg‐AD) were used to study the effect of sulforaphane. Sulforaphane enhanced neuronal BDNF expression and increased levels of neuronal and synaptic molecules such as MAP2, synaptophysin, and PSD‐95 in primary cortical neurons and 3 × Tg‐AD mice. Sulforaphane elevated levels of synaptic TrkB signaling pathway components, including CREB, CaMKII, ERK, and Akt in both primary cortical neurons and 3 × Tg‐AD mice. Sulforaphane increased global acetylation of histone 3 (H3) and H4, inhibited HDAC activity, and decreased the level of HDAC2 in primary cortical neurons. Chromatin immunoprecipitation analysis revealed that sulforaphane increased acetylated H3 and H4 at BDNF promoters, suggesting that sulforaphane regulates BDNF expression via HDAC inhibition. Conclusion These findings suggest that sulforaphane has the potential to prevent neuronal disorders such as Alzheimer's disease by epigenetically enhancing neuronal BDNF expression and its TrkB signaling pathways. Proposed model for sulforaphane‐mediated epigenetic increase in neuronal BDNF expression and regulation of neurotrophic TrkB pathways. Sulforaphane inhibits HDAC activity and increases histone‐tail acetylation, thereby increasing BDNF levels and enhancing activation of BDNF‐TrkB signaling pathways. As a consequence, ERK facilitates neuronal differentiation and growth, Akt promotes survival of neurons, and CaMKII and CREB induce synaptic plasticity and LTP. Thus, an epigenetically increased level of BDNF may be responsible, at least in part, for the ability of sulforaphane to enhance neuronal and cognitive functions in BDNF‐deficient neuronal disorders such as Alzheimer's disease.