Smilagenin attenuates beta amyloid (25-35)-induced degeneration of neuronal cells via stimulating the gene expression of brain-derived neurotrophic factor.

The development of drugs that attenuate neurodegeneration is important for the treatment of Alzheimer's disease (AD). We previously found that smilagenin (SMI), a steroidal sapogenin from traditional Chinese medicinal herbs improves memory in animal models, is neither a cholinesterase inhibitor nor a glutamate receptor antagonist, but can significantly elevate the declined muscarinic receptor (M receptor) density. In this article, to clarify whether SMI represents a new approach for treating neurodegeneration disease, we first demonstrate that SMI pretreatment significantly attenuates the neurodegenerative changes induced by beta amyloid 25-35 (Aβ(25-35)) in cultured rat cortical neurons, including decreased cholinergic neuron number, shortened neurite outgrowth length, and declined M receptor density. Brain-derived neurotrophic factor (BDNF) protein levels in the culture medium were also decreased by Aβ(25-35) and significantly elevated by SMI. Parallel experiments revealed that when the trk receptors were inhibited by K252a or the action of BDNF was inhibited by a neutralizing anti-BDNF antibody, the effects of SMI on the Aβ(25-35)-induced neurodegeneration in rat cortical neurons were almost completely abolished. In the all-trans retinoic acid (RA)-differentiated SH-SY5Y neuroblastoma cells, the BDNF transcription rate measured by a nuclear run-on assay was significantly suppressed by Aβ(25-35) and elevated by SMI, but the BDNF degradation rate measured by half-life determination was unchanged by Aβ(25-35) and SMI. Transcript analysis of the SH-SY5Y cells using quantitative RT-PCR (qRT-PCR) showed that the IV and VI transcripts of BDNF mRNA were significantly decreased by Aβ(25-35) and elevated by SMI. Taken together, we conclude that SMI attenuates Aβ(25-35)-induced neurodegeneration in cultured rat cortical neurons and SH-SY5Y cells mainly through stimulating BDNF mRNA transcription implicating that SMI may represent a novel therapeutic strategy for AD.