title: Smilagenin attenuates beta amyloid (25-35)-induced degeneration of neuronal cells via stimulating the gene expression of brain-derived neurotrophic factor.
abstract: 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.
authors.affiliation: Research Laboratory of Cell Regulation, Shanghai Jiaotong University School of Medicine, 280 South Chongqing Road, Shanghai 200025, China.
authors.forename: R
authors.initials: R
authors.lastname: Zhang
authors.forename: Z
authors.initials: Z
authors.lastname: Wang
authors.forename: P A
authors.initials: PA
authors.lastname: Howson
authors.forename: Z
authors.initials: Z
authors.lastname: Xia
authors.forename: S
authors.initials: S
authors.lastname: Zhou
authors.forename: E
authors.initials: E
authors.lastname: Wu
authors.forename: Z
authors.initials: Z
authors.lastname: Xia
authors.forename: Y
authors.initials: Y
authors.lastname: Hu
mesh_terms: D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000096:biosynthesis*; D002460:Cell Line; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D009410:Nerve Degeneration / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013150:Spirostans / Q000494:pharmacology*
chemical_list: D016229:Amyloid beta-Peptides; D019208:Brain-Derived Neurotrophic Factor; D013150:Spirostans; C046297:sarsasapogenin