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Saikosaponin‐d impedes hippocampal neurogenesis and causes cognitive deficits by inhibiting the survival of neural stem/progenitor cells via neurotrophin receptor signaling in mice

神经发生 神经干细胞 低亲和力神经生长因子受体 原肌球蛋白受体激酶B 神经营养素 神经营养因子 脑源性神经营养因子 细胞生物学 海马结构 祖细胞 神经科学 干细胞 生物 受体 生物化学
作者
Tingting Qin,Ziqiao Yuan,Jiayu Yu,Xinxin Fu,Xueyang Deng,Qiang Fu,Zhanqiang Ma,Qiang Fu
出处
期刊:Clinical and translational medicine [Wiley]
卷期号:10 (8) 被引量:12
标识
DOI:10.1002/ctm2.243
摘要

Neural stem/progenitor cells (NPCs) are multipotent stem cells in the central nervous system. Damage to NPCs has been demonstrated to cause adverse effects on neurogenesis and to contribute to neurological diseases. Our previous research suggested that saikosaponin-d (SSd), a cytostatic drug belonging to the bioactive triterpenoid saponins, exhibited neurotoxicity by inhibiting hippocampal neurogenesis, but the underlying mechanism remained elusive. This study was performed to clarify the role of SSd in cognitive function and the mechanism by which SSd induced damage to hippocampal neurogenesis and NPCs. Our results indicated that SSd caused hippocampus-dependent cognitive deficits and inhibited hippocampal neurogenesis by reducing the numbers of newborn neurons in mice. RNA sequencing analysis revealed that SSd-induced neurotoxicity in the hippocampus involved neurotrophin receptor-interacting MAGE (NRAGE)/neurotrophin receptor interacting factor (NRIF)/p75NTR-associated cell death executor (NADE) cell signaling activated by the p75 neurotrophin receptor (p75NTR). Mechanistic studies showed that a short hairpin RNA targeting p75NTR intracellular domain reversed SSd-increased NRAGE/NRIF/NADE signaling and the c-Jun N-terminal kinase/caspase apoptotic pathway, subsequently contributing to the survival of NPCs, as well as cell proliferation and differentiation. The addition of recombinant brain-derived neurotrophic factor (BDNF) ameliorated the SSd-induced inhibition of BDNF/Tyrosine kinase receptor B (TrkB) neurotrophic signaling, but did not affect SSd-activated pro-BDNF/p75NTR signaling. Moreover, the SSd-induced elevation of cytosolic Ca2+ concentration was responsible for damage to NPCs. The extracellular Ca2+ chelator ethylene glycol-bis(2-aminoethylether)-N,N,N',N'-tetraacetic acid (EGTA), rather than the intracellular Ca2+ chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid tetrakis(acetoxymethyl ester) (BAPTA/AM), attenuated SSd-induced cytosolic Ca2+ dysfunction and SSd-disordered TrkB/p75NTR signaling. Overall, this study demonstrated a new mechanism for the neurotoxic effect of SSd, which has emerging implications for pharmacological research of SSd and provides a better understanding of neurotoxicity induced by cytostatic drugs.
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