Saikosaponin-d impedes hippocampal neurogenesis and causes cognitive deficits by inhibiting the survival of neural stem/progenitor cells via neurotrophin receptor signaling in mice.
Saikosaponin-d impedes hippocampal neurogenesis and causes cognitive deficits by inhibiting the survival of neural stem/progenitor cells via neurotrophin receptor signaling in mice.
复制标题
Saikosaponin-d 通过神经营养蛋白受体信号传导抑制小鼠神经干/祖细胞的存活，从而阻碍海马神经发生并导致认知缺陷。
DOI：
10.1002/ctm2.243
复制
发表时间：
2020-12
影响因子：
10.6
通讯作者：
Ma S
中科院分区：
文献类型：
--
作者：
Qin T;Yuan Z;Yu J;Fu X;Deng X;Fu Q;Ma Z;Ma S
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. Saikosaponin‐d induced cognitive dysfunction by inhibiting the survival of hippocampal neural stem/progenitor cells. This neural damage is through the activation of p75NTR cell death signaling and inhibition of TrkB signaling, engaged by disordered BDNF pathway dependent on the dysregulation of cellular calcium homeostasis. These results present a neurological base for saikosaponin‐d‐induced neurotoxicity and provide a better understanding of neurotoxic effects induced by the cytostatic drug.
登录
查看更多内容
影响因子：
3.7
作者：
Arellano, Jon I.;Harding, Brian;Thomas, Jean-Leon
通讯作者：
Thomas, Jean-Leon
影响因子：
5.3
作者：
Harrington, AW;Kim, JY;Yoon, SO
通讯作者：
Yoon, SO
影响因子：
5
作者：
Dennis CV;Suh LS;Rodriguez ML;Kril JJ;Sutherland GT
通讯作者：
Sutherland GT
影响因子：
25
作者：
Denise, A;Garcia, R;Sofroniew, MV
通讯作者：
Sofroniew, MV
DOI：
10.1073/pnas.91.14.6501
发表时间：
1994-07-05
影响因子：
11.1
作者：
BARRETT, GL;BARTLETT, PF
通讯作者：
BARTLETT, PF