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

Tingting Qin; Ziqiao Yuan; Jiayu Yu; Xinxin Fu; Xueyang Deng; Qiang Fu; Zhanqiang Ma; Shiping Ma

doi:10.1002/ctm2.243

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

Clin Transl Med. 2020 Dec;10(8):e243. doi: 10.1002/ctm2.243.

Authors

Tingting Qin¹, Ziqiao Yuan², Jiayu Yu¹, Xinxin Fu¹, Xueyang Deng¹, Qiang Fu¹, Zhanqiang Ma¹, Shiping Ma^{1

3}

Affiliations

¹ Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, Nanjing, China.
² Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, China.
³ Qinba Traditional Chinese Medicine Resources Research and Development Center, AnKang University, Ankang, China.

Abstract

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)/p75^NTR -associated cell death executor (NADE) cell signaling activated by the p75 neurotrophin receptor (p75^NTR ). Mechanistic studies showed that a short hairpin RNA targeting p75^NTR 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/p75^NTR 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/p75^NTR 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.

Keywords: TrkB; neurogenesis; neurotoxicity; p75NTR; saikosaponin-d.

Abstract

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