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. 2025 Feb 5:19:793-810.
doi: 10.2147/DDDT.S509208. eCollection 2025.

Asiaticoside Attenuates Chronic Restraint Stress-Induced Hippocampal CA1 Neuronal Ferroptosis via Activating BDNF/Nrf2/GPX4 Signaling Pathway

An Zhou  1   2   3 , Hao-Yinghua Feng  4 , Chu-Ning Fan  3 , Jun Wang  3 , Zhong-Yu Yuan  3 , Guang-Hui Xu  5 , Cheng-Fu Li  6 , Wei-Feng Huang  1 , Li-Tao Yi  3   7   8
Affiliations

Asiaticoside Attenuates Chronic Restraint Stress-Induced Hippocampal CA1 Neuronal Ferroptosis via Activating BDNF/Nrf2/GPX4 Signaling Pathway

An Zhou et al. Drug Des Devel Ther. .

Abstract

Purpose: Ferroptosis, characterized by iron-dependent lipid reactive oxygen species accumulation, plays a critical role in the pathophysiology of depression. Our research aims to elucidate the potential antidepressant mechanisms of asiaticoside, a bioactive compound known for its neuroprotective and immunomodulatory properties.

Methods: The antidepressant-like properties of asiaticoside in a model of chronic restraint stress (CRS)-induced depression in mice, with a particular focus on its interaction with ferroptosis-related pathways.

Results: The behavioral results revealed that asiaticoside significantly ameliorated CRS-induced depressive symptoms, as evidenced by increased sucrose preference and reduced immobility time. At the molecular level, asiaticoside enhanced the expression of brain-derived neurotrophic factor (BDNF), phosphorylated tropomyosin receptor kinase B (pTrkB), phosphorylated nuclear factor erythroid 2-related factor 2 (pNrf2), glutathione peroxidase 4 (GPX4), and solute carrier family 7 member 11 (SLC7A11), indicating its neuroprotective and antioxidative effects. In addition, asiaticoside suppressed the expression of ferroptosis markers, including ferritin light chain (FLC) and transferrin receptor only in CA1 region. Transmission electron microscopy (TEM) further confirmed that asiaticoside preserved mitochondrial integrity in CA1 neuronal cells.

Conclusion: In conclusion, our findings suggest that asiaticoside exerts its antidepressant-like effects through the modulation of BDNF/Nrf2/GPX4 signaling pathway against neuronal ferroptosis in the hippocampal CA1 region.

Keywords: BDNF; GPX4; Nrf2; antidepressant; asiaticoside; ferroptosis.

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Conflict of interest statement

The authors declare that there is no conflict of interest.

Figures

Figure 1
Figure 1
Administration with asiaticoside alleviated CRS-induced depression-like behaviors in mice (n=11). (A) Schematic illustration of the procedure for the experiment. (B) Sucrose preference, an anhedonia symptom was elevated by asiaticoside. (C) Immobility time, as despair symptom was decreased by asiaticoside. **P<0.01, *** P<0.001.
Figure 2
Figure 2
Administration with asiaticoside alleviated CRS-induced microglial activation in the hippocampus of mice (n=5). (A) Representative immunofluorescence images. (B) Statistical histogram of the number of microglia in the hippocampus DG region. (C) Statistical histogram of the number of microglia in the hippocampus CA1 region. (D) Statistical histogram of the number of microglia in the hippocampus CA3 region. *P<0.05.
Figure 3
Figure 3
Effects of asiaticoside on BDNF/TrkB signaling pathway in mice induced by CRS (n=5-6). (A) Representative Western Blot. (B) Statistical histogram of BDNF. (C) Statistical histogram of pTrkB. (D) Statistical histogram of TrkB. (E) Statistical histogram of ratio of pTrkB to TrkB. (F) Statistical histogram of Synaptophysin. (G) Statistical histogram of PSD95. *P<0.05 and ** P<0.01.
Figure 4
Figure 4
Asiaticoside treatment promoted hippocampus neurogenesis in mice induced by CRS (n=5). (A) Representative immunofluorescence images. (B) Statistical histogram of the number of newborn neurons. ** P<0.01.
Figure 5
Figure 5
Asiaticoside treatment improved microscopic morphology of hippocampal CA1 neurons in mice induced by CRS (n=6). (A) Representative diagram of the synaptic structure of neurons. (B) Statistical histogram of the number of synapses per unit area. (C) Statistical histogram of synaptic length of neurons. (D) Statistical column of synaptic gap width of neurons. ** P<0.01, ***P<0.001.
Figure 6
Figure 6
Effects of asiaticoside on Nrf2/GPX4 signaling pathway in mice induced by CRS (n=6). (A) Representative Western Blot. (B) Statistical histogram of pNrf2. (C) Statistical histogram of Nrf2. (D) Statistical histogram of ratio of pNrf2 to Nrf2. (E) Statistical histogram of GPX4. (F) Statistical histogram of SLC7A11. (G) Statistical histogram of HO-1. *P<0.05, **P<0.01.
Figure 7
Figure 7
Effects of asiaticoside on GPX4 expression in hippocampal DG, CA1 and CA3 regions of mice induced by CRS (n=5). (A) Representative immunofluorescence images in DG. (B) GPX4 relative intensity in DG. (C) Representative immunofluorescence images in CA1. (D) GPX4 relative intensity in CA1. (E) Representative immunofluorescence images in CA3. (F) GPX4 relative intensity in CA3. *P<0.05 and ** P<0.01.
Figure 8
Figure 8
Effects of asiaticoside on SLC7A11 expression in hippocampal DG, CA1 and CA3 regions of mice induced by CRS (n=5). (A) Representative immunofluorescence images in DG. (B) SLC7A11 relative intensity in DG. (C) Representative immunofluorescence images in CA1. (D) SLC7A11 relative intensity in CA1. (E) Representative immunofluorescence images in CA3. (F) SLC7A11 relative intensity in CA3. *P<0.05, ** P<0.01 and *** P<0.001.
Figure 9
Figure 9
Effects of asiaticoside on the iron related proteins in mice induced by CRS (n=5 or 6). (A) Western Blot representative graph and statistical histogram of FLC. (B) Western Blot representative graph and statistical histogram of Transferrin Receptor. (C) Representative immunofluorescence images of FLC in DG. (D) FLC relative intensity in DG. (E) Representative immunofluorescence images of FLC in CA1. (F) FLC relative intensity in CA1. (G) Representative immunofluorescence images of FLC in CA3. (H) FLC relative intensity in CA3. (I) Representative immunofluorescence images of transferrin receptor in DG. (J) Transferrin receptor relative intensity in DG. (K) Representative immunofluorescence images of transferrin receptor in CA1. (L) Transferrin receptor relative intensity in CA1. (M) Representative immunofluorescence images of transferrin receptor in CA3. (N) Transferrin receptor relative intensity in CA3. *P<0.05, **P<0.01.
Figure 10
Figure 10
Effects of asiaticoside on morphology and number of mitochondria hippocampal CA1 neurons in mice induced by CRS (n=6). (A) Mitochondrial transmission electron microscopy. (B) Local magnification of transmission electron microscopy. (C) Statistical histogram of the number of damaged mitochondria per unit area. (D) Statistical histogram of the number of total mitochondria per unit area. (E) Statistical histogram of the proportion of damaged mitochondria. * P<0.05.
Figure 11
Figure 11
The involvement of BDNF/TrkB/Nrf2/GPX4/SLC7A11 mediated ferroptosis signaling pathway in the antidepressant-like effects of asiaticoside.
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