This experimental paper below connects depression to iron overload in the hippocampus. IMO, it would be fascinating to see if a safe, almost "physiological" iron chelator ATH434 ( in stead of deferoxamine used in this paper) could work in treating depression.Nrf2 regulates iron-dependent hippocampal synapses and functional connectivity damage in depression
Ting Zeng # 1 2, Junjie Li # 1, Lingpeng Xie # 3, Zhaoyang Dong 4, Qing Chen 1, Sha Huang 1, Shuwen Xie 1, Yuqi Lai 1, Jun Li 1, Weixin Yan 5, YuHua Wang 1, Zeping Xie 1, Changlei Hu 1, Jiayi Zhang 1, Shanshan Kuang 1, Yuhong Song 6, Lei Gao 7, Zhiping Lv 8AffiliationsPMCID: PMC10512501 DOI: 10.1186/s12974-023-02875-x
- PMID: 37735410
Abstract
Neuronal iron overload contributes to synaptic damage and neuropsychiatric disorders. However, the molecular mechanisms underlying iron deposition in depression remain largely unexplored. Our study aims to investigate how nuclear factor-erythroid 2 (NF-E2)-related factor 2 (Nrf2) ameliorates hippocampal synaptic dysfunction and reduces brain functional connectivity (FC) associated with excessive iron in depression. We treated mice with chronic unpredictable mild stress (CUMS) with the iron chelator deferoxamine mesylate (DFOM) and a high-iron diet (2.5% carbonyl iron) to examine the role of iron overload in synaptic plasticity. The involvement of Nrf2 in iron metabolism and brain function was assessed using molecular biological techniques and in vivo resting-state functional magnetic resonance imaging (rs-fMRI) through genetic deletion or pharmacologic activation of Nrf2. The results demonstrated a significant correlation between elevated serum iron levels and impaired hippocampal functional connectivity (FC), which contributed to the development of depression-induced CUMS. Iron overload plays a crucial role in CUMS-induced depression and synaptic dysfunction, as evidenced by the therapeutic effects of a high-iron diet and DFOM. The observed iron overload in this study was associated with decreased Nrf2 levels and increased expression of transferrin receptors (TfR). Notably, inhibition of iron accumulation effectively attenuated CUMS-induced synaptic damage mediated by downregulation of brain-derived neurotrophic factor (BDNF). Nrf2-/- mice exhibited compromised FC within the limbic system and the basal ganglia, particularly in the hippocampus, and inhibition of iron accumulation effectively attenuated CUMS-induced synaptic damage mediated by downregulation of brain-derived neurotrophic factor (BDNF). Activation of Nrf2 restored iron homeostasis and reversed vulnerability to depression. Mechanistically, we further identified that Nrf2 deletion promoted iron overload via upregulation of TfR and downregulation of ferritin light chain (FtL), leading to BDNF-mediated synapse damage in the hippocampus. Therefore, our findings unveil a novel role for Nrf2 in regulating iron homeostasis while providing mechanistic insights into poststress susceptibility to depression. Targeting Nrf2-mediated iron metabolism may offer promising strategies for developing more effective antidepressant therapies.
https://jneuroinflammation.biomedcentral.com/articles/10.1186/s12974-023-02875-x
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