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Neuroprotective effect of deferoxamine on erastininduced ferroptosis in primary cortical neurons.

ABSTRACT: The iron chelator deferoxamine has been shown to inhibit ferroptosis in spinal cord injury. However, it is unclear whether deferoxamine directly protects neurons from ferroptotic cell death. By comparing the survival rate and morphology of primary neurons and SH-SY5Y cells exposed to erastin, it was found that these cell types respond differentially to the duration and concentration of erastin treatment. Therefore, we studied the mechanisms of ferroptosis using primary cortical neurons from E16 mouse embryos. After treatment with 50 ?M erastin for 48 hours, reactive oxygen species levels increased, and the expression of the cystine/glutamate antiporter system light chain and glutathione peroxidase 4 decreased. Pretreatment with deferoxamine for 12 hours inhibited these changes, reduced cell death, and ameliorated cellular morphology. Pretreatment with the apoptosis inhibitor Z-DEVD-FMK or the necroptosis inhibitor necrostain-1 for 12 hours did not protect against erastin-induced ferroptosis. Only deferoxamine protected the primary cortical neurons from ferroptosis induced by erastin, confirming the specificity of the in vitro ferroptosis model. This study was approved by the Animal Ethics Committee at the Institute of Radiation Medicine of the Chinese Academy of Medical Sciences, China (approval No. DWLL-20180913) on September 13, 2018.

SUBMITTER: Zhang Y

PROVIDER: S-EPMC7059591 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Neuroprotective effect of deferoxamine on erastininduced ferroptosis in primary cortical neurons.

Zhang Yan Y Fan Bao-You BY Pang Yi-Lin YL Shen Wen-Yuan WY Wang Xu X Zhao Chen-Xi CX Li Wen-Xiang WX Liu Chang C Kong Xiao-Hong XH Ning Guang-Zhi GZ Feng Shi-Qing SQ Yao Xue X

Neural regeneration research 20200801 8

The iron chelator deferoxamine has been shown to inhibit ferroptosis in spinal cord injury. However, it is unclear whether deferoxamine directly protects neurons from ferroptotic cell death. By comparing the survival rate and morphology of primary neurons and SH-SY5Y cells exposed to erastin, it was found that these cell types respond differentially to the duration and concentration of erastin treatment. Therefore, we studied the mechanisms of ferroptosis using primary cortical neurons from E16 ...[more]

PMID: 31997820

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Project description:Background Transforming growth factor β1 (TGF-β1) has a neuroprotective function in traumatic brain injury (TBI) through its anti-inflammatory and immunomodulatory properties. In our previous study, we found that TGF-β1 played a critical role in inhibiting apoptosis and increasing neuronal activity in murine cortical neurons following trauma. However, the precise mechanisms underlying the neuroprotective actions of TGF-β1 on the cortex require further investigation. Methods Thus, in this study, we were aimed to investigate the regulatory function of TGF-β1 on neuronal autophagy and apoptosis using an in vitro primary cortical neuron trauma-injury model. Results To establish the landscape of differentially expressed genes (DEGs) with or without TGF-β1 (10ng/ml) treatment for 24 hours, we performed RNA-sequencing. We observed significant enrichment of DEGs related to autophagy, apoptosis, and the lysosome pathway in trauma-injured cortical neurons. Additionally, transmission electron microscopy (TEM) confirmed the presence of autophagosomes as well as autophagolysosomes. Western blot analysis revealed upregulation of autophagy-related protein light chain 3 (LC3)-Ⅱ/LC3-Ⅰ, sequestosome 1 (SQSTM1)/p62, along with apoptosis-related protein Cleaved-caspase3 in trauma-injured primary cortical neurons. Furthermore, mechanically injured neurons showed an upregulation of lysosomal marker protein lysosomal marker protein (LAMP1) and lysosomal enzyme mature cathepsin D (mCTSD), but a decrease in the activity of CTSD enzyme. These results indicated that apoptosis was up-regulated in mechanically injured neurons at 24 hours, accompanied by lysosomal dysfunction and impaired autophagic flux. Notably, TGF-β1 significantly reversed these changes. Conclusions Therefore, our findings suggested that TGF-β1 exerted neuroprotective effects on mechanically injured neurons by reducing lysosomal dysfunction, decreasing the accumulation of autophagosomes and autophagolysosomes, and enhancing autophagic flux.

Dataset Information

Neuroprotective effect of deferoxamine on erastininduced ferroptosis in primary cortical neurons.

Publications

Neuroprotective effect of deferoxamine on erastininduced ferroptosis in primary cortical neurons.

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