Ferrostatin-1 Alleviates White Matter Injury Via Decreasing Ferroptosis Following Spinal Cord Injury

Ge, Hongfei; Xue, Xingsen; Xian, Jishu; Yuan, Liqin; Wang, Long; Zou, Yongjie; Zhong, Jun; Jiang, Zhouyang; Shi, Jiandang; Chen, Tunan; Su, Hong; Feng, Hua; Hu, S. Jack

doi:10.1007/s12035-021-02571-y

Cited by 73 publications

(56 citation statements)

References 56 publications

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“…Ferroptosis has been previously reported a form of neuronal death in SCI. The pathogenesis of cell rupture, hemorrhaging, hemolysis, and supernumerary iron post SCI caused excess ROS accumulation, which results in ferroptosis occurrence ( Hu et al, 2021 ; Ge et al, 2022 ). Our results showed that ferroptosis-related protein GPX4, primarily expressed in neurons, significantly decreased while ACSL4 increased both in vitro and in vivo .…”

Section: Discussionmentioning

confidence: 99%

Growth Differentiation Factor 15 Regulates Oxidative Stress-Dependent Ferroptosis Post Spinal Cord Injury by Stabilizing the p62-Keap1-Nrf2 Signaling Pathway

Xia

Zhang

et al. 2022

Front. Aging Neurosci.

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BackgroundSpinal cord injury (SCI) is a severe traumatic disorder of the central nervous system (CNS) that causes irreversible damage to the nervous tissue. The consequent hemorrhage contributed by trauma induces neuronal ferroptosis post SCI, which is an important death mode to mediate neuronal loss. Growth differentiation factor 15 (GDF15) is a cytokine that regulates cell proliferation, differentiation, and death. However, the specific role of GDF15 in neuronal ferroptosis post SCI remains unknown.Materials and MethodsNeuronal ferroptosis in vitro was measured by detection of lipid peroxidation, glutathione, iron content, and reactive oxidative stress. In vivo, western blotting and immunofluorescence (IF) staining was utilized to measure ferroptosis post SCI. IF staining, TUNEL staining, hematoxylin-eosin staining, and Nissl staining were used to measure neurological damage. Finally, locomotor function recovery was analyzed using the Basso Mouse Scale and Louisville Swim Scale.ResultsGDF15 was significantly increased in neuronal ferroptosis and silencing GDF15 aggravated ferroptosis both in vitro and in vivo. Besides, GDF15-mediated inhibition of neuronal ferroptosis is through p62-dependent Keap1-Nrf2 pathway. In SCI mice, knockdown of GDF15 significantly exacerbated neuronal death, interfered with axon regeneration and remyelination, aggravated ferroptosis-mediated neuroinflammation, and restrained locomotor recovery.ConclusionGDF15 effectively alleviated neuronal ferroptosis post SCI via the p62-Keap1-Nrf2 signaling pathway and promoted locomotor recovery of SCI mice, which is suggested as a potential target on SCI pathogenesis and treatment.

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Section: Discussionmentioning

confidence: 99%

Growth Differentiation Factor 15 Regulates Oxidative Stress-Dependent Ferroptosis Post Spinal Cord Injury by Stabilizing the p62-Keap1-Nrf2 Signaling Pathway

Xia

Zhang

et al. 2022

Front. Aging Neurosci.

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“…Given that, ferroptotic factors and ferroptosis-related signaling pathways have now been considered as potential diagnostic/prognostic biomarkers and therapeutic targets of NDDs. It is also worth-noting that ferroptosis has been reported to participate in neuroinflammation and neuronal death post-acute brain damage, which may play a role in the pathogenesis of NDDs as well ( Mao et al, 2020 ; Cao et al, 2021 ; Cui et al, 2021 ; Ge et al, 2022 ; Qu et al, 2022 ).…”

Section: Emerging Links Of Ferroptosis To Neurodegenerative Diseasesmentioning

confidence: 99%

Mechanisms of Ferroptosis and Emerging Links to the Pathology of Neurodegenerative Diseases

Sun

Xia

Basnet

et al. 2022

Front. Aging Neurosci.

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Neurodegenerative diseases are a diverse class of diseases attributed to chronic progressive neuronal degeneration and synaptic loss in the brain and/or spinal cord, including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis and multiple sclerosis. The pathogenesis of neurodegenerative diseases is complex and diverse, often involving mitochondrial dysfunction, neuroinflammation, and epigenetic changes. However, the pathogenesis of neurodegenerative diseases has not been fully elucidated. Recently, accumulating evidence revealed that ferroptosis, a newly discovered iron-dependent and lipid peroxidation-driven type of programmed cell death, provides another explanation for the occurrence and progression of neurodegenerative diseases. Here, we provide an overview of the process and regulation mechanisms of ferroptosis, and summarize current research progresses that support the contribution of ferroptosis to the pathogenesis of neurodegenerative diseases. A comprehensive understanding of the emerging roles of ferroptosis in neurodegenerative diseases will shed light on the development of novel therapeutic technologies and strategies for slowing down the progression of these diseases.

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“…Oligodendrocytes are the main components of white matter formation and biological functions. In a recent study, it was found that in a rat model, ferrostatin-1 attenuated iron and ROS deposition in oligodendrocytes, inhibited their ferroptosis, attenuated white matter injury and promoted nerve conduction ( 121 ). In a similar study, it was revealed that in a model of RSL-3-induced ferroptosis in oligodendrocytes, liproxstatin-1 depressed mitochondrial membrane lipid peroxidation, restored GSH and GPX4 expression, thus showing stronger effect of blocking ferroptosis than DFO ( 122 ).…”

Section: Ferroptosis In Scimentioning

confidence: 99%

Mechanism of Ferroptosis and Its Role in Spinal Cord Injury

Wang

Chen

et al. 2022

Front. Neurol.

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Ferroptosis is a non-necrotic form of regulated cell death (RCD) that is primarily characterized by iron-dependent membrane lipid peroxidation and is regulated by cysteine transport, glutathione synthesis, and glutathione peroxidase 4 function as well as other proteins including ferroptosis suppressor protein 1. It has been found that ferroptosis played an important role in many diseases, such as neurodegenerative diseases and ischemia-reperfusion injury. Spinal cord injury (SCI), especially traumatic SCI, is an urgent problem worldwide due to its high morbidity and mortality, as well as the destruction of functions of the human body. Various RCDs, including ferroptosis, are found in SCI. Different from necrosis, since RCD is a form of cell death regulated by various molecular mechanisms in cells, the study of the role played by RCD in SCI will contribute to a deeper understanding of the pathophysiological process, as well as the treatment and functional recovery. The present review mainly introduces the main mechanism of ferroptosis and its role in SCI, so as to provide a new idea for further exploration.

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Ferrostatin-1 Alleviates White Matter Injury Via Decreasing Ferroptosis Following Spinal Cord Injury

Cited by 73 publications

References 56 publications

Growth Differentiation Factor 15 Regulates Oxidative Stress-Dependent Ferroptosis Post Spinal Cord Injury by Stabilizing the p62-Keap1-Nrf2 Signaling Pathway

Growth Differentiation Factor 15 Regulates Oxidative Stress-Dependent Ferroptosis Post Spinal Cord Injury by Stabilizing the p62-Keap1-Nrf2 Signaling Pathway

Mechanisms of Ferroptosis and Emerging Links to the Pathology of Neurodegenerative Diseases

Mechanism of Ferroptosis and Its Role in Spinal Cord Injury

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