Ferroptosis In Neuronal Cells Research Articles

Lactobacillus reuteri-derived γ-amino butyric acid alleviates MPTP-induced Parkinson’s disease through inhibiting ferroptosis via the AKT-GSK3β-GPX4 axis

Parkinson’s disease (PD) is a debilitating neurological disorder characterized by motor dysfunction, which has been associated with alterations in the gut microbiota. Lactobacillus reuteri (L. reuteri), a safe and versatile probiotic, exhibits potent immunomodulatory functions and neuroprotective effects. However, the extent and mechanisms by which L. reuteri mitigates PD remain unclear. Here, we demonstrated that L. reuteri significantly alleviated MPTP-induced PD in mice. Importantly, we found that the protective effects of L. reuteri are mediated by its bioactive metabolites rather than the bacteria themselves. Specifically, L. reuteri elevated the levels of γ-aminobutyric acid (GABA). Administration of GABA to mice mitigated MPTP-induced PD. Mechanistically, GABA inhibited MPTP-induced ferroptosis in neuronal cells through activation of the AKT-GSK3β-GPX4 pathway via the GABA receptor. Collectively, our research elucidates that L. reuteri-derived GABA attenuates MPTP-induced PD by inhibiting ferroptosis via the AKT-GSK3β-GPX4 axis, providing a potential therapeutic approach for the prevention and treatment of PD.

Vitamin D can mitigate sepsis-associated neurodegeneration by inhibiting exogenous histone-induced pyroptosis and ferroptosis: Implications for brain protection and cognitive preservation

BackgroundSepsis-induced neurodegeneration and cognitive dysfunction remain critical challenges worldwide. Vitamin D was reported to reduce neuronal injury and neurotoxicity and its deficiency was associated with neurocognitive disorders. This study investigates the mechanisms by which vitamin D exerts neuroprotective potential against damage-associated molecular patterns (DAMPs), specifically extracellular histones, in sepsis-related brain dysfunction. MethodsThe cultured mouse hippocampal neuronal HT22 cells were exposed to 20 µg/ml exogenous histone for 24 h to induce pyroptosis and ferroptosis in the presence or absence of the active form of vitamin D, calcitriol (1 nM). A cecal ligation and puncture mouse sepsis model was used to evaluate histone release and pyroptosis/ferroptosis biomarkers in the brain together with neurobehavioral performance with or without calcitriol treatment (1 µg/kg, i.p. injection) at 24 h or 1 week after sepsis onset. ResultsIn vitro, histone exposure triggered both pyroptosis and ferroptosis in neuronal cells, which was significantly suppressed by calcitriol treatment with the reduced expression of caspase-1 by 38 %, GSDMD by 30 %, ACSL4 by 33 %, and the increased expression of GPX4 by 35 % (n = 6, P < 0.05). Similarly, in vivo, calcitriol treatment inhibited both neuronal pyroptosis and ferroptosis by reducing expression of pyroptosis marker, GSDMD/NeuN (11.6 ± 1.2 % vs. 19.4 ± 1.1 %) and increasing expression of ferroptosis marker, GPX4/NeuN (21.4 ± 1.7 % vs. 13.5 ± 1.1 %), in the brain of septic mice (n = 6, P < 0.01). In addition, calcitriol increased survival rate (72 % vs. 41 %) and ameliorated cognitive dysfunction of septic mice (n = 8–13, P < 0.05). ConclusionsThis study demonstrates that vitamin D exerts a neuroprotective effect against sepsis by attenuating histone-induced pyroptosis and ferroptosis. These findings highlight the potential therapeutic role of vitamin D supplementation in mitigating brain dysfunction associated with sepsis which needs for further investigation.

The regulatory role of miR-21 in ferroptosis by targeting FTH1 and the contribution of microglia-derived miR-21 in exosomes to arsenic-induced neuronal ferroptosis

The regulatory role of miR-21 in ferroptosis by targeting FTH1 and the contribution of microglia-derived miR-21 in exosomes to arsenic-induced neuronal ferroptosis

BMSC-derived exosomal miR-219-5p alleviates ferroptosis in neuronal cells caused by spinal cord injury via the UBE2Z/NRF2 pathway

BMSC-derived exosomal miR-219-5p alleviates ferroptosis in neuronal cells caused by spinal cord injury via the UBE2Z/NRF2 pathway

Oroxin A alleviates early brain injury after subarachnoid hemorrhage by regulating ferroptosis and neuroinflammation

BackgroundSubarachnoid hemorrhage (SAH), a severe subtype of stroke, is characterized by notably high mortality and morbidity, largely due to the lack of effective therapeutic options. Although the neuroprotective potential of PPARg and Nrf2 has been recognized, investigative efforts into oroxin A (OA), remain limited in preclinical studies.MethodsSAH was modeled in vivo through filament perforation in male C57BL/6 mice and in vitro by exposing HT22 cells to hemin to induce neuronal damage. Following the administration of OA, a series of methods were employed to assess neurological behaviors, brain water content, neuronal damage, cell ferroptosis, and the extent of neuroinflammation.ResultsThe findings indicated that OA treatment markedly improved survival rates, enhanced neurological functions, mitigated neuronal death and brain edema, and attenuated the inflammatory response. These effects of OA were linked to the suppression of microglial activation. Moreover, OA administration was found to diminish ferroptosis in neuronal cells, a critical factor in early brain injury (EBI) following SAH. Further mechanistic investigations uncovered that OA facilitated the translocation of nuclear factor erythroid 2-related factor 2 (Nrf-2) from the cytoplasm to the nucleus, thereby activating the Nrf2/GPX4 pathway. Importantly, OA also upregulated the expression of FSP1, suggesting a significant and parallel protective effect against ferroptosis in EBI following SAH in synergy with GPX4.ConclusionIn summary, this research indicated that the PPARg activator OA augmented the neurological results in rodent models and diminished neuronal death. This neuroprotection was achieved primarily by suppressing neuronal ferroptosis. The underlying mechanism was associated with the alleviation of cellular death through the Nrf2/GPX4 and FSP1/CoQ10 pathways.

Apolipoprotein E Receptor 2 is associated with Alzheimer’s disease pathogenesis

Abstract BackgroundGenetic variations to apolipoprotein E (apoE) underlie the strongest risk for Alzheimer´s disease (AD) after aging but it is not yet known how apoE confers risk for AD. While most research is focusing on dysregulations associated with the presence of the risk allele of apoE, several aspects of apoE biology remain poorly understood. In particular, the physiological relevance of apoE interaction with members of the low‐density lipoprotein (LDL) receptor gene family is not well understood.MethodFerroptosis was induced in the N27 neuronal cell model of ferroptosis using multiple agents (erastin, RSL3, iron, cysteine depletion). Genetic variants of apolipoprotein E receptor 2 (apoER2) were generated via site‐directed mutagenesis and expressed in N27 neurons. The severity of ferroptosis was measured by several toxicity assays (MTT, LDH) and lipid peroxide probe (C11BODIPY). The association between apoER2 polymorphism and cognition were investigated in two longitudinal studies: the Alzheimer’s Disease Neuroimaging Initiative (ADNI) and the Australian Imaging Biomarkers and Lifestyle Study of Ageing (AIBL).ResultWe recently reported that apoE is a potent inhibitor of ferroptosis in neuronal cells in a mechanism that involves a receptor‐mediated activation of the PI3K/AKT signaling pathway. In this study, we identified genetic variants of apoER2 (also known as LRP8, a member of the LDL receptor family) that were associated with slower cognitive decline in clinical cohorts of AD. In preliminary work, we show that one apoER2 variant was associated with an increased protection from ferroptosis in an apoE‐dependent process.ConclusionWe present evidence for a biological role of apoER2 and its genetic variation on pathologies associated with Alzheimer’s disease, which may help develop new diagnostic and therapeutic approaches towards the disease.

Co-exposure to Fe, Zn, and Cu induced neuronal ferroptosis with associated lipid metabolism disorder via the ERK/cPLA2/AA pathway

Co-exposure to Fe, Zn, and Cu induced neuronal ferroptosis with associated lipid metabolism disorder via the ERK/cPLA2/AA pathway

ALOX5-mediated ferroptosis acts as a distinct cell death pathway upon oxidative stress in Huntington's disease.

Although it is well established that Huntington's disease (HD) is mainly caused by polyglutamine-expanded mutant huntingtin (mHTT), the molecular mechanism of mHTT-mediated actions is not fully understood. Here, we showed that expression of the N-terminal fragment containing the expanded polyglutamine (HTTQ94) of mHTT is able to promote both the ACSL4-dependent and the ACSL4-independent ferroptosis. Surprisingly, inactivation of the ACSL4-dependent ferroptosis fails to show any effect on the life span of Huntington's disease mice. Moreover, by using RNAi-mediated screening, we identified ALOX5 as a major factor required for the ACSL4-independent ferroptosis induced by HTTQ94. Although ALOX5 is not required for the ferroptotic responses triggered by common ferroptosis inducers such as erastin, loss of ALOX5 expression abolishes HTTQ94-mediated ferroptosis upon reactive oxygen species (ROS)-induced stress. Interestingly, ALOX5 is also required for HTTQ94-mediated ferroptosis in neuronal cells upon high levels of glutamate. Mechanistically, HTTQ94 activates ALOX5-mediated ferroptosis by stabilizing FLAP, an essential cofactor of ALOX5-mediated lipoxygenase activity. Notably, inactivation of the Alox5 gene abrogates the ferroptosis activity in the striatal neurons from the HD mice; more importantly, loss of ALOX5 significantly ameliorates the pathological phenotypes and extends the life spans of these HD mice. Taken together, these results demonstrate that ALOX5 is critical for mHTT-mediated ferroptosis and suggest that ALOX5 is a potential new target for Huntington's disease.

Transcriptome Analysis Unveils That Exosomes Derived from M1-Polarized Microglia Induce Ferroptosis of Neuronal Cells.

Microglia play a vital role in neurodegenerative diseases. However, the effects of microglia-derived exosomes on neuronal cells are poorly understood. This study aimed to explore the role of M1-polarized microglia exosomes in neuronal cells by transcriptome analysis. Exosomes isolated from resting M0-phenotype BV2 (M0-BV2) microglia and M1-polarized BV2 (M1-BV2) microglia were analyzed using high-throughput sequencing of the transcriptome. Differentially expressed genes (DEGs) between the two types of exosomes were identified by analyzing the sequencing data. The biological functions and pathways regulated by the identified DEGs were then identified using bioinformatics analyses. Finally, we evaluated the effects of exosomes on neuronal cells by coculturing M0-BV2 and M1-BV2 exosomes with primary neuronal cells. Enrichment analyses revealed that DEGs were significantly enriched in the ferroptosis pathway (p = 0.0137). M0-BV2 exosomes had no distinct effects on ferroptosis in neuronal cells, whereas M1-BV2 exosomes significantly reduced ferroptosis suppressor proteins (GPX4, SLC7A11, and FTH1) and elevated the levels of intracellular and mitochondrial ferrous iron and lipid peroxidation in neuronal cells. Polarized M1-BV2 microglia exosomes can induce ferroptosis in neuronal cells, thereby aggravating neuronal damage. Taken together, these findings enhance knowledge of the pathogenesis of neurological disorders and suggest potential therapeutic targets against neurodegenerative diseases.

Protective Effects of Maprotiline in 6-Hydroxydopamine (6-OHDA)-Induced Ferroptosis in Neuronal Cells

Neurotoxin 6-Hydroxydopamine (6-OHDA) has been associated with pathological progress of Parkinson’s disease (PD). Maprotiline is a licensed drug widely used in clinics as an antidepressant. However, maprotiline’s effect on PD is unclear. We constructed an in vitro model in SH-SY5Y neuronal cells using 6-OHDA, followed by introduction of 2.5 and 5 μM maprotiline for 24 h. Increased intracellular reactive oxygen species (ROS) and markedly enhanced Malondialdehyde (MDA) levels were found in SH-SY5Y cells challenged by 6-OHDA, which were signally alleviated by maprotiline.Moreover, the increased Fe2+ level, upregulated ferroportin (FPN), prostaglandin-endoperoxide synthase 2 (PTGS2), and anti-acyl-CoA synthetase long-chain family member 4 (ACSL4), downregulated Ferritin and enhanced Lactate dehydrogenase (LDH) release were observed in 6-OHDA-challenged SH-SY5Y cells, which were observably rescued by maprotiline. Furthermore, Nrf2 was found to be extremely downregulated in SH-SY5Y neuronal challenged with 6-OHDA, the level of which was increased by maprotiline. The regulatory function of maprotiline on ferroptosis-associated biomarkers was markedly abrogated by ML385, which is an antagonist of Nrf2. Collectively, maprotiline ameliorated ferroptosis in 6-OHDA-challenged SH-SY5Y cells by activating Nrf2.

Cimicifuga racemosa Extract Ze 450 Re-Balances Energy Metabolism and Promotes Longevity

Recently, we reported that the Cimicifuga racemosa extract Ze 450 mediated protection from oxidative cell damage through a metabolic shift from oxidative phosphorylation to glycolysis. Here, we investigated the molecular mechanisms underlying the effects of Ze 450 against ferroptosis in neuronal cells, with a particular focus on mitochondria. The effects of Ze 450 on respiratory complex activity and hallmarks of ferroptosis were studied in isolated mitochondria and in cultured neuronal cells, respectively. In addition, Caenorhabditis elegans served as a model organism to study mitochondrial damage and longevity in vivo. We found that Ze 450 directly inhibited complex I activity in mitochondria and enhanced the metabolic shift towards glycolysis via cMyc and HIF1α regulation. The protective effects against ferroptosis were mediated independently of estrogen receptor activation and were distinct from effects exerted by metformin. In vivo, Ze 450 protected C. elegans from the mitochondrial toxin paraquat and promoted longevity in a dose-dependent manner. In conclusion, Ze 450 mediated a metabolic shift to glycolysis via direct effects on mitochondria and altered cell signaling, thereby promoting sustained cellular resilience to oxidative stress in vitro and in vivo.

Inhibition of TLR4 prevents hippocampal hypoxic-ischemic injury by regulating ferroptosis in neonatal rats

Inhibition of TLR4 prevents hippocampal hypoxic-ischemic injury by regulating ferroptosis in neonatal rats

Chemically Induced Models of Parkinson’s Disease: History and Perspectives for the Involvement of Ferroptosis

Ferroptosis is a newly discovered form of necrotic cell death characterized by its dependency on iron and lipid peroxidation. Ferroptosis has attracted much attention recently in the area of neurodegeneration since the involvement of ferroptosis in Parkinson’s disease (PD), a major neurodegenerative disease, has been indicated using animal models. Although PD is associated with both genetic and environmental factors, sporadic forms of PD account for more than 90% of total PD. Following the importance of environmental factors, various neurotoxins are used as chemical inducers of PD both in vivo and in vitro. In contrast to other neurodegenerative diseases such as Alzheimer’s and Huntington’s diseases (AD and HD), many of the characteristics of PD can be reproduced in vivo by the use of specific neurotoxins. Given the indication of ferroptosis in PD pathology, several studies have been conducted to examine whether ferroptosis plays role in the loss of dopaminergic neurons in PD. However, there are still few reports showing an authentic form of ferroptosis in neuronal cells during exposure to the neurotoxins used as PD inducers. In this review article, we summarize the history of the uses of chemicals to create PD models in vivo and in vitro. Besides, we also survey recent reports examining the possible involvement of ferroptosis in chemical models of PD.

NCOA4-Mediated Ferritinophagy Is Essential for HT22 Neuronal Cell Survival During Iron Deficiency (OR15-07-19)

NCOA4-Mediated Ferritinophagy Is Essential for HT22 Neuronal Cell Survival During Iron Deficiency (OR15-07-19)

BID links ferroptosis to mitochondrial cell death pathways

BID links ferroptosis to mitochondrial cell death pathways

The Protective Role of Mitochondrial Ferritin on Erastin-Induced Ferroptosis

Ferroptosis, a newly identified form of regulated cell death, is characterized by overwhelming iron-dependent accumulation of lethal lipid reactive oxygen species (ROS). Preventing cellular iron overload by reducing iron uptake and increasing iron storage may contribute to inhibit ferroptosis. Mitochondrial ferritin (FtMt) is an iron-storage protein that is located in the mitochondria, which has a significant role in modulating cellular iron metabolism. Recent studies showed that FtMt played inhibitory effects on oxidative stress-dependent neuronal cell damage. However, the potential role of FtMt in the progress of ferroptosis in neuronal cells has not been studied. To explore this, we established ferroptosis models of cell and drosophila by erastin treatment. We found that overexpression of FtMt in neuroblastoma SH-SY5Y cells significantly inhibited erastin-induced ferroptosis, which very likely was achieved by regulation of iron homeostasis. Upon erastin treatment, significant increases of cellular labile iron pool (LIP) and cytosolic ROS were observed in wild-type SH-SY5Y cells, but not in the FtMt-overexpressed cells. Consistent with that, the alterations of iron-related proteins in FtMt-overexpressed cells were different from that of the control cells. We further investigated the role of FtMt in erastin-induced ferroptosis in transgenic drosophila. We found that the wild-type drosophilas fed an erastin-containing diet didn't survive more than 3 weeks. In contrast, the FtMt overexpressing drosophilas fed the same diet were survival very well. These results indicated that FtMt played a protective role in erastin-induced ferroptosis.