Ferrostatin-1 ameliorates Bupivacaine-Induced spinal neurotoxicity in rats by inhibiting ferroptosis

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Abstract

<p xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="first" id="d13112749e158">Bupivacaine (BUP) has previously been shown to trigger neurotoxicity after spinal anesthesia. Further, ferroptosis has been implicated in the pathological processes associated with various central nervous system diseases. Although the impact of ferroptosis on BUP-induced neurotoxicity in the spinal cord has not been fully understood, this research aims to investigate this relationship in rats. Additionally, this study aims to determine whether ferrostatin-1 (Fer-1), a potent inhibitor of ferroptosis, can provide protection against BUP-induced spinal neurotoxicity. The experimental model for BUP-induced spinal neurotoxicity involved the administration of 5% bupivacaine through intrathecal injection. Then, the rats were randomized into the Control, BUP, BUP + Fer-1, and Fer-1 groups. BBB scores, %MPE of TFL, and H&E and Nissl stainings showed that intrathecal Fer-1 administration improved functional recovery, histological outcomes, and neural survival in BUP-treated rats. Moreover, Fer-1 has been found to alleviate the BUP-induced alterations related to ferroptosis, such as mitochondrial shrinkage and disruption of cristae, while also reducing the levels of malondialdehyde (MDA), iron, and 4-hydroxynonenal (4HNE). Fer-1 also inhibits the accumulation of reactive oxygen species (ROS) and restores the normal levels of glutathione peroxidase 4 (GPX4), cystine/glutamate transporter (xCT), and glutathione (GSH). Furthermore, double-immunofluorescence staining revealed that GPX4 is primarily localized in the neurons instead of microglia or astroglia in the spinal cord. In summary, we demonstrated that ferroptosis play a pivotal role in mediating BUP-induced spinal neurotoxicity, and Fer-1 ameliorated BUP-induced spinal neurotoxicity by reversing the underlying ferroptosis-related changes in rats. </p>

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Ferroptosis: an iron-dependent form of nonapoptotic cell death.

Scott J. Dixon, Kathryn Lemberg, Michael Lamprecht … (2012)

Nonapoptotic forms of cell death may facilitate the selective elimination of some tumor cells or be activated in specific pathological states. The oncogenic RAS-selective lethal small molecule erastin triggers a unique iron-dependent form of nonapoptotic cell death that we term ferroptosis. Ferroptosis is dependent upon intracellular iron, but not other metals, and is morphologically, biochemically, and genetically distinct from apoptosis, necrosis, and autophagy. We identify the small molecule ferrostatin-1 as a potent inhibitor of ferroptosis in cancer cells and glutamate-induced cell death in organotypic rat brain slices, suggesting similarities between these two processes. Indeed, erastin, like glutamate, inhibits cystine uptake by the cystine/glutamate antiporter (system x(c)(-)), creating a void in the antioxidant defenses of the cell and ultimately leading to iron-dependent, oxidative death. Thus, activation of ferroptosis results in the nonapoptotic destruction of certain cancer cells, whereas inhibition of this process may protect organisms from neurodegeneration. Copyright © 2012 Elsevier Inc. All rights reserved.

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Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease

Suzy Torti, Donna D. Zhang, K.A. Woerpel … (2019)

Ferroptosis is a form of regulated cell death characterized by the iron-dependent accumulation of lipid hydroperoxides to lethal levels. Emerging evidence suggests that ferroptosis represents an ancient vulnerability caused by the incorporation of polyunsaturated fatty acids into cellular membranes, and cells have developed complex systems that exploit and defend against this vulnerability in different contexts. The sensitivity to ferroptosis is tightly linked to numerous biological processes, including amino acid, iron, and polyunsaturated fatty acid metabolism, and the biosynthesis of glutathione, phospholipids, NADPH, and coenzyme Q10. Ferroptosis has been implicated in the pathological cell death associated with degenerative diseases (i.e., Alzheimer's, Huntington's, and Parkinson's diseases), carcinogenesis, stroke, intracerebral hemorrhage, traumatic brain injury, ischemia-reperfusion injury, and kidney degeneration in mammals and is also implicated in heat stress in plants. Ferroptosis may also have a tumor-suppressor function that could be harnessed for cancer therapy. This Primer reviews the mechanisms underlying ferroptosis, highlights connections to other areas of biology and medicine, and recommends tools and guidelines for studying this emerging form of regulated cell death.

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Ferroptosis: process and function.

Y Xie, W Hou, X Song … (2016)

Ferroptosis is a recently recognized form of regulated cell death. It is characterized morphologically by the presence of smaller than normal mitochondria with condensed mitochondrial membrane densities, reduction or vanishing of mitochondria crista, and outer mitochondrial membrane rupture. It can be induced by experimental compounds (e.g., erastin, Ras-selective lethal small molecule 3, and buthionine sulfoximine) or clinical drugs (e.g., sulfasalazine, sorafenib, and artesunate) in cancer cells and certain normal cells (e.g., kidney tubule cells, neurons, fibroblasts, and T cells). Activation of mitochondrial voltage-dependent anion channels and mitogen-activated protein kinases, upregulation of endoplasmic reticulum stress, and inhibition of cystine/glutamate antiporter is involved in the induction of ferroptosis. This process is characterized by the accumulation of lipid peroxidation products and lethal reactive oxygen species (ROS) derived from iron metabolism and can be pharmacologically inhibited by iron chelators (e.g., deferoxamine and desferrioxamine mesylate) and lipid peroxidation inhibitors (e.g., ferrostatin, liproxstatin, and zileuton). Glutathione peroxidase 4, heat shock protein beta-1, and nuclear factor erythroid 2-related factor 2 function as negative regulators of ferroptosis by limiting ROS production and reducing cellular iron uptake, respectively. In contrast, NADPH oxidase and p53 (especially acetylation-defective mutant p53) act as positive regulators of ferroptosis by promotion of ROS production and inhibition of expression of SLC7A11 (a specific light-chain subunit of the cystine/glutamate antiporter), respectively. Misregulated ferroptosis has been implicated in multiple physiological and pathological processes, including cancer cell death, neurotoxicity, neurodegenerative diseases, acute renal failure, drug-induced hepatotoxicity, hepatic and heart ischemia/reperfusion injury, and T-cell immunity. In this review, we summarize the regulation mechanisms and signaling pathways of ferroptosis and discuss the role of ferroptosis in disease.