Cisplatin induced neurotoxicity is mediated by Sarm1 and calpain activation

Cetinkaya-Fisgin, Aysel; Luan, Xinghua; Reed, Nicole; Jeong, Ye Eun; Oh, Byoung Chol; Höke, Ahmet

doi:10.1038/s41598-020-78896-w

Cited by 35 publications

(29 citation statements)

References 31 publications

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“…In addition, mouse models of paclitaxel have shown that axonal degeneration occurs in the central and peripheral axon branches of DRG cells (Tasnim et al, 2016). Axonal blebbing and degeneration have been reported in other studies of 50B11 cells treated with cisplatin (Cetinkaya-Fisgin et al, 2020). Our study demonstrated occurrence of axonal blebbing and decreased neurite length in DRG sensory cells after paclitaxel treatment.…”

Section: Discussionsupporting

confidence: 83%

TMI-1, TNF-α-Converting Enzyme Inhibitor, Protects Against Paclitaxel-Induced Neurotoxicity in the DRG Neuronal Cells In Vitro

et al. 2022

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Background: Chemotherapy-induced peripheral neuropathy (CIPN) negatively impacts cancer survivors’ quality of life and is challenging to treat with existing drugs for neuropathic pain. TNF-α is known to potentiate TRPV1 activity, which contributes to CIPN. Here, we assessed the role of TMI-1, a TNF-α-converting enzyme inhibitor, in paclitaxel (PAC)-induced neurotoxicity in dorsal root ganglion (DRG) cells.Materials and Methods: Immortalized DRG neuronal 50B11 cells were cultured and treated with PAC or PAC with TMI-1 following neuronal differentiation. Cell viability, analysis of neurite growth, immunofluorescence, calcium flow cytometry, western blotting, quantitative RT-PCR, and cytokine quantitation by ELISA were performed to determine the role of TMI-1 in neurotoxicity in neuronal cells.Results: PAC administration decreased the length of neurites and upregulated the expression of TRPV1 in 50B11 cells. TMI-1 administration showed a protective effect by suppressing inflammatory signaling, and secretion of TNF-α.Conclusion: TMI-1 partially protects against paclitaxel-induced neurotoxicity by reversing the upregulation of TRPV1 and decreasing levels of inflammatory cytokines, including TNF-α, IL-1β, and IL-6 in neuronal cells.

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Section: Discussionsupporting

confidence: 83%

TMI-1, TNF-α-Converting Enzyme Inhibitor, Protects Against Paclitaxel-Induced Neurotoxicity in the DRG Neuronal Cells In Vitro

et al. 2022

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“…Certainly, animal model studies suggest so. SARM1 deletion alleviates chemotherapy-induced peripheral neuropathy with vincristine, paclitaxel, bortezomib, cisplatin and oxaliplatin and neuropathy in a type 2 diabetes model using a high fat diet [ 157 , 158 , 208 , 214 , 226 , 227 ], all of which suggest relevance to more common disorders of peripheral nerve. Association with idiopathic peripheral neuropathy, inflammatory neuropathies and other toxic neuropathies, building on findings with vacor as well as cancer chemotherapy drugs will also be important to explore.…”

Section: Future Perspectives: Outstanding Questionsmentioning

confidence: 99%

Lessons from Injury: How Nerve Injury Studies Reveal Basic Biological Mechanisms and Therapeutic Opportunities for Peripheral Nerve Diseases

Arthur‐Farraj

Coleman

2021

Neurotherapeutics

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Since Waller and Cajal in the nineteenth and early twentieth centuries, laboratory traumatic peripheral nerve injury studies have provided great insight into cellular and molecular mechanisms governing axon degeneration and the responses of Schwann cells, the major glial cell type of peripheral nerves. It is now evident that pathways underlying injury-induced axon degeneration and the Schwann cell injury-specific state, the repair Schwann cell, are relevant to many inherited and acquired disorders of peripheral nerves. This review provides a timely update on the molecular understanding of axon degeneration and formation of the repair Schwann cell. We discuss how nicotinamide mononucleotide adenylyltransferase 2 (NMNAT2) and sterile alpha TIR motif containing protein 1 (SARM1) are required for axon survival and degeneration, respectively, how transcription factor c-JUN is essential for the Schwann cell response to nerve injury and what each tells us about disease mechanisms and potential therapies. Human genetic association with NMNAT2 and SARM1 strongly suggests aberrant activation of programmed axon death in polyneuropathies and motor neuron disorders, respectively, and animal studies suggest wider involvement including in chemotherapy-induced and diabetic neuropathies. In repair Schwann cells, cJUN is aberrantly expressed in a wide variety of human acquired and inherited neuropathies. Animal models suggest it limits axon loss in both genetic and traumatic neuropathies, whereas in contrast, Schwann cell secreted Neuregulin-1 type 1 drives onion bulb pathology in CMT1A. Finally, we discuss opportunities for drug-based and gene therapies to prevent axon loss or manipulate the repair Schwann cell state to treat acquired and inherited neuropathies and neuronopathies.

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“…Injured or diseased axons initiate a self-destruction program known as Wallerian degeneration. SARM1 triggers this pathological axon degeneration (1), and is a key driver of pathology in models of chemotherapy-induced peripheral neuropathy (2)(3)(4)(5), traumatic brain injury (6)(7)(8)(9)(10), glaucoma (11), and retinal degeneration (12,13). SARM1 also participates in antiviral defense.…”

Section: Introductionmentioning

confidence: 99%

The SARM1 TIR NADase: Mechanistic Similarities to Bacterial Phage Defense and Toxin-Antitoxin Systems

2021

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The Toll/interleukin-1 receptor (TIR) domain is the signature signalling motif of innate immunity, with essential roles in innate immune signalling in bacteria, plants, and animals. TIR domains canonically function as scaffolds, with stimulus-dependent multimerization generating binding sites for signalling molecules such as kinases and ligases that activate downstream immune mechanisms. Recent studies have dramatically expanded our understanding of the TIR domain, demonstrating that the primordial function of the TIR domain is to metabolize NAD+. Mammalian SARM1, the central executioner of pathological axon degeneration, is the founding member of the TIR-domain class of NAD+ hydrolases. This unexpected NADase activity of TIR domains is evolutionarily conserved, with archaeal, bacterial, and plant TIR domains all sharing this catalytic function. Moreover, this enzymatic activity is essential for the innate immune function of these proteins. These evolutionary relationships suggest a link between SARM1 and ancient self-defense mechanisms that has only been strengthened by the recent discovery of the SARM1 activation mechanism which, we will argue, is strikingly similar to bacterial toxin-antitoxin systems. In this brief review we will describe the regulation and function of SARM1 in programmed axon self-destruction, and highlight the parallels between the SARM1 axon degeneration pathway and bacterial innate immune mechanisms.

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Cisplatin induced neurotoxicity is mediated by Sarm1 and calpain activation

Cited by 35 publications

References 31 publications

TMI-1, TNF-α-Converting Enzyme Inhibitor, Protects Against Paclitaxel-Induced Neurotoxicity in the DRG Neuronal Cells In Vitro

TMI-1, TNF-α-Converting Enzyme Inhibitor, Protects Against Paclitaxel-Induced Neurotoxicity in the DRG Neuronal Cells In Vitro

Lessons from Injury: How Nerve Injury Studies Reveal Basic Biological Mechanisms and Therapeutic Opportunities for Peripheral Nerve Diseases

The SARM1 TIR NADase: Mechanistic Similarities to Bacterial Phage Defense and Toxin-Antitoxin Systems

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