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Molsidomine provides neuroprotection against vincristine-induced peripheral neurotoxicity through soluble guanylyl cyclase activation
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Molsidomine provides neuroprotection against vincristine-induced peripheral neurotoxicity through soluble guanylyl cyclase activation
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Journal Article
Molsidomine provides neuroprotection against vincristine-induced peripheral neurotoxicity through soluble guanylyl cyclase activation
2024
Overview
Peripheral neurotoxicity is a dose-limiting adverse reaction of primary frontline chemotherapeutic agents, including vincristine. Neuropathy can be so disabling that patients drop out of potentially curative therapy, negatively impacting cancer prognosis. The hallmark of vincristine neurotoxicity is axonopathy, yet its underpinning mechanisms remain uncertain. We developed a comprehensive drug discovery platform to identify neuroprotective agents against vincristine-induced neurotoxicity. Among the hits identified, SIN-1—an active metabolite of molsidomine—prevents vincristine-induced axonopathy in both motor and sensory neurons without compromising vincristine anticancer efficacy. Mechanistically, we found that SIN-1’s neuroprotective effect is mediated by activating soluble guanylyl cyclase. We modeled vincristine-induced peripheral neurotoxicity in rats to determine molsidomine therapeutic potential in vivo. Vincristine administration induced severe nerve damage and mechanical hypersensitivity that were attenuated by concomitant treatment with molsidomine. This study provides evidence of the neuroprotective properties of molsidomine and warrants further investigations of this drug as a therapy for vincristine-induced peripheral neurotoxicity.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 631/378
/ 631/67
/ 631/92
/ Animals
/ Biology
/ Humanities and Social Sciences
/ Humans
/ Male
/ Molsidomine - analogs & derivatives
/ Neurons
/ Neuroprotective Agents - pharmacology
/ Neurotoxicity Syndromes - drug therapy
/ Neurotoxicity Syndromes - etiology
/ Neurotoxicity Syndromes - metabolism
/ Neurotoxicity Syndromes - prevention & control
/ Peripheral Nervous System Diseases - chemically induced
/ Peripheral Nervous System Diseases - drug therapy
/ Peripheral Nervous System Diseases - prevention & control
/ Rats
/ Science
/ Soluble Guanylyl Cyclase - metabolism
/ Toxicity
