Endothelial Glycocalyx in the Peripheral Capillaries is Injured Under Oxaliplatin-Induced Neuropathy

• Published in: The journal of pain Vol. 25; no. 6; p. 104462
• Main Authors: Kuroda, Takahiro, Suzuki, Akio, Okada, Hideshi, Shimizu, Masayoshi, Watanabe, Daichi, Suzuki, Keiko, Mori, Kosuke, Ohmura, Kazufumi, Niwa, Ayumi, Imaizumi, Yuko, Matsuo, Mikiko, Ichihashi, Koki, Okubo, Takafumi, Taniguchi, Toshiaki, Kanayma, Tomohiro, Kobayashi, Ryo, Sugie, Shigeyuki, Hara, Akira, Tomita, Hiroyuki
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.06.2024
• Subjects: Animals; Antineoplastic Agents - pharmacology; Capillaries - drug effects; Capillaries - pathology; Capillary Permeability - drug effects; Capillary Permeability - physiology; Disease Models, Animal; Endothelial glycocalyx; Glycocalyx - drug effects; Glycocalyx - metabolism; Glycocalyx - pathology; Hyperalgesia - chemically induced; Hyperalgesia - pathology; Male; Mice; Mice, Inbred C57BL; Nafamostat mesilate; Neuropathy; Oxaliplatin; Oxaliplatin - toxicity; Peripheral capillary; Peripheral Nervous System Diseases - chemically induced; Peripheral Nervous System Diseases - pathology; Endothelial glycocalyx; Oxaliplatin; Neuropathy; Peripheral capillary; Nafamostat mesilate
• DOI: 10.1016/j.jpain.2024.01.005
• ISSN: 1526-5900; 1528-8447

Oxaliplatin, a platinum-based anticancer drug, is associated with peripheral neuropathy (oxaliplatin-induced peripheral neuropathy, OIPN), which can lead to worsening of quality of life and treatment interruption. The endothelial glycocalyx, a fragile carbohydrate-rich layer covering the luminal surface of endothelial cells, acts as an endothelial gatekeeper and has been suggested to protect nerves, astrocytes, and other cells from toxins and substances released from the capillary vessels. Mechanisms underlying OIPN and the role of the glycocalyx remain unclear. This study aimed to define changes in the three-dimensional ultrastructure of capillary endothelial glycocalyx near nerve fibers in the hind paws of mice with OIPN. The mouse model of OPIN revealed disruption of the endothelial glycocalyx in the peripheral nerve compartment, accompanied by vascular permeability, edema, and damage to the peripheral nerves. To investigate the potential treatment interventions, nafamostat mesilate, a glycocalyx protective agent was used in tumor-bearing male mice. Nafamostat mesilate suppressed mechanical allodynia associated with neuropathy. It also prevented intra-epidermal nerve fiber loss and improved vascular permeability in the peripheral paws. The disruption of endothelial glycocalyx in the capillaries that lie within peripheral nerve bundles is a novel finding in OPIN. Furthermore, these findings point toward the potential of a new treatment strategy targeting endothelial glycocalyx to prevent vascular injury as an effective treatment of neuropathy as well as of many other diseases. OIPN damages the endothelial glycocalyx in the peripheral capillaries, increasing vascular permeability. In order to prevent OIPN, this work offers a novel therapy approach that targets endothelial glycocalyx. •Oxaliplatin-induced endothelial glycocalyx injury and increased vascular permeability.•Oxaliplatin-induced endothelial glycocalyx injury was visualized by three-dimensional image.•Maintenance of the glycocalyx by nafamostat suppressed oxaliplatin-induced peripheral neuropathy.•Protecting the endothelial glycocalyx may be a novel strategy to prevent OIPN.