title: Amelioration of cisplatin-induced experimental peripheral neuropathy by a small molecule targeting p75 NTR.
abstract: Cisplatin is an effective and widely used first-line chemotherapeutic drug for treating cancers. However, many patients sustain cisplatin-induced peripheral neuropathy (CIPN), often leading to a reduction in drug dosages or complete cessation of treatment altogether. Therefore, it is important to understand cisplatin mechanisms in peripheral nerve tissue mediating its toxicity and identify signaling pathways for potential intervention. Rho GTPase activation is increased following trauma in several models of neuronal injury. Thus, we investigated whether components of the Rho signaling pathway represent important neuroprotective targets with the potential to ameliorate CIPN and thereby optimize current chemotherapy treatment regimens. We have developed a novel CIPN model in the mouse. Using this model and primary neuronal culture, we determined whether LM11A-31, a small-molecule, orally bioavailable ligand of the p75 neurotrophin receptor (p75(NTR)), can modulate Rho GTPase signaling and reduce CIPN. Von Frey filament analysis of sural nerve function showed that LM11A-31 treatment prevented decreases in peripheral nerve sensation seen with cisplatin treatment. Morphometric analysis of harvested sural nerves revealed that cisplatin-induced abnormal nerve fiber morphology and the decreases in fiber area were alleviated with concurrent LM11A-31 treatment. Cisplatin treatment increased RhoA activity accompanied by the reduced tyrosine phosphorylation of SHP2, which was reversed by LM11A-31. LM11A-31 also countered the effects of calpeptin, which activated RhoA by inhibiting SHP2 tyrosine phosphatase. Therefore, suppression of RhoA signaling by LM11A-31 that modulates p75(NTR) or activates SHP2 tyrosine phosphatase downstream of the NGF receptor enhances neuroprotection in experimental CIPN in mouse model.
authors.affiliation: Department of Anatomy and Cell Biology, The Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA; Leo Jenkins Cancer Center, The Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA.
authors.forename: Amy
authors.initials: A
authors.lastname: Friesland
authors.affiliation: Department of Anatomy and Cell Biology, The Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA; School of Pharmaceutical Science and Yunnan Key Laboratory of Pharmacology for Natural Products, Kunming Medical University, Kunming 650500, China.
authors.forename: Zhiying
authors.initials: Z
authors.lastname: Weng
authors.affiliation: Department of Anatomy and Cell Biology, The Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Duenas
authors.affiliation: Department of Neurology Veterans Administration Medical Center and University of California at San Francisco, San Francisco, CA 94121, USA.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Massa
authors.affiliation: Department of Neurology and Neurological Science, Stanford University, Stanford, CA 94305, USA.
authors.forename: Frank M
authors.initials: FM
authors.lastname: Longo
authors.affiliation: Department of Anatomy and Cell Biology, The Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA; Leo Jenkins Cancer Center, The Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA. Electronic address: luq@ecu.edu.
authors.forename: Qun
authors.initials: Q
authors.lastname: Lu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D002478:Cells, Cultured; D002945:Cisplatin / Q000633:toxicity*; D005260:Female; D007532:Isoleucine / Q000031:analogs & derivatives* / Q000494:pharmacology; D008024:Ligands; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009025:Morpholines / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced* / Q000378:metabolism; D010766:Phosphorylation; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000378:metabolism; D017475:Receptors, Nerve Growth Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013497:Sural Nerve / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D055698:Touch Perception / Q000187:drug effects; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C575077:LM11A-31; D008024:Ligands; D009025:Morpholines; D018696:Neuroprotective Agents; D017475:Receptors, Nerve Growth Factor; C517634:Ngfr protein, mouse; D007532:Isoleucine; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D020742:rhoA GTP-Binding Protein; D002945:Cisplatin
keywords: Chemotherapeutics; Kinases and phosphatases; Peripheral neuropathy; Rho GTPases; p75(NTR)