Amelioration of cisplatin-induced experimental peripheral neuropathy by a small molecule targeting p75NTR

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 (p75NTR), 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 SHP-2, which was reversed by LM11A-31. LM11A-31 also countered the effects of calpeptin, which activated RhoA by inhibiting SHP-2 tyrosine phosphatase. Therefore, suppression of RhoA signaling by LM11A-31 that blocks proNGF binding to p75NTR or activates SHP-2 tyrosine phosphatase downstream of NGF receptor enhances neuroprotection in experimental CIPN in mouse model.

Vascularization converts the lineage fate of bone mesenchymal stem cells to endothelial cells in tissue-engineered bone grafts by modulating FGF2-RhoA/ROCK signaling

“…7a ). In contrast, the level of phosphorylated RhoA (p-RhoA, a marker of the inactive form of RhoA) 32 was significantly increased in BMSCs co-cultured with RAOECs (Fig. 7b ), indicating that RhoA signaling was inhibited when BMSCs were co-cultured with RAOECs.…”

Therapeutic Effect of Y-27632 on Tumorigenesis and Cisplatin-Induced Peripheral Sensory Loss through RhoA–NF-κB

“…Suppression of small GTPase RhoA signaling, either through inhibition of its upstream p75 NTR or the downstream effector Rho kinase/p160 ROCK , reversed and prevented experimental CIPN in non-tumor-bearing mice (8,23). This study demonstrated, for the first time, that Y-27632 had dual therapeutic effects on tumor suppression and peripheral neuroprotection in an immunocompetent, tumor-bearing CIPN mouse model.…”

“…On the other hand, increased activity of RhoA, a member of Rho family small GTPases, has been observed in a variety of neuronal injuries (5). LM11A-31, a ligand mimetic of p75 neurotrophin receptor (p75 NTR ) that is upstream of the RhoA signaling pathway (6,7), could partially protect peripheral nerves from being damaged by cisplatin (8). The notion of RhoA involvement in CIPN was further supported because Y-27632, a selective inhibitor of Rho kinase/ p160 ROCK directly downstream of RhoA (9), reversed the neurodegeneration caused by cisplatin (9).…”

Depletion of nerve growth factor in chemotherapy-induced peripheral neuropathy associated with hematologic malignancies

“…For CIPN, rhNGF improved results of nerve conduction study on cisplatin neurotoxicity in rodents [ 14 , 17 ]. In addition, p53 pan-neurotrophin receptor ( p 75 NTR ), one of NGF receptors, agonist also decreased CIPN incidence [ 35 ]. However, well-designed human trial has not been performed, probably because of uncertainty.…”