Rho kinase inhibitor Y-27632 facilitates recovery from experimental peripheral neuropathy induced by anti-cancer drug cisplatin

Abstract

Chemotherapy drugs have neurotoxicity associated with treatment, which can become a doselimiting problem when clinical presentation is severe. However, there is no effective therapy to circumvent the neurotoxicity of anti-cancer drug treatment. In this study, we utilized a newly designed mouse model of cisplatin-induced peripheral neuropathy to determine both the severity of neurotoxicity induced by drug treatment and the effectiveness of the Rho kinase inhibitor Y-27632 in post-treatment recovery. Sensory nerve conduction studies revealed a significant increase in mean distal (peak) latency with cisplatin treatment, indicating a deterioration of sensory nerve function. Also, hind paw touch sensitivity decreased steadily with increasing cumulative dose of cisplatin. Histological and immunohistochemical analyses of the sural nerve using neuronal marker protein gene product 9.5 (PGP 9.5) demonstrated abnormal nerve fiber morphology in cisplatin-treated mice. Remarkably, post-treatment with Y-27632 improved the sural nerve distal (peak) latency and sensory threshold to return to pre-treatment levels. Sural nerve histology worsened in the absence of Y-27632 during recovery. These studies suggest that Rho kinase inhibitor Y-27632 can initiate regeneration of damaged nerves following cisplatin treatment.

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

“…All animals were subjected to Von Frey/Semmes-Weinstein monofilament sensory threshold testing of the hind paws as previously described (James et al, 2010) every two weeks for the 10 week treatment period. Briefly, animals were placed within a clear plastic barrier upon an elevated screen and allowed to acclimate for 10 to 15 minutes.…”

“…In vitro studies from our laboratory have demonstrated that Rho pathway inhibition, either upstream with a p75 neurotrophin receptor (p75 NTR ) small molecule ligand (LM11A-31, Massa et al, 2006) or downstream with a selective p160 ROCK / Rho kinase inhibitor (Y-27632), facilitates neuronal recovery in neuronal cultures treated with cisplatin (James et al, 2008). Subsequent in vivo studies, using a CIPN mouse model, demonstrated that Y-27632 inhibited cisplatin-induced RhoA pathway activation and promoted recovery from peripheral neuropathy (James et al, 2010). These findings highlight the potential importance of RhoA signaling in CIPN and raise the possibility that a clinically viable way to inhibit RhoA activation might serve to inhibit neuronal toxicity and thereby enhance current cisplatin treatment paradigms.…”

Expression of Serum Response Factor in Gastric Carcinoma and Its Molecular Mechanisms Involved in the Regulation of the Invasion and Migration of SGC-7901 Cells

“…[15][16][17][18] It has also been reported that Y-27632 has a protective effect on human embryonic stem cells, human bone marrow-derived mesenchymal stem cells, and endothelial cells. [19][20][21] It has been shown that Y-27632 has a suppressive effect on the invasion and migration of human bladder cancer TSGH cells 14 and on the adhesion and mobility of esophageal squamous cancer cells.…”

Sıçanlarda Bortezomib İndüklü Karaciğer Hasarında B-1,3-(D)-Glukan’ın Hepatoprotektif Etkileri

“…The drug has been shown beneficial in animal-model studies of autoimmune diseases such as myasthenia gravis, psoriasis, arthritis, and autoimmune encephalomyelitis [6] . Therapeutic effectiveness of anti-cancer drugs is associated with severe side effects due to their toxicity [7] . Bortezomib is one of the more widely used anti-cancer drugs for a number of cancers and is metabolized in the liver, which can develop drug toxicity due to these metabolisms [8] .…”