Gabapentin prevents oxaliplatin-induced mechanical hyperalgesia in mice.

Oxaliplatin, a platinum-based chemotherapy drug, frequently causes acute and chronic peripheral neuropathies including mechanical hyperalgesia. These adverse effects hinder anticancer therapy with the drug. In this study, we examined several drugs that might prevent oxaliplatin-induced peripheral neuropathy. Single intraperitoneal (i.p.) injection of oxaliplatin (10 mg/kg) induced cold allodynia (acetone test) and mechanical hyperalgesia (von Frey test). Gabapentin, but not simvastatin and atorvastatin, prevented oxaliplatin-induced mechanical hyperalgesia without affecting cold allodynia. Moreover, oxaliplatin caused phosphorylation of cofilin protein in the spinal cord, which has been shown to be involved in the neuropathic hyperalgesia. This increased phosphorylation of cofilin was also attenuated by gabapentin treatment. These results suggest that gabapentin is useful for relieving oxaliplatin-induced mechanical hyperalgesia and that the pathogenic mechanisms of cold allodynia and mechanical hyperalgesia differ.

Effect of Ninjin'yoeito on the Loss of Skeletal Muscle Function in Cancer-Bearing Mice.

Ninjin'yoeito (NYT), a traditional Japanese Kampo medicine formula, is used as a remedy for conditions, and physical weakness. Cancer cachexia is seen in advanced cancer patients and is defined by an ongoing loss of skeletal-muscle mass that leads to progressive functional impairment. In the present study, we examined the hypothesis whether NYT improves the functional loss of skeletal muscle cancer cachexia. Male C57/BL 6J mice with B16BF6 melanoma tumor showed decreased expression of myosin heavy chain (MHC) in the gastrocnemius muscle. Moreover, the expression of SOCS3 and phosphorylated STAT3 and AMPK was increased, and the expression of phosphorylated 4E-BP1 was decreased in the gastrocnemius muscle of tumor-bearing mice. These data suggested that amino acid metabolism was altered in tumor-bearing mice, which were normalized by the NYT intervention. The present study showed that NYT might be a novel therapeutic option for the treatment of sarcopenia occurring cancer cachexia.

Possible Involvement of Insulin Resistance in the Progression of Cancer Cachexia in Mice.

Malnutrition is a common problem among cancer patients, affecting up to 85% of patients with certain cancers. In severe cases, malnutrition can progress to cachexia, a specific form of malnutrition characterized by loss of lean body mass and muscle wasting. Although this muscle wasting might be a product of enhanced protein degradation, the precise mechanisms of cancer cachexia are not fully elucidated. Based on basic and clinical research, glucose intolerance and insulin resistance have been postulated to be associated with cancer cachexia. Since insulin in the skeletal muscle inhibits protein degradation and promotes protein synthesis, insulin resistance could be a possible cause of cancer cachexia. Therefore, we investigated the involvement of insulin resistance in the development of cancer cachexia in tumor-bearing mice. The signaling protein in the insulin cascade was attenuated in the skeletal muscle and hypothalamus from tumor-bearing mice. We identified Chrysanthemum morifolium RAMAT., known as Kikuka, as a peroxisome proliferator-activated receptor γ (PPARγ) ligand. Treatment with Kikuka attenuates the skeletal muscle changes in tumor-bearing mice. These results suggest that this natural PPARγ activator might be an attractive candidate for the treatment of cancer cachexia. In the symposium, we presented the PPARγ activator-induced improvement of cancer cachexia.