Influence of dosing times on cisplatin-induced peripheral neuropathy in rats

Abstract

Background: Although cis-diamminedichloro-platinum (CDDP) exhibits strong therapeutic effects in cancer chemotherapy, its adverse effects such as peripheral neuropathy, nephropathy, and vomiting are dose-limiting factors. Previous studies reported that chronotherapy decreased CDDP-induced nephropathy and vomiting. In the present study, we investigated the influence of dosing times on CDDP-induced peripheral neuropathy in rats.

Methods: CDDP (4 mg/kg) was administered intravenously at 5:00 or 17:00 every 7 days for 4 weeks to male Sprague-Dawley rats, and saline was given to the control group. To assess the dosing time dependency of peripheral neuropathy, von-Frey test and hot-plate test were performed.

Results: In order to estimate hypoalgesia, the hot-plate test was performed in rats administered CDDP weekly for 4 weeks. On day 28, the withdrawal latency to thermal stimulation was significantly prolonged in the 17:00-treated group than in the control and 5:00-treated groups. When the von-Frey test was performed to assess mechanical allodynia, the withdrawal threshold was significantly lower in the 5:00 and 17:00-treated groups than in the control group on day 6 after the first CDDP dose. The 5:00-treated group maintained allodynia throughout the experiment with the repeated administration of CDDP, whereas the 17:00-treated group deteriorated from allodynia to hypoalgesia.

Conclusions: It was revealed that the severe of CDDP-induced peripheral neuropathy was inhibited in the 5:00-treated group, whereas CDDP-treated groups exhibited mechanical allodynia. These results suggested that the selection of an optimal dosing time ameliorated CDDP-induced peripheral neuropathy.

Keywords: Chronotherapy; Cisplatin; Peripheral neuropathy.

Fig. 1

Influence of CDDP dosing times on adverse effects (a Change rate in body weight, b BUN) in rats. CDDP was administered every 7 days at 5:00 or 17:00. Saline was administered to the control group. Each value represents the mean with S.E.M. (a control group (n = 12); each CDDP-treated group (n = 10). b each control group (n = 6); each CDDP-treated group (n = 10)). a **: P < 0.01 versus the control group; #: P < 0.05 and ##: P < 0.01 versus the 5:00-treated group using Scheffe’s test. b *: P < 0.05 and **: P < 0.01 versus the control group at 5:00; #: P < 0.05 and ##: P < 0.01 versus the control group at 17:00 using Scheffe’s test

Fig. 2

Influence of CDDP dosing times on recovery from mechanical allodynia in rats after a single dose (a von-Frey test, b Hot plate test on day 24). CDDP was administered to rats at 5:00 or 17:00. Saline was administered to the control group. Each value represents the mean with S.E.M. (n = 8). *: P < 0.05, **: P < 0.01 versus the control group; #: P < 0.05 versus the 5:00-treated group using Scheffe’s test

Fig. 3

Influence of CDDP dosing times on withdrawal thresholds during its administration to rats. CDDP was administered every 7 days at 5:00 or 17:00. Saline was administered to the control group. Each value represents the mean with S.E.M. (n = 8). **: P < 0.01 versus the control group; ##: P < 0.01 versus the 5:00-treated group using Scheffe’s test

Fig. 4

Influence of CDDP dosing times on hypoalgesia during its repeated administration to rats. CDDP was administered every 7 days at 5:00 or 17:00. Saline was administered to the control group. Each value represents the mean with S.E.M. a (n = 4); b (n = 8). P < 0.01 using Scheffe’s test

Fig. 5

Influence of CDDP dosing times on its concentration in the dorsal root ganglia (DRG) after its first (a) or fourth (b) administration. CDDP was administered every 7 days at 5:00 or 17:00. Each value represents the mean with S.E.M. (n = 6)