Repeated Valproic Acid Administration Fundamentally Ameliorated Cisplatin-Induced Mechanical Allodynia in Rats

Abstract

Cisplatin (cis-diamminedichloro-platinum; CDDP) is a chemotherapeutic agent that frequently induces peripheral neuropathy characterized by mechanical allodynia. Herein, we aimed to determine the effects of valproic acid (VPA) on cisplatin-induced mechanical allodynia in rats and elucidate the underlying mechanisms. A single administration of VPA (150 mg/kg) transiently suppressed CDDP-induced mechanical allodynia, correlating with serum VPA concentrations. Repeated VPA administration before or after the onset of CDDP-induced mechanical allodynia significantly attenuated allodynia even after VPA discontinuation, suggesting fundamental treatment potential. Mechanistically, CDDP increased the expression of neurokinin 1 receptor (NK1R) mRNA in the dorsal horn of the spinal cord, and this increased expression was suppressed by repeated VPA administration. Treatment with an NK1R antagonist alleviated CDDP-induced mechanical allodynia, indicating the involvement of NK1R in allodynia. In vitro assays revealed that VPA did not affect the cytotoxicity of CDDP in Walker 256 cells, suggesting that VPA does not interfere with the antitumor activity of CDDP. Overall, repeated VPA administration may fundamentally ameliorate CDDP-induced peripheral neuropathy by suppressing the CDDP-induced increased NK1R expression without compromising the antitumor effects of CDDP. These findings provide insights into the potential use of VPA as a therapeutic agent for managing CDDP-induced peripheral neuropathy.

Keywords: cisplatin; mechanical allodynia; valproic acid.

Figure 1

Dose–response effects and temporal changes after a single administration of VPA on CDDP-induced mechanical allodynia in rats. (A) CDDP (4 mg/kg) was intravenously administered at 5:00 on day 0, with saline administered to the control group. VPA (75, 150, or 300 mg/kg/day) was orally administered at 8:00 on day 3, and the von Frey test was performed on days −1 and 3. Each value represents the mean and standard error (SEM; n = 4). (B) CDDP (4 mg/kg) was intravenously administered at 5:00 on day 0, and VPA (150 mg/kg) was orally administered at 8:00 on day 3. The von Frey test was performed 2, 4, 6, 8, 10, 12, 14, 16, and 24 h after the VPA administration. Each value represents the mean and SEM (n = 6). *: p < 0.05, **: p < 0.01, N.S. means not significant among all groups. CDDP, cisplatin (cis-diamminedichloro-platinum); VPA, valproic acid.

Figure 2

Effect of repeated administration of VPA on CDDP-induced mechanical allodynia in rats. (A) CDDP (4 mg/kg) or saline was intravenously administered at 5:00 on day 0. VPA (150 mg/kg) or simple syrup was orally administered twice daily (8:00 and 20:00) for 7 days (day −1 to day 6). Each value represents the mean and standard error (SEM; n = 5–6). *: p < 0.05, **: p < 0.01 vs. control; #: p < 0.05, ##: p < 0.01 vs. CDDP + VPA. (B) CDDP (4 mg/kg) or saline was intravenously administered at 5:00 on day 0. VPA (150 mg/kg) or simple syrup was orally administered twice daily (8:00 and 20:00) for 7 days (days 5 to 11). Each value represents the mean and SEM (n = 7–8). *: p < 0.05, **: p < 0.01 vs. control; #: p < 0.05, ##: p < 0.01 vs. CDDP + VPA. CDDP, cisplatin (cis-diamminedichloro-platinum); VPA, valproic acid.

Figure 3

Effects of single and repeated VPA administration on Nk1r mRNA expression in the spinal cord dorsal horn of rats. (A) Expression of Nk1r mRNA in the spinal cord dorsal horn after a single administration of VPA. CDDP (4 mg/kg) or saline was intravenously administered at 5:00 on day 0. VPA (150 mg/kg) or simple syrup was orally administered at 8:00 on day 6. Each value represents the mean and standard error (SEM; n = 6). (B) Expression of Nk1r mRNA level in the spinal cord dorsal horn after repeated VPA administration. CDDP (4 mg/kg) or saline was intravenously administered at 5:00 on day 0. VPA (150 mg/kg) or simple syrup was orally administered twice daily (8:00 and 20:00) for 7 days (day −1 to day 6). Each value represents the mean and SEM (n = 6). CDDP. CDDP, cisplatin (cis-diamminedichloro-platinum); VPA, valproic acid.

Figure 4

Effects of NK1R antagonist on CDDP-induced mechanical allodynia in rats. CDDP (4 mg/kg) or saline was intravenously administered at 5:00 on day 0. An NK1R antagonist, aprepitant (2 mg/kg), or vehicle was orally administered at 8:00 on day 6. The von Frey test was performed 4 h after aprepitant administration. Each value represents the mean and standard error (SEM; n = 6). CDDP. CDDP, cisplatin (cis-diamminedichloro-platinum); VPA, valproic acid.

Figure 5

Effect of VPA on the viability of tumor cells. Walker 256 cells were incubated with VPA (A) or CDDP 10 μM + VPA (B) for 24 h, and cell viability was assessed. Each value represents the mean and standard error (SEM; A: n = 6, B: n = 3). N.S. means not significant among all groups. CDDP, cisplatin (cis-diamminedichloro-platinum); VPA, valproic acid.