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. 2023 Oct 3;147(3):1025–1042. doi: 10.1093/brain/awad339

Figure 6.

Figure 6

RAGE antisense prevents and reverses oxaliplatin, paclitaxel and bortezomib CIPN. Top: Separate groups of male rats were treated intrathecally (i.t.) with antisense (AS)- or sense (SE)-oligodeoxynucleotides (ODN) (both 120 μg in 20 μl/day) against RAGE mRNA, once a day, starting 3 days before the chemotherapy agents, for seven doses, over 10 days. Rats received: (A) oxaliplatin [2 mg/kg, intravenously (i.v.), on Day 0]; (B) paclitaxel [1 mg/kg, intraperitoneally (i.p.), on Days 0, 2, 4 and 6]; or (C) bortezomib (0.2 mg/kg, i.v., on Days 0, 2, 4 and 6). The mechanical nociceptive threshold was evaluated before the first intrathecal administration of ODN (Day −3) and then from Days 0 to 28. In the RAGE AS-ODN-treated groups, CIPN hyperalgesia was markedly inhibited in the oxaliplatin-, paclitaxel- and bortezomib-treated rats (A, B and C, respectively), and this attenuation was undiminished for the 28-day testing period. Statistical analyses for (A) oxaliplatin: two-way repeated-measures ANOVA, Time × RAGE AS-ODN interaction, F(5,50) = 6.772, P < 0.0001; RAGE AS-ODN treatment, F(1,10) = 637.3, P < 0.0001; Bonferroni's multiple post hoc comparisons test, ****P < 0.0001 (RAGE SE-ODN versus AS-ODN); (B) paclitaxel: two-way repeated-measures ANOVA, Time × RAGE AS-ODN interaction, F(7,70) = 21.52, P < 0.0001; RAGE AS-ODN treatment, F(1,10) = 151.6, P < 0.0001; Bonferroni's multiple post hoc comparisons test, ***P = 0.0002, ****P < 0.0001, aaaP = 0.0006, cccP = 0.0004 (RAGE SE-ODN versus AS-ODN); and (C) bortezomib: two-way repeated-measures ANOVA, Time × RAGE AS-ODN interaction, F(6,60) = 19.11, P < 0.0001; RAGE AS-ODN treatment, F(1,10) = 238.3, P < 0.0001; Bonferroni's multiple post hoc comparisons test, **P = 0.0071, ****P < 0.0001, ***P = 0.0002, aaaP = 0.0007, cccP = 0.0006 (RAGE SE-ODN versus AS-ODN). Bottom: Separate groups of male rats received: (D) oxaliplatin (2 mg/kg, i.v., on Day 0); (E) paclitaxel (1 mg/kg, i.p., on Days 0, 2, 4 and 6); or (F) bortezomib (0.2 mg/kg, i.v., on Days 0, 2, 4 and 6). Each group was then treated intrathecally with an AS-ODN or SE-ODN (both 120 μg in 20 μl/day) against RAGE mRNA once a day starting 3 days after the last dose of chemotherapy drug, for seven doses, over 10 days. The mechanical nociceptive threshold was evaluated from Days 0 to 28. In the RAGE AS-ODN-treated groups, CIPN hyperalgesia was markedly attenuated in oxaliplatin-, paclitaxel- and bortezomib-treated rats, and this attenuation was undiminished for the 28-day testing period. Statistical analyses for (D) oxaliplatin: two-way repeated-measures ANOVA, Time × RAGE AS-ODN interaction, F(4,40) = 94.86, P < 0.0001; RAGE AS-ODN treatment, F(1,10) = 862.4, P < 0.0001; Bonferroni's multiple post hoc comparisons test, ****P < 0.0001 (RAGE SE-ODN versus AS-ODN); (E) paclitaxel: two-way repeated-measures ANOVA, Time × RAGE AS-ODN interaction, F(4,40) = 91.51, P < 0.0001; RAGE AS-ODN treatment, F(1,10) = 69.15, P < 0.0001; Bonferroni's multiple post hoc comparisons test, ****P < 0.0001 (RAGE SE-ODN versus AS-ODN); and (F) bortezomib: two-way repeated-measures ANOVA, Time × RAGE AS-ODN interaction, F(6,60) = 78.44, P < 0.0001; RAGE AS-ODN treatment, F(1,10) = 246.5, P < 0.0001; Bonferroni's multiple post hoc comparisons test, ****P < 0.0001 (RAGE SE-ODN versus AS-ODN). n = 6 paws for each group. All data are mean ± SEM. CIPN = chemotherapy-induced peripheral neuropathy.