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. 2017 Nov 10;6:e29626. doi: 10.7554/eLife.29626

Figure 3. P7C3-A20 and P7C3-S321 are dose-dependently neuroprotective, improve general health, and attenuate premature death associated with PTX.

(A–C) AUCs to mechanical (A) and cold (B) stimulation and IENF densities (C) showing the dose-dependent neuroprotective effects of P7C3-A20 and P7C3-S321. Horizontal lines represent mean AUC ±SEM calculated from individual rat AUC values shown as small circles. ****p<0.0001, ***p<0.001, **p<0.01, *p<0.05 vs. Veh/PTX by one-way ANOVA with Dunnett’s post-hoc test, n = 5–17 rats/group. (D and E). Correlation analyses between individual rat IENF density and their respective mechanical (D) or cold (E) AUC (Pearson, two-tailed, p<0.0001). Black lines are linear regression curves with 95% confidence bands. Colors reflect treatment group as defined in Figure 3A–C. (F) Study attrition by treatment group. For each behavioral experiment, the number of rats removed due to >20% wt loss or death was divided by the total number of rats per treatment group. Data represent mean ± SEM, n = 1–4 independent experiments. (G) Survival curves showing attrition of rats treated only with PTX (red line) typically occurred between days 8–11, which was abolished by P7C3-A20 treatment. *p=0.0206 (χ2=13.32) by the Mantel-Cox log-rank test.

Figure 3—source data 1. Raw datasets for Figure 3 and all figure supplements.
Body weights, leukocytes, mechanical baselines, cold baselines, IENF density calculations, IENF-behavior correlation analyses, plasma drug levels for every rat by treatment group in the dose-response study.
elife-29626-fig3-data1.xlsx (405.6KB, xlsx)
DOI: 10.7554/eLife.29626.011

Figure 3.

Figure 3—figure supplement 1. Dose-dependent effects of P7C3-A20 and P7C3-S321 on PTX-induced mechanical and cold allodynia.

Figure 3—figure supplement 1.

(A and B) Timecourse of changes in paw nociceptive thresholds of rats treated with P7C3-A20 to mechanical (A) and cold (B) stimuli. (D and E) Timecourse of changes in paw nociceptive thresholds of rats treated with P7C3-S321 to mechanical (D) and cold (E) stimuli. (C and F) Plasma levels of P7C3-A20 (C) and P7C3-S321 (F). Plasma was acquired 16 hr after the final injection on day 16. Data are expressed as mean ±SEM, n = 7–17 rats/group. Drug doses (mg/kg/day) are indicated by numbers in parentheses.
Figure 3—figure supplement 2. Body weight, leukocyte counts, mechanical thresholds, and cold thresholds of all individual rats treated with vehicle or P7C3-A20 ± PTX.

Figure 3—figure supplement 2.

Individual timecourses of paw nociceptive thresholds for all rats in each treatment group in the dose-response experiment. Each treatment group is represented by n = 7–17 rats/group (weight, mechanical, cold) or 4 rats/group (leukocytes).
Figure 3—figure supplement 3. Effects of P7C3-A20 and P7C3-S321 on PTX-induced weight loss and leukopenia.

Figure 3—figure supplement 3.

(A and B) A maximal dose of P7C3-A20 (20 mg/kg/day) did not alter PTX-induced weight loss (A), but partially reduced leukopenia (B). (C and D) P7C3-S321 did not alter PTX-induced body weight loss (C) or leukopenia (D). Data are expressed as mean ± SEM, n = 7–17 rats/group (weight) or 4 rats/group (leukocyte counts). ****p<0.0001 vs. Veh/PTX by two-way ANOVA with Sidak’s post-hoc test.
Figure 3—figure supplement 4. P7C3-A20 improved general health of PTX-treated rats.

Figure 3—figure supplement 4.

Rats treated with vehicle or P7C3-A20 alone (top row) exhibited no overt signs of toxicity. The general health on day 7 of rats treated with PTX alone (middle row) was poor, with increased observations of diarrhea, mild hair loss, chromodacryorrhea, piloerection, grimacing, reduced grooming, standing/walking on ‘tip-toes,’ paw hovering, and jump responses. Comparatively, health indices for rats co-treated with P7C3-A20 and PTX (bottom row) were improved (see also Table 1).