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. 2021 Apr 15;162(10):2599–2612. doi: 10.1097/j.pain.0000000000002256

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Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the International Association for the Study of Pain.

This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

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Figure 5. — The DLK inhibitor IACS′8287 prevents cisplatin-induced cognitive impairments. Behavioral tests including Y-maze, NOPRT, and the puzzle box tests were started 1 week after the last administration of IACS′8287 and cisplatin. (A) IACS′8287 prevented cisplatin-induced spatial working memory deficits in the Y-maze test. The percentage of perfect alternations (alternation rate) was calculated (n = 12, two-way ANOVA reveals significant main effect on interaction: F (1, 44) = 5.398, P = 0.0251; Tukey post hoc analysis: *P < 0.05). (B) IACS′8287 prevented cisplatin-induced spatial memory deficits in NOPRT. The discrimination index was used as a measure for the preference for the novel object (n = 12, two-way ANOVA reveals significant main effect on interaction: F (1, 44) = 9.598, P = 0.034; Tukey post hoc analysis: **P < 0.01, ***P < 0.0001). (C) IACS′8287 prevented cisplatin-induced impairments in executive functioning tested in the puzzle box test. Trials 1 to 4, the underpass was unobstructed; trials 5 to 7, the underpass was filled with corncob bedding; trials 8 to 11, the underpass was covered by the cardboard plug. The time it took for the mice to enter the goal box was used as an index for executive functioning. (n = 12, two-way ANOVA reveals significant main effect on interaction: F (30, 402) = 12.08, P < 0.0001; Tukey post hoc analysis: **P < 0.01, ***P < 0.001 vs Veh+PBS, ^^P < 0.01, ^^^P < 0.001, ^^^^P < 0.0001 vs IACS′8287+cisplatin). (D) fMRI analysis of connectome global efficiency. IACS′8287 prevented cisplatin-induced disruption of functional connectome global efficiency (n = 4, nonparametric permutation testing, *P < 0.05, **P < 0.01). (E) Oxygen consumption rates were analyzed in isolated synaptosomes using the Seahorse XFe24 Flux Analyzer. Changes induced by cisplatin and IACS′8287 in basal OCR, MRC, and SRC (n = 8, two-way ANOVA reveals significant main effect on interaction: F (1, 28) = 11, P = 0.0025 for MRC; F (1, 28) = 8.933, P = 0.0058 for SRC; Tukey post hoc analysis: *P < 0.05). Results are expressed as mean ± SEM. ANOVA, analysis of variance; DLK, dual leucine zipper kinase; fMRI, resting state functional magnetic resonance imaging; MRC, maximal respiratory capacity.