PARP inhibitor compound 4a attentuates mechanical allodynia, thermal hyperalgesia, and cold hyperalgesia associated with cisplatin and oxaliplatin-induced neuropathy.

<p><b>(A)</b> After baseline behavioral testing, mice are randomized to experimental groups and PARP inhibitor compound 4a treatment by i.p. injection started two days before and continued with cisplatin or oxaliplatin drug regimen. Behavioral testing were conducted 24 hours after the last 10^th doses at week 3, and at post- chemotherapy or follow up evaluation at weeks 6 and 8. Behavioral assays: VF (VonFrey), RH (Radiant Heat), CP (Cold Plate). <b>(B)</b> Dosing with 50 mg/kg compound 4a or 25 mg/kg compound 4a in combination with cisplatin reversibly reduces mechanical allodynia in cisplatin- induced neuropathy mice compared to cisplatin alone at weeks 3, 6, and 8. Similarly, i.p. dosing with 50 mg/kg compound 4a in combination with oxaliplatin prevents mechanical allodynia in oxaliplatin-induced neuropathy mice compared to oxaliplatin alone at weeks 3 and 6. <b>(C)</b>. Dosing with 50 mg/kg of compound 4a in combination with cisplatin improves thermal hyperalgesia in cisplatin-induced neuropathy mice compared to cisplatin alone at weeks 3, 6, and 8. Similarly, dosing with 25 mg of compound 4a in combination with cisplatin reduces thermal hyperalgesia in cisplatin-induced neuropathy mice compared to cisplatin alone at weeks 6 and 8. Oxaliplatin did not elicit thermal hyperalgesia in mice. <b>(D)</b>. Dosing with 50 mg/kg compound 4a in combination with oxaliplatin reduces oxaliplatin-induced cold hyperalgesia compared to oxaliplatin alone at weeks 3, 6, and 8. Cisplatin did not induce cold hyperalgesia in mice. No effect of compound 4a on control mice. Data represent the mean ± S.E.M. of 7–8 mice, *<i>P</i><0.05; **<i>P</i><0.01; ***<i>P</i><0.001, two-way ANOVA followed with post hoc analysis.