Comparing the Neuroprotective Efficacy of P7C3‐A20 to Novel P7C3 Derivatives in a Rodent Model of Paclitaxel‐Induced Peripheral Neuropathy

Abstract

Chemotherapy‐induced peripheral neuropathy (CIPN) is a prevalent adverse effect of anti‐cancer chemotherapeutics like paclitaxel (PTX), a microtubule targeting agent known to induce severe and persistent neuropathic pain. The development of CIPN not only diminishes the quality of life of cancer patients, but also downgrades their cancer prognosis as dose reduction or cessation of their anti‐cancer regimen are the only clinical interventions currently available for CIPN. Thus, the development of a pharmacological intervention that limits the neuropathic side‐effects of anti‐cancer chemotherapy is urgently needed. Here we tested the neuroprotective effects of the aminopropyl carbazole, P7C3‐A20 (A20), and several A20 derivatives in a rat model of paclitaxel‐induced peripheral neuropathy. All experiments were done by investigators blinded to the drug treatments. Racemic A20 (2.2, 6.6, 20 mg/kg, i.p., q.d.), or vehicle, was administered daily to male Sprague‐Dawley rats over a 14‐day period beginning 2 days before PTX treatment (11.7 mg/kg/day, i.p.; every other day for 3 injections). A20 dose‐dependently attenuated PTX‐induced mechanical allodynia in rats. Evaluation of intraepidermal nerve fiber (IENF) density in rat paw biopsies using immunohistochemical staining revealed that treatment with PTX produced a profound loss in IENF density that was prevented by treatment with A20. Further, statistical analysis indicated strong correlations between IENF density, a diagnostic marker of CIPN in humans, and nociceptive threshold to mechanical stimuli. Enantiomer specific mixtures of A20 (20 mg/kg, i.p., q.d.), racemic A20 (20 mg/kg, i.p., q.d.), or vehicle were then administered utilizing the same behavioral paradigm and PTX dosing schedule as above. Consistent with our previous data, racemic A20 attenuated PTX‐induced mechanical allodynia and the S‐enantiomer was identified as the active component of the racemic mixture. We have also tested the neuroprotective efficacy of four novel A20 derivatives coded as compounds A through D. The A20 derivatives were administered daily at 20 mg/kg by i.p. injection and mechanical allodynia was assayed as described above. One compound, Drug C, provided robust protection against PTX‐induced mechanical allodynia, whereas the compounds A, B, and D demonstrated limited neuroprotective efficacy. Taken together, A20 and perhaps its derivatives are an exciting new class of pharmacological agents that may have clinical utility for alleviating peripheral neuropathies caused by various anti‐cancer chemotherapeutics.Support or Funding InformationSupported in part by Calico Life Sciences and Proneurotech.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.