Characterization of the potent and selective Peroxisome Proliferator-Activated Receptor-α (PPAR- α) agonist Pemafibrate in a mouse model of Chemotherapy-Induced Peripheral Neuropathy (CIPN)

The lifetime probability of developing an invasive cancer like breast, ovarian, or lung is roughly 40% in both men and women (Siegel et al., 2020). Of these patients that are treated with paclitaxel, a cancer chemotherapeutic, up to 70% are likely to develop some degree of chemotherapy-induced peripheral neuropathy (CIPN) with symptoms of numbness, lost sense of proprioception, tingling, and mechanical and thermal allodynia (Boyette-Davis et al., 2018; Park et al., 2013). However, recent CIPN rodent model studies have shown that activation of the nuclear receptor Peroxisome Proliferator- Activated Receptor-α (PPARα) using choline fenofibrate produced partial reversal and prevention of paclitaxel-induced mechanical and cold hypersensitivity. Unfortunately, not only was CIPN not fully reversed or prevented, but fibrates are also associated with a number of adverse side effects, like damage to the kidneys, liver, and the development of myopathy when co-administered with statins (Jacobson et al., 2009; Škop et al., 2016; Post et al., 2001). With these limitations, we investigated if pemafibrate, a new, more specific, and more potent PPARα agonists, could be more efficacious in reversing and preventing CIPN than previously seen choline fenofibrate. To answer this question, we first observed that acute administration of pemafibrate dose- and time-dependently reversed paclitaxel-induced mechanical and cold hypersensitivity through PPARα activation. Our second aim investigated if the effects of acute pemafibrate administration could be maintained after repeated treatment or would tolerance to the drug develop. Lastly, after we observed that repeated oral administration of pemafibrate reverses paclitaxel-induced mechanical and cold hypersensitivity and reduction of NAP amplitude without the development of tolerance, in our third aim, we then saw the prevention of these same measurements after both the pretreatment of pemafibrate and coadministration of pemafibrate and paclitaxel. Ultimately, the findings within this study show the therapeutic potential of pemafibrate in the reversal and prevention of the effects of paclitaxel-induced peripheral neuropathy