Neuropathic pain alleviating effects of an LRP1-targeting peptide against paclitaxel-induced peripheral neuropathy

Chemotherapy-induced peripheral neuropathy (CIPN) is a common, toxic side effect of chemotherapy agents. It affects over half of the 28 million cancer survivors in the US. CIPN can be described as sensory nerve impairment accompanied by chronic pain (paresthesia, tingling), often with devastating losses of quality of life. CIPN-induced pain frequently results in a dose reduction and a decrease in treatment adherence, which could impair the successful outcome of cancer treatment. There are no curative treatments for CIPN, and currently therapeutic options such as opioids or anti-seizure drugs aim at temporarily reducing pain to a manageable level; however, they can cause severe side effects, addiction and are not neuroprotective. Herein, we tested an innovative 17 AA peptide derived from -1-Antitrypsin (AAT), SP16. This peptide shows safety and tolerability during Phase 1 and 2 clinical trials for acute myocardial infarction (AMI). Pharmacologically, SP16 is an agonist of the low-density lipoprotein receptor-related protein-1 (LRP1), and activation of LRP1 results in anti-inflammatory and pro-survival action through the NF-κB and the AKT signaling pathways in glia and neural cells. Our published findings, suggest that LRP1 would be a robust therapeutic target to manage neuropathic pain. Using surface plasmon resonance (SPR), we demonstrate that SP16 binds to LRP1 with high affinity (Kd; 697 nM) whereas a scrambled SP16 peptide showed no specific binding. Next, we established a CIPN model using paclitaxel in male mice. Paclitaxel (PXT) is one of the most effective and widely used chemotherapy agents. First, we administered PXT to scLRP1+/+ and scLRP1-/- mice (conditional deletion of LRP1 in peripheral glia, Schwann cells). A cumulative dose of PXT was achieved by administering 4mg/kg i.p. every other day for eight days. Pain-related behaviors, including cold allodynia (acetone test) and mechanical hypersensitivity (von frey) were measured weekly. Both scLRP1+/+ and scLRP1-/- mice showed increased mechanical hypersensitivity and cold allodynia immediately following the PXT treatment and the effects were sustained for 4 weeks. Next, we administered SP16 (2 mg/kg 3X per week, s.c.) at the start of PXT treatment in scLRP1+/+ mice and measured pain related behaviors. SP16-treated PXT mice showed significantly reduced mechanical hypersensitivity (P<0.05) after PXT treatment, compared to vehicle treated PXT mice, that was sustained for 4 weeks. Moreover, SP16-treated PXT mice demonstrated significantly reduced cold allodynia (P<0.05) by week 4 after PXT treatment. Taken collectively, SP16 treatment mitigates pain related behaviors induced by PXT treatment, and LRP1 is a potential therapeutic target for treating CIPN.