Targeting the low-density lipoprotein receptor-related protein for treating pain
- Author(s): Wang, Zixuan
- Advisor(s): Campana, Wendy M
- Yang, Jerry
- et al.
The low-density lipoprotein receptor-related protein-1 (LRP1) is an endocytic and cell signaling receptor, highly involved in innate immunity. Although activation of membrane-bound LRP1 results in anti-inflammatory activity in vitro and in vivo, and genetic deletion of LRP1 in Schwann cells increase neuropathic pain, the ability of LRP1 agonists to alleviate pain is unknown. Thus, we tested whether a novel small peptide, SP16, derived from alpha-1-anti-trypsin and binds LRP1 with high affinity, could regulate pain states in three distinct mice models. Initially, we determined that SP16 robustly activates cell signaling in PC12 cells via an LRP1 dependent manner. SP16 also increased neurite length and expression of regenerative genes in cultured adult primary sensory neurons. In response to intraplantar capsaicin, SP16, two SP16 analogs (A2-5, A15) and a well-known LRP1 activator, enzymatically inactive (EI)-tissue plasminogen activator (tPA) significantly reduced paw licking time compared to vehicle. SP16 blocked the development of tactile allodynia after partial sciatic nerve ligation (P<0.05). The underlying mechanism includes limited recruitment of CD11b+ inflammatory cells (P<0.01) into the nerve injury site and reduced levels of Toll-like receptor-4 (TLR4) (P<0.05). In injured DRGs, SP16 reduced the presence of CD11b+ cells and GFAP, suggesting that inflammatory and satellite cell activation was inhibited. Following intraplantar formalin injection, SP16-treated mice showed reduced responses in phase 1 (P<0.01) and delayed the onset of phase 2 (P<0.05). We conclude that SP16 inhibits acute nociceptive, inflammatory, and neuropathic pain-related behaviors, suggesting that LRP1 agonists have uniquely broad anti-inflammatory activities that minimize the development of pain states.