LRP1 Agonist SP16 Reduces Pain Behaviors and Neuroinflammation in Mouse Model of Chemotherapy-Induced Peripheral Neuropathy

Pharmacological activation of the low-density lipoprotein receptor-related protein 1 (LRP1) in Schwann cells (SCs) attenuated pain-related behaviors and neuroinflammation in a mouse model of chemotherapy-induced painful peripheral neuropathy (CIPPN), according to new preclinical findings.¹ The results reinforce LRP1 as a mechanistically distinct target for neuropathic pain and build on a growing body of work linking SC biology to the development and maintenance of chronic pain.

The findings were featured among the abstracts at the 2026 Peripheral Nerve Society (PNS) Annual Meeting in Maastricht, Netherlands. Led by Wendy Campana, PhD, Chair of the Department of Cell Biology and Human Anatomy at UC Davis and a specialist in Schwann cell physiology and peripheral nerve injury, the study examined the effects of SP16, a synthetic peptide LRP1 agonist, in a paclitaxel (PTX)-induced neuropathy model.

Background

Paclitaxel is among the most widely used chemotherapeutic agents for solid tumors and is a leading cause of CIPPN, a dose-limiting toxicity affecting a substantial proportion of treated patients and for which no approved disease-modifying therapy exists. Mechanistically, paclitaxel has been shown to induce SC denervation, disrupt mitochondrial morphology in peripheral nerve fibers, and trigger neuroinflammation in the dorsal root ganglia (DRG) and sciatic nerve.²

LRP1 is a multifunctional endocytic and cell signaling receptor expressed on SCs that regulates SC survival, bioenergetics, and neuroinflammatory signaling. Conditional deletion of LRP1 in SCs in mice results in failed sensory recovery after peripheral nerve injury, increased neuropathic pain, and ultrastructural abnormalities in Remak bundles, the unmyelinated axon-SC complexes most relevant to pain processing.³ Prior work from the Campana laboratory demonstrated that SP16, a 17-amino acid peptide derived from the carboxyl terminus of alpha-1 antitrypsin and containing LRP1 recognition sequences, reduces nociceptive and neuropathic pain behaviors in rodents when administered systemically, with efficacy in both acute and chronic pain models.⁴

Methods

SP16 binding affinity to purified human LRP1 was measured by surface plasmon resonance. Mice with conditional deletion of LRP1 in SCs (scLRP1-/-) and littermate controls (scLRP1+/+) were randomized to vehicle, PTX, or PTX plus SP16 treatment groups. Mechanical hypersensitivity was assessed using von Frey filaments and the up-down method; cold hyperalgesia was measured by acetone response. Sciatic nerve lysates were profiled by cytokine array, and expression of CD11b and SDF-1 in sciatic nerve and DRGs was examined by immunofluorescence.

Key Findings

SP16 bound human LRP1 with strong affinity, with a dissociation constant (Kd) of approximately 700 nM.¹ In scLRP1+/+ mice, SP16 significantly reduced mechanical hypersensitivity acutely following PTX treatment (P < .01) and attenuated cold-evoked pain behaviors at chronic endpoints of 4 to 6 weeks (P < .01). Critically, in scLRP1-/- mice lacking LRP1 specifically in SCs, SP16 did not mitigate pain-related behaviors, confirming that the analgesic effects are SC LRP1-dependent rather than off-target.¹

Immunofluorescent staining of sciatic nerve in scLRP1+/+ mice showed an increase in CD11b-positive macrophage-lineage cells in the PTX group that was absent in PTX plus SP16-treated animals, suggesting SP16 attenuates macrophage infiltration. Cytokine array analysis revealed upregulation of SDF-1 and M-CSF in the PTX group relative to vehicle, with both cytokines downregulated in the PTX plus SP16 group in scLRP1+/+ mice. These pro-inflammatory changes were not modulated by SP16 in scLRP1-/- animals, further supporting LRP1 dependency of the mechanism.¹

Clinical Context

CIPPN affects an estimated 30 to 40% of patients receiving neurotoxic chemotherapy and can persist long after treatment completion, significantly impairing quality of life and often limiting chemotherapy dose intensity. Current management relies primarily on duloxetine, the only agent with conditional guideline support for CIPPN-associated pain, and symptomatic approaches including gabapentinoids and tricyclic antidepressants, none of which address underlying nerve pathology.⁵

Limitations

The study is preclinical and conducted in a mouse model, and translation to humans will require further development of SP16 or related LRP1 agonists as drug candidates. The small molecule or peptide pharmacology of LRP1 agonism at the clinical scale remains to be established. No human safety or pharmacokinetic data are available for SP16.

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REFERENCES
1. Wang Z, Migliorini M, Strickland D, Campana W. Therapeutic potential of an LRP1 agonist for chemotherapy-induced neuropathic pain. Abstract submitted to: Peripheral Nerve Society Annual Meeting; June 13-16, 2026; Maastricht, Netherlands. Abstract P 256.
2. Martellucci S, Heredia M, Wang Z, et al. The low-density lipoprotein receptor-related protein-1 (LRP1) in Schwann cells controls mitochondria homeostasis in peripheral nerves. Pain. 2025. doi:10.1097/j.pain.0000000000003555. https://pubmed.ncbi.nlm.nih.gov/40541732/
3. Orita S, Henry KW, Mantuano E, et al. Schwann cell LRP1 regulates Remak bundle ultrastructure and axonal interactions to prevent neuropathic pain. J Neurosci. 2013;33(13):5590-5602. doi:10.1523/JNEUROSCI.2blah-12.2013. https://pmc.ncbi.nlm.nih.gov/articles/PMC3816524/
4. Wang Z, Martellucci S, Van Enoo A, et al. Systemically administered SP16, a low-density lipoprotein receptor related protein LRP1 agonist, demonstrates efficacy for treating acute and neuropathic pain. FASEB J. 2022;36(1):e22093. doi:10.1096/fj.202101359R. https://pmc.ncbi.nlm.nih.gov/articles/PMC8669735/
5. Loprinzi CL, Lacchetti C, Bleeker J, et al. Prevention and management of chemotherapy-induced peripheral neuropathy in survivors of adult cancers: ASCO guideline update. J Clin Oncol. 2020;38(28):3325-3348. doi:10.1200/JCO.20.01399. https://doi.org/10.1200/JCO.20.01399