Targeting the vascular endothelial growth factor A/neuropilin 1 axis for relief of neuropathic pain

Harrison J. Stratton, Lisa Boinon, Kimberly Gomez, Laurent Martin, Paz Duran, Dongzhi Ran, Yuan Zhou, Shizhen Luo, Samantha Perez-Miller, Marcel Patek, Mohab M. Ibrahim, Amol Patwardhan, Aubin Moutal, Rajesh Khanna

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Vascular endothelial growth factor A (VEGF-A) is a pronociceptive factor that causes neuronal sensitization and pain. We reported that blocking the interaction between the membrane receptor neuropilin 1 (NRP1) and VEGF-A-blocked VEGF-A-mediated sensory neuron hyperexcitability and reduced mechanical hypersensitivity in a rodent chronic neuropathic pain model. These findings identified the NRP1-VEGF-A signaling axis for therapeutic targeting of chronic pain. In an in-silico screening of approximately 480 K small molecules binding to the extracellular b1b2 pocket of NRP1, we identified 9 chemical series, with 6 compounds disrupting VEGF-A binding to NRP1. The small molecule with greatest efficacy, 4′-methyl-2′-morpholino-2-(phenylamino)-[4,5′-bipyrimidin]-6(1H)-one, designated NRP1-4, was selected for further evaluation. In cultured primary sensory neurons, VEGF-A enhanced excitability and decreased firing threshold, which was blocked by NRP1-4. In addition, NaV1.7 and CaV2.2 currents and membrane expression were potentiated by treatment with VEGF-A, and this potentiation was blocked by NRP1-4 cotreatment. Neuropilin 1-4 reduced VEGF-A-mediated increases in the frequency and amplitude of spontaneous excitatory postsynaptic currents in dorsal horn of the spinal cord. Neuropilin 1-4 did not bind to more than 300 G-protein-coupled receptors and receptors including human opioids receptors, indicating a favorable safety profile. In rats with spared nerve injury-induced neuropathic pain, intrathecal administration of NRP1-4 significantly attenuated mechanical allodynia. Intravenous treatment with NRP1-4 reversed both mechanical allodynia and thermal hyperalgesia in rats with L5/L6 spinal nerve ligation-induced neuropathic pain. Collectively, our findings show that NRP1-4 is a first-in-class compound targeting the NRP1-VEGF-A signaling axis to control voltage-gated ion channel function, neuronal excitability, and synaptic activity that curb chronic pain.

Original languageEnglish (US)
Pages (from-to)1473-1488
Number of pages16
JournalPain
Volume164
Issue number7
DOIs
StatePublished - Jul 1 2023

Keywords

  • CaV2.2
  • Chronic pain
  • NaV1.7
  • Neuropilin
  • VEGF-A

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology
  • Anesthesiology and Pain Medicine

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