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

Autor:	Stratton HJ; Department of Pharmacology, College of Medicine, The University of Arizona, Tucson, AZ, United States., Boinon L; Department of Pharmacology, College of Medicine, The University of Arizona, Tucson, AZ, United States., Gomez K; Department of Molecular Pathobiology, College of Dentistry, New York University, New York, NY, United States.; NYU Pain Research Center, New York, NY, United States., Martin L; Department of Anesthesiology, College of Medicine, The University of Arizona, Tucson, AZ, United States., Duran P; Department of Molecular Pathobiology, College of Dentistry, New York University, New York, NY, United States.; NYU Pain Research Center, New York, NY, United States., Ran D; Department of Pharmacology, College of Medicine, The University of Arizona, Tucson, AZ, United States., Zhou Y; Department of Pharmacology, College of Medicine, The University of Arizona, Tucson, AZ, United States., Luo S; Department of Pharmacology, College of Medicine, The University of Arizona, Tucson, AZ, United States., Perez-Miller S; Department of Molecular Pathobiology, College of Dentistry, New York University, New York, NY, United States.; NYU Pain Research Center, New York, NY, United States., Patek M; BrightRock Path, LLC, Tucson, AZ, United States., Ibrahim MM; Department of Anesthesiology, College of Medicine, The University of Arizona, Tucson, AZ, United States., Patwardhan A; Department of Anesthesiology, College of Medicine, The University of Arizona, Tucson, AZ, United States., Moutal A; Department of Pharmacology and Physiology, School of Medicine, Saint Louis University, Saint Louis, MO, United States., Khanna R; Department of Molecular Pathobiology, College of Dentistry, New York University, New York, NY, United States.; NYU Pain Research Center, New York, NY, United States.
Jazyk:	angličtina
Zdroj:	Pain [Pain] 2023 Jul 01; Vol. 164 (7), pp. 1473-1488. Date of Electronic Publication: 2022 Dec 19.
DOI:	10.1097/j.pain.0000000000002850
Abstrakt:	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. (Copyright © 2023 International Association for the Study of Pain.)
Databáze:	MEDLINE
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