Nerve growth factor derivative NGF61/100 promotes outgrowth of primary sensory neurons with reduced signs of nociceptive sensitization

C. Severini, P. Petrocchi Passeri, M. T. Ciotti, F. Florenzano, C. Petrella, F. Malerba, B. Bruni, M. D'Onofrio, I. Arisi, R. Brandi, R. Possenti, P. Calissano, A. Cattaneo

Research output: Contribution to journalArticlepeer-review

Abstract

Nerve Growth Factor (NGF) is being considered as a therapeutic candidate for Alzheimer's disease. However, the development of an NGF-based therapy is limited by its potent pain activity. We have developed a “painless” derivative form of human NGF (NGF61/100), characterized by identical neurotrophic properties but a reduced nociceptive sensitization activity in vivo. Here we characterized the response of rat dorsal root ganglia neurons (DRG) to the NGF derivative NGF61/100, in comparison to that of control NGF (NGF61), analyzing the expression of noxious pro-nociceptive mediators. NGF61/100 displays a neurotrophic activity on DRG neurons comparable to that of control NGF61, despite a reduced activation of PLCγ, Akt and Erk1/2. NGF61/100 does not differ from NGF61 in its ability to up-regulate Substance P (SP) and Calcitonin Gene Related Peptide (CGRP) expression. However, upon Bradykinin (BK) stimulation, NGF61/100-treated DRG neurons release a much lower amount of SP and CGRP, compared to control NGF61 pre-treated neurons. This effect of painless NGF is explained by the reduced up-regulation of BK receptor 2 (B2R), respect to control NGF61. As a consequence, BK treatment reduced phosphorylation of the transient receptor channel subfamily V member 1 (TRPV1) in NGF61/100-treated cultures and induced a significantly lower intracellular Ca2+ mobilization, responsible for the lower release of noxious mediators. Transcriptomic analysis of DRG neurons treated with NGF61/100 or control NGF allowed identifying a small number of nociceptive-related genes that constitute an “NGF pain fingerprint”, whose differential regulation by NGF61/100 provides a strong mechanistic basis for its selective reduced pain sensitizing actions.

Original languageEnglish
Pages (from-to)134-148
Number of pages15
JournalNeuropharmacology
Volume117
DOIs
Publication statusPublished - May 1 2017

Keywords

  • Bradykinin receptors
  • CGRP
  • Dorsal root ganglion neurons
  • NGF
  • Substance P

ASJC Scopus subject areas

  • Pharmacology
  • Cellular and Molecular Neuroscience

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