Nerve growth factor derivative NGF61/100 promotes outgrowth of primary sensory neurons with reduced signs of nociceptive sensitization. (1st May 2017)

• Record Type: Journal Article
• Authors: Severini, C.; Petrocchi Passeri, P.; Ciotti, M.T.; Florenzano, F.; Petrella, C.; Malerba, F.; Bruni, B.; D'Onofrio, M.; Arisi, I.; Brandi, R.; Possenti, R.; Calissano, P.; Cattaneo, A.
• Is Part Of: Neuropharmacology. Volume 117(2017)
• Page Start: 134
• Page End: 148
• Publication Date: 2017-05-01
• Subjects: NGF -- Dorsal root ganglion neurons -- Substance P -- CGRP -- Bradykinin receptors; AD Alzheimers' disease -- BK bradykinin -- B2R bradykinin 2 receptor -- CGRP calcitonin gene-related peptide -- DRG dorsal root ganglion neurons -- Fluo-3 AM calcium sensitive fluorescent dye indicator -- NGF nerve growth factor -- NGF61 control NGF -- NGF61/100 painless NGF -- PPTA preprotachykinin A -- SP substance P -- TrkA tyrosine kinase receptor 1 -- TRPV1 vanilloid receptor subtype 1; Neuropsychopharmacology -- Periodicals; Autonomic Agents -- Periodicals; Neuropsychopharmacologie -- Périodiques; Neuropsychopharmacology; Periodicals; Electronic journals; 615.78
• DOI: 10.1016/j.neuropharm.2017.01.035
• Languages: English
• ISSNs: 0028-3908

Abstract

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 Ca 2+ 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. Highlights: NGF61 and NGF61/100 equally support DRGs viability and the synthesis of SP and CGRP. NGF61/100 induces a reduced synthesis of bradykinin receptor 2. It reduces the SP and CGRP release in response to bradykinin treatment. NGF61/100 causes a reduced TRPV1 phosphorylation and Ca ++ influx in response to BK. NGF61/100 induces differential expression of genes implicated in the pain response.