Nerve growth factor derivative NGF61/100 promotes outgrowth of primary sensory neurons with reduced signs of nociceptive sensitization.
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.
Institute of Cellular Biology and Neurobiology, CNR, Via del Fosso di Fiorano, 64, 00143, Rome, Italy; I.R.C.C.S. Fondazione S. Lucia, Via del Fosso di Fiorano, 64, 00143, Rome, Italy.
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Severini
Institute of Cellular Biology and Neurobiology, CNR, Via del Fosso di Fiorano, 64, 00143, Rome, Italy.
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Petrocchi Passeri
European Brain Research Institute (EBRI), Via del Fosso di Fiorano, 64, 00143, Rome, Italy.
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Ciotti
European Brain Research Institute (EBRI), Via del Fosso di Fiorano, 64, 00143, Rome, Italy.
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Florenzano
Institute of Cellular Biology and Neurobiology, CNR, Via del Fosso di Fiorano, 64, 00143, Rome, Italy; I.R.C.C.S. Fondazione S. Lucia, Via del Fosso di Fiorano, 64, 00143, Rome, Italy.
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Petrella
European Brain Research Institute (EBRI), Via del Fosso di Fiorano, 64, 00143, Rome, Italy.
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Malerba
European Brain Research Institute (EBRI), Via del Fosso di Fiorano, 64, 00143, Rome, Italy.
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Bruni
European Brain Research Institute (EBRI), Via del Fosso di Fiorano, 64, 00143, Rome, Italy.
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D'Onofrio
European Brain Research Institute (EBRI), Via del Fosso di Fiorano, 64, 00143, Rome, Italy.
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Arisi
European Brain Research Institute (EBRI), Via del Fosso di Fiorano, 64, 00143, Rome, Italy.
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Brandi
Department of Medicine of Systems, University of Rome "Tor Vergata", 001, Rome, Italy.
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Possenti
European Brain Research Institute (EBRI), Via del Fosso di Fiorano, 64, 00143, Rome, Italy.
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Calissano
European Brain Research Institute (EBRI), Via del Fosso di Fiorano, 64, 00143, Rome, Italy; Scuola Normale Superiore, P.le Cavalieri, 7, 56100, Pisa, Italy. Electronic address: antonino.cattaneo@sns.it.
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Cattaneo
D000818:Animals; D001920:Bradykinin / Q000494:pharmacology; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D005727:Ganglia, Spinal / Q000378:metabolism; D020869:Gene Expression Profiling; D006801:Humans; D020932:Nerve Growth Factor / Q000009:adverse effects* / Q000494:pharmacology*; D010146:Pain / Q000139:chemically induced* / Q000378:metabolism; D010446:Peptide Fragments / Q000009:adverse effects* / Q000494:pharmacology; D061251:Primary Cell Culture; D051381:Rats; D018002:Receptors, Bradykinin / Q000378:metabolism; D011984:Sensory Receptor Cells / Q000166:cytology*; D013373:Substance P / Q000378:metabolism; D050916:TRPV Cation Channels / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
C502240:NGF protein, human; D010446:Peptide Fragments; D018002:Receptors, Bradykinin; D050916:TRPV Cation Channels; C493922:Trpv1 protein, rat; D013373:Substance P; D020932:Nerve Growth Factor; D015740:Calcitonin Gene-Related Peptide; D001920:Bradykinin; D002118:Calcium
Bradykinin receptors; CGRP; Dorsal root ganglion neurons; NGF; Substance P