TY - JOUR
T1 - Nerve growth factor derivative NGF61/100 promotes outgrowth of primary sensory neurons with reduced signs of nociceptive sensitization
AU - Severini, C.
AU - Petrocchi Passeri, P.
AU - Ciotti, M. T.
AU - Florenzano, F.
AU - Petrella, C.
AU - Malerba, F.
AU - Bruni, B.
AU - D'Onofrio, M.
AU - Arisi, I.
AU - Brandi, R.
AU - Possenti, R.
AU - Calissano, P.
AU - Cattaneo, A.
PY - 2017/5/1
Y1 - 2017/5/1
N2 - 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.
AB - 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.
KW - Bradykinin receptors
KW - CGRP
KW - Dorsal root ganglion neurons
KW - NGF
KW - Substance P
UR - http://www.scopus.com/inward/record.url?scp=85011965307&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85011965307&partnerID=8YFLogxK
U2 - 10.1016/j.neuropharm.2017.01.035
DO - 10.1016/j.neuropharm.2017.01.035
M3 - Article
C2 - 28163105
AN - SCOPUS:85011965307
VL - 117
SP - 134
EP - 148
JO - Neuropharmacology
JF - Neuropharmacology
SN - 0028-3908
ER -