hNGF Peptides Elicit the NGF-TrkA Signalling Pathway in Cholinergic Neurons and Retain Full Neurotrophic Activity in the DRG Assay

Abstract

In the last decade, Nerve Growth Factor (NGF)-based clinical approaches have lacked specific and efficient Tyrosine Kinase A (TrkA) agonists for brain delivery. Nowadays, the characterization of novel small peptidomimetic is taking centre stage in preclinical studies, in order to overcome the main size-related limitation in brain delivery of NGF holoprotein for Central Nervous System (CNS) pathologies. Here we investigated the NGF mimetic properties of the human NGF 1–14 sequence (hNGF1–14) and its derivatives, by resorting to primary cholinergic and dorsal root ganglia (DRG) neurons. Briefly, we observed that: 1) hNGF1–14 peptides engage the NGF pathway through TrkA phosphorylation at tyrosine 490 (Y490), and activation of ShcC/PI3K and Plc-γ/MAPK signalling, promoting AKT-dependent survival and CREB-driven neuronal activity, as seen by levels of the immediate early gene c-Fos, of the cholinergic marker Choline Acetyltransferase (ChAT), and of Brain Derived Neurotrophic Factor (BDNF); 2) their NGF mimetic activity is lost upon selective TrkA inhibition by means of GW441756; 3) hNGF1–14 peptides are able to sustain DRG survival and differentiation in absence of NGF. Furthermore, the acetylated derivative Ac-hNGF1–14 demonstrated an optimal NGF mimetic activity in both neuronal paradigms and an electrophysiological profile similar to NGF in cholinergic neurons. Cumulatively, the findings here reported pinpoint the hNGF1–14 peptide, and in particular its acetylated derivative, as novel, specific and low molecular weight TrkA specific agonists in both CNS and PNS primary neurons.

Pilot Investigation on p75ICD Expression in Laryngeal Squamous Cell Carcinoma

“…NGF and its receptors (TrkA and p75NTR) are implicated in cancer growth, CSC proliferation, and immune system evasion [ 21 ]. p75NTR has been shown to exert anti-apoptotic functions, possibly upon stimulation by the precursor form of NGF (proNGF), in tumor growth and spreading, which is largely independent of the mitogenic NGF/TrkA pathway [ 22 ]. Despite preliminary indications regarding the role of p75NTR maturation in cancer progression, the control of p75ICD generation by regulated cleavage and its expression and distribution in LSCC of relevance for cancer progression and metastatization have not been addressed so far.…”

Nerve growth factor enhances the therapeutic effect of mesenchymal stem cells on diabetic periodontitis

“…GW441756 is a highly specific inhibitor of TrkA. Numerous studies have proved that GW441756 has a good effect on TrkA inhibition (35,36), so it was applied in the present study. The present results demonstrated that TrkA receptor inhibition completely blocked these functions of NGF.…”

Novel Targets and Therapeutic Strategies for Promoting Organ Repair and Regeneration

“…The study by Triaca et al investigates the therapeutic potential of small stable nerve growth factor (NGF) peptides as tropomyosin receptor kinase A (TrkA) agonists for treating pathologies of the central and peripheral nervous system [23]. NGF is the founding member of a family of extracellularly secreted growth factors in the nervous system that collectively are called neurotrophins, which also include brain-derived neurotrophic factor, neurotrophin-3, and neurotrophin 4/5 [24].…”

“…An alternative and possibly promising approach has been to design small peptide ligands based on the N-terminal region in NGF, which binds the extracellular portion of the TrkA receptor. In this issue, Triaca et al investigated the ability of peptide derivatives of human NGF (hNGF) to activate TrkA receptor signaling [23]. The authors found that a small peptide, encoding amino acids 1-14 in the N terminal region NGF (hNGF1-14), was able to trigger established TrkA pathways with high efficacy.…”

“…The authors found that a small peptide, encoding amino acids 1-14 in the N terminal region NGF (hNGF1-14), was able to trigger established TrkA pathways with high efficacy. In cholinergic and dorsal root ganglia neurons, hNGF1-14 stimulated the expression of markers driving neuronal activity and survival, indicating that the peptide can retain the biological activity of native NGF [23]. Incubation with an acetylated counterpart of hNGF1-14 (Ac-hNGF1-14) showed even greater potency in stimulating TrkA signaling, suggesting that enhancing the stability of the peptide may affect the formation of the ligand-receptor complex.…”