Differentiating effects of the glucagon-like peptide-1 analogue exendin-4 in a human neuronal cell model

Abstract

Glucagon-like peptide-1 (GLP-1) is an insulinotropic peptide with neurotrophic properties, as assessed in animal cell models. Exendin-4, a GLP-1 analogue, has been recently approved for the treatment of type 2 diabetes mellitus. The aim of this study was to morphologically, structurally, and functionally characterize the differentiating actions of exendin-4 using a human neuronal cell model (i.e., SH-SY5Y cells). We found that exendin-4 increased the number of neurites paralleled by dramatic changes in intracellular actin and tubulin distribution. Electrophysiological analyses showed an increase in cell membrane surface and in stretch-activated-channels sensitivity, an increased conductance of Na(+) channels and amplitude of Ca(++) currents (T- and L-type), typical of a more mature neuronal phenotype. To our knowledge, this is the first demonstration that exendin-4 promotes neuronal differentiation in human cells. Noteworthy, our data support the claimed favorable role of exendin-4 against diabetic neuropathy as well as against different neurodegenerative diseases.

Pleiotropic Effects of Glucagon-like Peptide-1 (GLP-1)-Based Therapies on Vascular Complications in Diabetes

“…Exendin-4 induces neuronal differentiation of SH-SY5Y cells, which is accompanied by multiple cytoskeletal rearrangements and increased conductance of Na + channels and amplitude of Ca ++ currents, one of the typical characteristics of more mature neuronal cell phenotype [63]. Further, exendin-4 was reported to block oxidative stress-induced injury in SH-SY5Y cells [63].…”

“…Further, exendin-4 was reported to block oxidative stress-induced injury in SH-SY5Y cells [63]. In addition, GLP-1 has been shown to protect against neuronal cell death evoked by nerve growth factor deprivation via suppression of pro-apoptotic protein Bim [64].…”

Exendin-4 Induces Cell Adhesion and Differentiation and Counteracts the Invasive Potential of Human Neuroblastoma Cells

“…Reagents for cell cultures were from Sigma Chemical Co. (St. Louis, MO, USA). The cells were seeded in six-well plates, maintained in low serum conditions (RPMI medium with 2% FBS), and treated with exendin-4 (0.3 µM) (Sigma) for 24 and 48 h. The morphological evaluation of the differentiation of FNC and SK-N-AS cells was performed as previously reported [17]. Human mesenchymal stromal cells (hMSC) were isolated in collaboration with Dr. Riccardo Saccardi (Haematology Unit, Careggi Hospital, Florence, Italy), as described previously [19] and maintained for 24 hours in serum-free medium to obtain conditioned medium for migration assays in which we detected the release of stromal derived factor-1 (SDF1) by Quantikine ELISA Human CXCL12/SDF-1α Immunoassay (R&D systems).…”

“…NB arises from the developing sympathetic nervous system and its etiology is not clearly understood; metastatic spread of NB can happen by both lymphatic and hematogenous routes [16]. We have previously demonstrated differentiating actions of exendin-4 in NB SH-SY5Y cells, as assessed by the increasing number of neurites, changes in intracellular actin and tubulin distribution and increase of both Na + channel conductance and Ca 2+ currents (T- and L-type) amplitude, typical of a more mature neuronal phenotype [17]. In this study we investigate the effects of exendin-4 on cell adhesion, differentiation and migration, which in turn affects tumor spread and metastatization, in two NB cell lines and in human neuronal precursors, as a non-tumoral counterpart.…”

Neuroprotective properties of incretin mimetics in brain ischemia and neurodegenerative diseases

“…В условиях in vitro эксендин-4 стимулировал пролиферацию и нейрональную дифференциацию в культуре нейрональных клеток человека [46]. Лира-глутид в условиях моделирования БА in vivo стиму-лировал нейрогенез в области зубчатой извилины гиппокампа, сопровождавшийся улучшением мел-кой моторики конечностей и пространственной па-мяти [22].…”