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Open AccessFeature PaperArticle

Octadecaneuropeptide (ODN) Induces N2a Cells Differentiation through a PKA/PLC/PKC/MEK/ERK-Dependent Pathway: Incidence on Peroxisome, Mitochondria, and Lipid Profiles

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Team Bio-PeroxIL, Biochemistry of the Peroxisome, Inflammation and Lipid Metabolism (EA7270)/University Bourgogne Franche-Comté (UBFC)/Inserm, 21000 Dijon, France
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Faculty of Science of Tunis, University Tunis El Manar, LR18ES03, Laboratory of Neurophysiology, Cellular Physiopathology and Biomolecules Valorisation, Tunis 2092, Tunisia
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Physiology of Nutrition & Toxicology (NUTox), Inserm U1231, University UBFC, 21000 Dijon, France
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UNIROUEN, Inserm U1239, Laboratory of Neuronal and Neuroendocrine Communication and Differentiation, Normandie University, 76000 Rouen, France
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UNIROUEN, Regional Cell Imaging Platform of Normandy (PRIMACEN), Normandie University, 76000 Rouen, France
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Laboratory of Medical Genetics and Neurogenetics, Foundation IRCCS Istituto Neurologico Carlo Besta, 20100 Milan, Italy
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Laboratory of Clinical Chemistry, Hospital of Varese, ASST-Settelaghi, 20100 Milan, Italy
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Institute of Genetics and Animal Breeding of the Polish Academy of Sciences, Jastrzebiec, 05-552 Magdalenka, Poland
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Department of Pharmacognosy, University of Vienna, 1010 Vienna, Austria
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Institute of Neurobiology, Bulgarian Academy of Sciences, 23 Acad. G. Bonchev str., 1113 Sofia, Bulgaria
*
Authors to whom correspondence should be addressed.
Molecules 2019, 24(18), 3310; https://doi.org/10.3390/molecules24183310
Received: 23 July 2019 / Revised: 28 August 2019 / Accepted: 5 September 2019 / Published: 11 September 2019
(This article belongs to the Special Issue Bioactive Molecules and Their Mechanisms of Action)
Neurodegenerative diseases are characterized by oxidative stress, mitochondrial damage, and death of neuronal cells. To counteract such damage and to favor neurogenesis, neurotrophic factors could be used as therapeutic agents. Octadecaneuropeptide (ODN), produced by astrocytes, is a potent neuroprotective agent. In N2a cells, we studied the ability of ODN to promote neuronal differentiation. This parameter was evaluated by phase contrast microscopy, staining with crystal violet, cresyl blue, and Sulforhodamine 101. The effect of ODN on cell viability and mitochondrial activity was determined with fluorescein diacetate and DiOC6(3), respectively. The impact of ODN on the topography of mitochondria and peroxisomes, two tightly connected organelles involved in nerve cell functions and lipid metabolism, was evaluated by transmission electron microscopy and fluorescence microscopy: detection of mitochondria with MitoTracker Red, and peroxisome with an antibody directed against the ABCD3 peroxisomal transporter. The profiles in fatty acids, cholesterol, and cholesterol precursors were determined by gas chromatography, in some cases coupled with mass spectrometry. Treatment of N2a cells with ODN (10−14 M, 48 h) induces neurite outgrowth. ODN-induced neuronal differentiation was associated with modification of topographical distribution of mitochondria and peroxisomes throughout the neurites and did not affect cell viability and mitochondrial activity. The inhibition of ODN-induced N2a differentiation with H89, U73122, chelerythrine and U0126 supports the activation of a PKA/PLC/PKC/MEK/ERK-dependent signaling pathway. Although there is no difference in fatty acid profile between control and ODN-treated cells, the level of cholesterol and some of its precursors (lanosterol, desmosterol, lathosterol) was increased in ODN-treated cells. The ability of ODN to induce neuronal differentiation without cytotoxicity reinforces the interest for this neuropeptide with neurotrophic properties to overcome nerve cell damage in major neurodegenerative diseases.
Keywords: octadecaneuropeptide (ODN), N2a cells; neuronal differentiation; mitochondria; peroxisome; fatty acids; cholesterol; cholesterol precursors octadecaneuropeptide (ODN), N2a cells; neuronal differentiation; mitochondria; peroxisome; fatty acids; cholesterol; cholesterol precursors
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Namsi, A.; Nury, T.; Khan, A.S.; Leprince, J.; Vaudry, D.; Caccia, C.; Leoni, V.; Atanasov, A.G.; Tonon, M.-C.; Masmoudi-Kouki, O.; Lizard, G. Octadecaneuropeptide (ODN) Induces N2a Cells Differentiation through a PKA/PLC/PKC/MEK/ERK-Dependent Pathway: Incidence on Peroxisome, Mitochondria, and Lipid Profiles. Molecules 2019, 24, 3310.

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