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Induction of Neuronal Differentiation of Murine N2a Cells by Two Polyphenols Present in the Mediterranean Diet Mimicking Neurotrophins Activities: Resveratrol and Apigenin

Team Bio-PeroxIL, ‘Biochemistry of the Peroxisome, Inflammation and Lipid Metabolism’ (EA7270)/University Bourgogne Franche-Comté/Inserm, 21000 Dijon, France
UR/11ES09, Lab. ‘Functional Neurophysiology and Pathology’, Faculty of Sciences of Tunis, University Tunis El Manar, Tunis 2092, Tunisia
LR12SP11 ‘Molecular Biology Applied to Cardiovascular Diseases, Hereditary Nephropathies and Pharmacogenomics’, Dept Biochemistry, CHU Sahloul, Sousse 4000, Tunisia
Bioactive Molecules Research Laboratory, Doctoral School of Sciences and Technologies, Faculty of Sciences, Lebanese University, Beirut 1103, Lebanon
Institut of Molecular Chemistry (ICMUB UMR 6302), Univ. Bourgogne Franche-Comté, 21000 Dijon, France
Author to whom correspondence should be addressed.
Diseases 2018, 6(3), 67;
Received: 21 June 2018 / Revised: 19 July 2018 / Accepted: 20 July 2018 / Published: 22 July 2018
(This article belongs to the Special Issue Wine and Vine Components and Health)
PDF [2885 KB, uploaded 22 July 2018]


In the prevention of neurodegeneration associated with aging and neurodegenerative diseases (Alzheimer’s disease, Parkinson’s disease), neuronal differentiation is of interest. In this context, neurotrophic factors are a family of peptides capable of promoting the growth, survival, and/or differentiation of both developing and immature neurons. In contrast to these peptidyl compounds, polyphenols are not degraded in the intestinal tract and are able to cross the blood–brain barrier. Consequently, they could potentially be used as therapeutic agents in neurodegenerative pathologies associated with neuronal loss, thus requiring the stimulation of neurogenesis. We therefore studied the ability to induce neuronal differentiation of two major polyphenols present in the Mediterranean diet: resveratrol (RSV), a major compound found in grapes and red wine, and apigenin (API), present in parsley, rosemary, olive oil, and honey. The effects of these compounds (RSV and API: 6.25–50 µM) were studied on murine neuro-2a (N2a) cells after 48 h of treatment without or with 10% fetal bovine serum (FBS). Retinoic acid (RA: 6.25–50 µM) was used as positive control. Neuronal differentiation was morphologically evaluated through the presence of dendrites and axons. Cell growth was determined by cell counting and cell viability by staining with fluorescein diacetate (FDA). Neuronal differentiation was more efficient in the absence of serum than with 10% FBS or 10% delipidized FBS. At concentrations inducing neuronal differentiation, no or slight cytotoxicity was observed with RSV and API, whereas RA was cytotoxic. Without FBS, RSV and API, as well as RA, trigger the neuronal differentiation of N2a cells via signaling pathways simultaneously involving protein kinase A (PKA)/phospholipase C (PLC)/protein kinase C (PKC) and MEK/ERK. With 10% FBS, RSV and RA induce neuronal differentiation via PLC/PKC and PKA/PLC/PKC, respectively. With 10% FBS, PKA and PLC/PKC as well as MEK/ERK signaling pathways were not activated in API-induced neuronal differentiation. In addition, the differentiating effects of RSV and API were not inhibited by cyclo[DLeu5] OP, an antagonist of octadecaneuropeptide (ODN) which is a neurotrophic factor. Moreover, RSV and API do not stimulate the expression of the diazepam-binding inhibitor (DBI), the precursor of ODN. Thus, RSV and API are able to induce neuronal differentiation, ODN and its receptor are not involved in this process, and the activation of the (PLC/PKC) signaling pathway is required, except with apigenin in the presence of 10% FBS. These data show that RSV and API are able to induce neuronal differentiation and therefore mimic neurotrophin activity. Thus, RSV and API could be of interest in regenerative medicine to favor neurogenesis. View Full-Text
Keywords: N2a murine neuronal cells; neuronal differentiation; neurotrophic effects; polyphenols; apigenin; resveratrol N2a murine neuronal cells; neuronal differentiation; neurotrophic effects; polyphenols; apigenin; resveratrol

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Namsi, A.; Nury, T.; Hamdouni, H.; Yammine, A.; Vejux, A.; Vervandier-Fasseur, D.; Latruffe, N.; Masmoudi-Kouki, O.; Lizard, G. Induction of Neuronal Differentiation of Murine N2a Cells by Two Polyphenols Present in the Mediterranean Diet Mimicking Neurotrophins Activities: Resveratrol and Apigenin. Diseases 2018, 6, 67.

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