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Co-Ultramicronized Palmitoylethanolamide/Luteolin Facilitates the Development of Differentiating and Undifferentiated Rat Oligodendrocyte Progenitor Cells

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Abstract

Oligodendrocytes, the myelin-producing cells of the central nervous system (CNS), have limited capability to bring about repair in chronic CNS neuroinflammatory demyelinating disorders such as multiple sclerosis (MS). MS lesions are characterized by a compromised pool of undifferentiated oligodendrocyte progenitor cells (OPCs) unable to mature into myelin-producing oligodendrocytes. An attractive strategy may be to replace lost OLs and/or promote their maturation. N-palmitoylethanolamine (PEA) is an endogenous fatty acid amide signaling molecule with anti-inflammatory and neuroprotective actions. Recent studies show a co-ultramicronized composite of PEA and the flavonoid luteolin (co-ultraPEALut) to be more efficacious than PEA in improving outcome in CNS injury models. Here, we examined the effects of co-ultraPEALut on development of OPCs from newborn rat cortex cultured under conditions favoring either differentiation (Sato medium) or proliferation (fibroblast growth factor-2 and platelet-derived growth factor (PDGF)-AA-supplemented serum-free medium (“SFM”)). OPCs in SFM displayed high expression of PDGF receptor alpha gene and the proliferation marker Ki-67. In Sato medium, in contrast, OPCs showed rapid decreases in PDGF receptor alpha and Ki-67 expression with a concomitant rise in myelin basic protein (MBP) expression. In these conditions, co-ultraPEALut (10 μM) enhanced OPC morphological complexity and expression of MBP and the transcription factor TCF7l2. Surprisingly, co-ultraPEALut also up-regulated MBP mRNA expression in OPCs in SFM. MBP expression in all cases was sensitive to inhibition of mammalian target of rapamycin. Within the context of strategies to promote endogenous remyelination in MS which focus on enhancing long-term survival of OPCs and stimulating their differentiation into remyelinating oligodendrocytes, co-ultraPEALut may represent a novel pharmacological approach.

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Acknowledgements

This study was supported in part by the MIUR, PON “Ricerca e Competitività 2007–2013” project PON01_02512, and by Regione Veneto project protocol 103173COF/14/LR52001C2/000051.

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Author notes

  1. Massimo Barbierato and Laura Facci contributed equally to this study.

Authors and Affiliations

  1. Department of Pharmaceutical and Pharmacological Sciences, University of Padua, Largo “Egidio Meneghetti” 2, 35131, Padua, Italy

    Stephen D. Skaper, Massimo Barbierato, Laura Facci, Mila Borri, Gabriella Contarini, Morena Zusso & Pietro Giusti

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  1. Stephen D. Skaper
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  2. Massimo Barbierato
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  3. Laura Facci
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  4. Mila Borri
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  5. Gabriella Contarini
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  6. Morena Zusso
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  7. Pietro Giusti
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Corresponding author

Correspondence to Stephen D. Skaper.

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The authors declare that they have no competing financial interests.

Human and Animal Rights and Informed Consent

Experiments were performed in accordance with Italian Ministry of Health (at. 31, D.L. 26/2014) guidelines for the care and use of laboratory animals, and were approved by the Institutional Animal Care and Use Committee of the University of Padua (958/2016-PR).

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Skaper, S.D., Barbierato, M., Facci, L. et al. Co-Ultramicronized Palmitoylethanolamide/Luteolin Facilitates the Development of Differentiating and Undifferentiated Rat Oligodendrocyte Progenitor Cells. Mol Neurobiol 55, 103–114 (2018). https://doi.org/10.1007/s12035-017-0722-0

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  • DOI: https://doi.org/10.1007/s12035-017-0722-0

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