Co-Ultramicronized Palmitoylethanolamide/Luteolin-Induced Oligodendrocyte Precursor Cell Differentiation is Associated With Tyro3 Receptor Upregulation.

Laura Facci,Pietro Giusti,Mariella Fusco,Morena Zusso,Massimo Barbierato

doi:10.3389/fphar.2021.698133

Laura Facci, Pietro Giusti + Show 3 more

Open Access

https://doi.org/10.3389/fphar.2021.698133

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Abstract

Remyelination in patients with multiple sclerosis frequently fails, especially in the chronic phase of the disease promoting axonal and neuronal degeneration and progressive disease disability. Drug-based therapies able to promote endogenous remyelination capability of oligodendrocytes are thus emerging as primary approaches to multiple sclerosis. We have recently reported that the co-ultramicronized composite of palmitoylethanolamide and the flavonoid luteolin (PEALut) promotes oligodendrocyte precursor cell (OPC) maturation without affecting proliferation. Since TAM receptor signaling has been reported to be important modulator of oligodendrocyte survival, we here evaluated the eventual involvement of TAM receptors in PEALut-induced OPC maturation. The mRNAs related to TAM receptors -Tyro3, Axl, and Mertk- were all present at day 2 in vitro. However, while Tyro3 gene expression significantly increased upon cell differentiation, Axl and Mertk did not change during the first week in vitro. Tyro3 gene expression developmental pattern resembled that of MBP myelin protein. In OPCs treated with PEALut the developmental increase of Tyro3 mRNA was significantly higher as compared to vehicle while was reduced gene expression related to Axl and Mertk. Rapamycin, an inhibitor of mTOR, prevented oligodendrocyte growth differentiation and myelination. PEALut, administered to the cultures 30 min after rapamycin, prevented the alteration of mRNA basal expression of the TAM receptors as well as the expression of myelin proteins MBP and CNPase. Altogether, data obtained confirm that PEALut promotes oligodendrocyte differentiation as shown by the increase of MBP and CNPase and Tyro3 mRNAs as well as CNPase and Tyro3 immunostainings. The finding that these effects are reduced when OPCs are exposed to rapamycin suggests an involvement of mTOR signaling in PEALut effects.

Highlights

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) characterized by axonal and neuronal degeneration
Within the context of these strategies, we have recently reported that the co-ultramicronized composite of palmitoylethanolamide and the flavonoid luteolin (PEALut) enhance morphological complexity and expression of both mRNA for the membrane-anchored myelin enzyme 2′,3′cyclic nucleotide 3′-phosphodiesterase (CNPase) and myelin basic protein (MBP)
PEALut has been shown to act as protective agent in different experimental models of CNS diseases (Caltagirone et al, 2016; Crupi et al, 2016; Siracusa et al, 2017)

Summary

Introduction

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) characterized by axonal and neuronal degeneration. It mainly affects individuals in their early adult life, and has an enormous impact on body functions, quality of life and social costs that rise with increasing disability. The CNS myelinating cells are oligodendrocytes which are generated from oligodendrocyte progenitor cells (OPCs). Injuries to oligodendrocytes can be followed by a remyelination process leading to the formation of new myelin sheaths by newly formed oligodendrocytes (Franklin and Ffrench-Constant, 2008). Remyelination can occur extensively in some people with MS (Patani et al, 2007), it often fails, especially in the chronic phase of the disease (Nakahara et al, 2009), promoting axonal and neuronal degeneration and progressive disease disability

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