Upregulation of Myelin Gene Expression by a Physically-Modified Saline via Phosphatidylinositol 3-Kinase-Mediated Activation of CREB: Implications for Multiple Sclerosis

Malabendu Jana,Supurna Ghosh,Kalipada Pahan

doi:10.1007/s11064-017-2435-1

Malabendu Jana, Supurna Ghosh + Show 1 more

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https://doi.org/10.1007/s11064-017-2435-1

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Abstract

An increase in central nervous system (CNS) remyelination and a decrease in CNS inflammation are important steps to halt the progression of multiple sclerosis (MS). RNS60 is a bioactive aqueous solution generated by subjecting normal saline to Taylor–Couette–Poiseuille flow under elevated oxygen pressure. Recently we have demonstrated that RNS60 exhibits anti-inflammatory properties. Here, we describe promyelinating property of RNS60. RNS60, but not normal saline (NS), RNS10.3 (TCP-modified saline without excess oxygen) or PNS60 (saline containing excess oxygen without TCP modification), stimulated the expression of myelin-specific genes and proteins (myelin basic protein, MBP; myelin oligodendrocyte glycoprotein, MOG and proteolipid protein, PLP) in primary mouse oligodendroglia and mixed glial cells. While investigating the mechanisms, we found that RNS60 treatment induced the activation of cAMP response element binding protein (CREB) in oligodendrocytes, ultimately leading to the recruitment of CREB to the promoters of myelin-specific genes. Furthermore, activation of type 1A p110β/α, but not type 1B p110γ, phosphatidylinositol-3 (PI-3) kinase by RNS60 together with abrogation of RNS60-mediated activation of CREB and upregulation of myelin genes by LY294002 (a specific inhibitor of PI-3 kinase) suggest that RNS60 upregulates the activation of CREB and the expression of myelin-specific molecules in oligodendrocytes via activation of PI3 kinase. These results highlight a novel promyelinating property of RNS60, which may be of benefit for MS and other demyelinating disorders.

Highlights

Myelination is a complex process that requires proliferation of oligodendrocytes progenitors, migration to various brain regions, differentiation, and synthesis and deposition of the myelin membrane
To investigate whether RNS60 containing charge-stabilized nano-structures induces the expression of myelin-specific genes in primary mouse oligodendrocytes, cells were treated with RNS60, PNS60, RNS10.3, or normal saline (NS) for 6 h
Under same treatment conditions, RNS10.3, saline that was processed with TCP flow in the absence of any excess oxygen, and PNS60, saline with same oxygen content as RNS60 (55 ± 5 ppm) that was exposed to the same device but not processed with TCP flow, did not increase the mRNA expression of myelin basic protein (MBP), myelin oligodendrocyte glycoprotein (MOG) and proteolipid protein (PLP) in oligodendrocytes (Fig. 1a, b), indicating the specificity of the effect

Summary

Introduction

Myelination is a complex process that requires proliferation of oligodendrocytes progenitors, migration to various brain regions, differentiation, and synthesis and deposition of the myelin membrane. Oligodendrocytes are the only specialized myelin-synthesizing cells in the CNS that express several myelin-specific genes like myelin basic protein (MBP), 2′,3′-cyclic nucleotide 3′-phosphodiesterase (CNPase), myelin oligodendrocyte glycoprotein (MOG), and proteolipid protein (PLP) [4, 5, 7,8,9,10]. Oligodendrocytes express galactosylceramidase (GalC) that is essential for the unperturbed lipid bilayer of the myelin membrane [11]. It has been reported that an increase in MBP, MOG and PLP expression is a prerequisite to maturation of oligodendrocytes [12]. Increases in the expression of myelin-specific genes are essential for CNS remyelination. Despite intense investigation, very few drugs are available that may increase or support the expression of myelin genes and help in remyelination

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