Neurochemical Research

, Volume 37, Issue 6, pp 1154–1169 | Cite as

Signaling and Regulatory Functions of Bioactive Sphingolipids as Therapeutic Targets in Multiple Sclerosis

  • Maria Podbielska
  • Hubert Krotkiewski
  • Edward L. Hogan
Review Article

Abstract

Spingolipids (SLs) are an important component of central nervous system (CNS) myelin sheaths and affect the viability of brain cells (oligodendrocytes, neurons and astrocytes) that is determined by signaling mediated by bioactive sphingoids (lyso-SLs). Recent studies indicate that two lipids, ceramide and sphingosine 1-phosphate (S1P), are particularly involved in many human diseases including the autoimmune inflammatory demyelination of multiple sclerosis (MS). In this review we: (1) Discuss possible sources of ceramide in CNS; (2) Summarize the features of the metabolism of S1P and its downstream signaling through G-protein-coupled receptors; (3) Link perturbations in bioactive SLs metabolism to MS neurodegeneration and (4) Compile ceramide and S1P relationships to this process. In addition, we described recent preclinical and clinical trials of therapies targeting S1P signaling, including 2-amino-2-propane-1,3-diol hydrochloride (FTY720, fingolimod) as well as proposed intervention to specify critical SL levels that tilt balances of apoptotic/active ceramide versus anti-apoptotic/inactive dihydroceramide that may offer a novel and important therapeutic approach to MS.

Keywords

Ceramide Glycosphingolipids Inhibitors Multiple sclerosis Signal transduction Sphingosine 1-phosphate 

Abbreviations

ASMase

Acid sphingomyelinase

CDase

Ceramidase

Cer

Ceramide

Cer1P

Ceramide 1-phosphate

CerS

Ceramide synthase (N-acyl transferase)

CNS

Central nervous system

CSF

Cerebrospinal fluid

DES

Dihydroceramide desaturase

DHSph

Dihydrosphingosine

EAE

Experimental autoimmune encephalomyelitis

GalCer

Galactosylceramide

GalCerS

Galactosylceramide synthase

GlcCer

Glucosylceramide

GlcCerC

Glucosylceramide synthase

GM

Gray matter

GSL

Glycosphingolipid

KDHR

3-keto-dihydrosphingosine reductase

KDHSph

3-keto-dihydrosphingosine

MS

Multiple sclerosis

NAWM

Normal appearing white matter

NSMase

Neutral sphingomyelinase

S1P

Sphingosine 1-phosphate

SM

Sphingomyelin

SMase

Sphingomyelinase

SMS

Sphingomyelin synthase

SpH

Sphingosine

SphK1

Sphingosine kinase 1

SphK2

Sphingosine kinase 2

Spl

Sphingosine 1-phosphate lyase

SPP1

Sphingosine 1-phosphate phosphatase 1

SPP2

Sphingosine 1-phosphate phosphatase 2

SPT

Serine palmitoyltransferase

Notes

Acknowledgments

We gratefully acknowledge financial support from the National Multiple Sclerosis Society (NMSS, NY, USA; Award #RG3473), and partial support from NINDS/NIH (NS 115666) (to ELH); from Multiple Sclerosis International Federation (Du Pré Grant) (to MP). The authors thank Mrs. Katarzyna Izydorczyk for her skillful assistance with Figures preparation. We apologize to those authors whose work we were unable to cite because of space limitations.

Conflict of interest

The authors declare that they have no conflict of interest.

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Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Maria Podbielska
    • 1
    • 2
  • Hubert Krotkiewski
    • 2
  • Edward L. Hogan
    • 1
    • 3
  1. 1.Institute of Molecular Medicine and Genetics, Department of NeurologyGeorgia Health Science UniversityAugustaUSA
  2. 2.Department of Immunochemistry, Ludwik Hirszfeld Institute of Immunology & Experimental TherapyPolish Academy of SciencesWrocławPoland
  3. 3.Department of MicrobiologyNational University of Ireland GalwayGalwayIreland

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