Sphingosine kinase inhibition ameliorates chronic hypoperfusion-induced white matter lesions

Ying Yang; Federico Torta; Ken Arai; Markus R Wenk; Deron R Herr; Peter T-H Wong; Mitchell K P Lai

doi:10.1016/j.neuint.2016.02.012

Sphingosine kinase inhibition ameliorates chronic hypoperfusion-induced white matter lesions

Neurochem Int. 2016 Mar:94:90-7. doi: 10.1016/j.neuint.2016.02.012. Epub 2016 Feb 24.

Authors

Ying Yang¹, Federico Torta², Ken Arai³, Markus R Wenk⁴, Deron R Herr¹, Peter T-H Wong⁵, Mitchell K P Lai⁶

Affiliations

¹ Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Kent Ridge, Singapore.
² Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Kent Ridge, Singapore.
³ Neuroprotection Research Laboratory, Departments of Radiology and Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA.
⁴ Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Kent Ridge, Singapore; Department of Biological Sciences, National University of Singapore, Kent Ridge, Singapore.
⁵ Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Kent Ridge, Singapore. Electronic address: peter_wong@nuhs.edu.sg.
⁶ Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Kent Ridge, Singapore. Electronic address: mitchell.lai@dementia-research.org.

PMID: 26921668
DOI: 10.1016/j.neuint.2016.02.012

Abstract

White matter lesions (WML) are thought to contribute to vascular cognitive impairment in elderly patients. Growing evidence show that failure of myelin formation arising from the disruption of oligodendrocyte progenitor cell (OPC) differentiation is a cause of chronic vascular white matter damage. The sphingosine kinase (SphK)/sphingosine-1-phosphate (S1P) signaling pathway regulates oligodendroglia differentiation and function, and is known to be altered in hypoxia. In this study, we measured SphK, S1P as well as markers of WML, hypoxia and OPC (NG2) in a mouse bilateral carotid artery stenosis (BCAS) model of chronic cerebral hypoperfusion. Our results indicated that BCAS induced hypoxia inducible factor (HIF)-1α, Sphk2, S1P, and NG2 up-regulation together with accumulation of WML. In contrast, BCAS mice treated with the SphK inhibitor, SKI-II, showed partial reversal of SphK2, S1P and NG2 elevation and amelioration of WML. In an in vitro model of hypoxia, SKI-II reversed the suppression of OPC differentiation. Our study suggests a mechanism for hypoperfusion-associated WML involving HIF-1α-SphK2-S1P-mediated disruption of OPC differentiation, and proposes the SphK signaling pathway as a potential therapeutic target for white matter disease.

Keywords: Bilateral carotid artery stenosis; Hypoperfusion; Sphingosine kinase; Sphingosine-1-phosphate; White matter lesions.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Brain / blood supply*
Brain / drug effects
Brain / enzymology*
Carotid Artery Diseases / drug therapy
Carotid Artery Diseases / enzymology*
Carotid Artery Diseases / pathology
Cells, Cultured
Chronic Disease
Enzyme Inhibitors / pharmacology
Enzyme Inhibitors / therapeutic use
Lysophospholipids / antagonists & inhibitors
Lysophospholipids / metabolism*
Male
Mice
Mice, Inbred C57BL
Phosphotransferases (Alcohol Group Acceptor) / antagonists & inhibitors
Phosphotransferases (Alcohol Group Acceptor) / metabolism*
Rats
Rats, Sprague-Dawley
Sphingosine / analogs & derivatives*
Sphingosine / antagonists & inhibitors
Sphingosine / metabolism
Thiazoles / pharmacology
Thiazoles / therapeutic use
White Matter / drug effects
White Matter / enzymology*
White Matter / pathology

Substances

4-(4-(4-chloro-phenyl)thiazol-2-ylamino)phenol
Enzyme Inhibitors
Lysophospholipids
Thiazoles
sphingosine 1-phosphate
Phosphotransferases (Alcohol Group Acceptor)
sphingosine kinase
Sphingosine