Rapid Alterations in Cerebral White Matter Lipid Profiles After Ischemic-Reperfusion Brain Injury in Fetal Sheep as Demonstrated by MALDI-Mass Spectrometry

Abstract

Background

Perinatal ischemia-reperfusion (I/R) injury of cerebral white matter causes long-term cognitive and motor disabilities in children. I/R damages or kills highly metabolic immature oligodendroglia via oxidative stress, excitotoxicity, inflammation, and mitochondrial dysfunction, impairing their capacity to generate and maintain mature myelin. However, the consequences of I/R on myelin lipid composition have not been characterized.

Objective

This study utilized matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) to assess alterations in cerebral supraventricular white matter myelin lipid profiles in a fetal sheep model of perinatal I/R.

Methods

Fetal sheep (127 days gestation) were studied after 30 minutes of bilateral carotid artery occlusion followed by 4 (n = 5), 24 (n = 7), 48 (n = 3), or 72 (n = 5) hours of reperfusion, or sham treatment (n = 5). White matter lipids were analyzed by negative ion mode MALDI-MS.

Results

Striking I/R-associated shifts in phospholipid and sphingolipid expression occurred over the 72-hour time course with most responses detected within 4 hours of reperfusion and progressing at the 48- and 72-hour points. I/R decreased expression of phosphatidic acid and phosphatidylethanol amine and increased phosphatidylinositol, sulfatide, and lactosylceramide.

Conclusions

Cerebral I/R in mid-gestation fetal sheep causes rapid shifts in white matter myelin lipid composition that may reflect injury, proliferation, or recovery of immature oligodendroglia.

Keywords

ischemia reperfusion white matter fetal brain sheep lipidomics mass spectrometry

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References

Distefano

Pratico

. Actualities on molecular pathogenesis and repairing processes of cerebral damage in perinatal hypoxic-ischemic encephalopathy. Ital J Pediatr 2010; 36: 63.

Torres-Cuevas

Parra-Llorca

Sanchez-Illana

et al.

Oxygen and oxidative stress in the perinatal period. Redox Biol 2017; 12: 674–681.

Bakthavachalam

Shanmugam

. Mitochondrial dysfunction—silent killer in cerebral ischemia. J Neurol Sci 2017; 375: 417–423.

Hirayama

Wagner

Abe

Ikebuchi

Ikeda

. Involvement of reactive oxygen species in hemoglobin oxidation and virus inactivation by 1,9-dimethylmethylene blue phototreatment. Biol Pharm Bull 2001; 24(4): 418–421.

Vesoulis

Mathur

. Cerebral autoregulation, brain injury, and the transitioning premature infant. Front Pediatr 2017; 5: 64.

Back

. White matter injury in the preterm infant: pathology and mechanisms. Acta Neuropathol 2017; 134(3): 331–349.

McIver

Muccigrosso

Gonzales

et al.

Oligodendrocyte degeneration and recovery after focal cerebral ischemia. Neuroscience 2010; 169(3): 1364–1375.

de la Monte SM Kay

Yalcin

Kril

Sheedy

Sutherland

. Imaging mass spectrometry of frontal white matter lipid changes in human alcoholics. Alcohol 2018; 67: 51–63.

Petersson

Pinar

Stopa

et al.

White matter injury after cerebral ischemia in ovine fetuses. Pediatr Res 2002; 51(6): 768–776.

10.

Chen

Threlkeld

Cummings

et al.

Ischemia-reperfusion impairs blood-brain barrier function and alters tight junction protein expression in the ovine fetus. Neuroscience 2012; 226: 89–100.

11.

Gunn

de Haan

Williams

Gluckman

. Dramatic neuronal rescue with prolonged selective head cooling after ischemia in fetal lambs. J Clin Invest 1997; 99(2): 248–256.

12.

Folch

Lees

Sloane Stanley

. A simple method for the isolation and purification of total lipides from animal tissues. J Biol Chem 1957; 226(1): 497–509.

13.

Yalcin

de la Monte

. Review of matrix-assisted laser desorption ionization-imaging mass spectrometry for lipid biochemical histopathology. J Histochem Cytochem 2015; 63(10): 762–771.

14.

Jackson

Wang

Woods

. In situ structural characterization of glycerophospholipids and sulfatides in brain tissue using MALDI-MS/MS. J Am Soc Mass Spectrom 2007; 18(1): 17–26.

15.

Yalcin

Nunez

Tong

de la Monte

. Differential sphingolipid and phospholipid profiles in alcohol and nicotine-derived nitrosamine ketone-associated white matter degeneration. Alcohol Clin Exp Res 2015; 39(12): 2324–2333.

16.

Bergkvist

Rusnakova

Sindelka

et al.

Gene expression profiling—clusters of possibilities. Methods 2010; 50(4): 323–335.

17.

Eisen

Spellman

Brown

Botstein

. Cluster analysis and display of genome-wide expression patterns. Proc Natl Acad Sci U S A 1998; 95(25): 14863–14868.

18.

Page RD. Visualizing phylogenetic trees using TreeView. Curr Protoc Bioinformatics. 2002;Chapter 6:Unit 6 2.

19.

Berry

Hankin

Barkley

Spraggins

Caprioli

Murphy

. MALDI imaging of lipid biochemistry in tissues by mass spectrometry. Chem Rev 2011; 111(10): 6491–6512.

20.

Quarles

Macklin

Morell

. Myelin Formation, Structure and Biochemistry, 6th ed. Philadelphia, PA: Elsevier, 2006.

21.

Takahashi

Suzuki

. Role of sulfatide in normal and pathological cells and tissues. J Lipid Res 2012; 53(8): 1437–1450.

22.

Carman

Henry

. Phosphatidic acid plays a central role in the transcriptional regulation of glycerophospholipid synthesis in Saccharomyces cerevisiae. J Biol Chem 2007; 282(52): 37293–37297.

23.

Athenstaedt

Daum

. Phosphatidic acid, a key intermediate in lipid metabolism. Eur J Biochem 1999; 266(1): 1–16.

24.

Stace

Manifava

Delon

Coadwell

Cockcroft

Ktistakis

. PA binding of phosphatidylinositol 4-phosphate 5-kinase. Adv Enzyme Regul 2008; 48: 55–72.

25.

Yoon

Sun

Arauz

Jiang

Chen

. Phosphatidic acid activates mammalian target of rapamycin complex 1 (mTORC1) kinase by displacing FK506 binding protein 38 (FKBP38) and exerting an allosteric effect. J Biol Chem 2011; 286(34): 29568–29574.

26.

Chrast

Saher

Nave

Verheijen

. Lipid metabolism in myelinating glial cells: lessons from human inherited disorders and mouse models. J Lipid Res 2011; 52(3): 419–434.

27.

Cockcroft

Carvou

. Biochemical and biological functions of class I phosphatidylinositol transfer proteins. Biochim Biophys Acta 2007; 1771(6): 677–691.

28.

Kim

Huang

Spector

. Phosphatidylserine in the brain: metabolism and function. Prog Lipid Res 2014; 56: 1–18.

29.

Huang

Akbar

Kevala

Kim

. Phosphatidylserine is a critical modulator for Akt activation. J Cell Biol 2011; 192(6): 979–992.

30.

Flores

Narayanan

Morse

et al.

Constitutively active Akt induces enhanced myelination in the CNS. J Neurosci 2008; 28(28): 7174–7183.

31.

Vos

Lopes-Cardozo

Gadella

. Metabolic and functional aspects of sulfogalactolipids. Biochim Biophys Acta 1994; 1211(2): 125–149.

32.

Honke

. Biosynthesis and biological function of sulfoglycolipids. Proc Jpn Acad Ser B Phys Biol Sci 2013; 89(4): 129–138.

33.

Kolesnick

Kronke

. Regulation of ceramide production and apoptosis. Ann Rev Physiol 1998; 60: 643–665.

34.

Eckhardt

. The role and metabolism of sulfatide in the nervous system. Mol Neurobiol 2008; 37(2–3): 93–103.

35.

Summers

. Ceramides in insulin resistance and lipotoxicity. Prog Lipid Res 2006; 45(1): 42–72.

36.

McClure

Riddle

Manese

et al.

Cerebral blood flow heterogeneity in preterm sheep: lack of physiologic support for vascular boundary zones in fetal cerebral white matter. J Cereb Blood Flow Metab 2008; 28(5): 995–1008.

37.

Back

Riddle

Hohimer

. Role of instrumented fetal sheep preparations in defining the pathogenesis of human periventricular white-matter injury. J Child Neurol 2006; 21(7): 582–589.

38.

Riddle

Luo

Manese

et al.

Spatial heterogeneity in oligodendrocyte lineage maturation and not cerebral blood flow predicts fetal ovine periventricular white matter injury. J Neurosci 2006; 26(11): 3045–3055.

39.

Perlman

Rollins

. Surveillance protocol for the detection of intracranial abnormalities in premature neonates. Arch Pediatr Adolesc Med 2000; 154(8): 822–826.

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