Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Cholesterol metabolism and brain injury in neonatal encephalopathy

Abstract

Neonatal encephalopathy (NE) results from impaired cerebral blood flow and oxygen delivery to the brain. The pathophysiology of NE is complex and our understanding of its underlying pathways continues to evolve. There is considerable evidence that cholesterol dysregulation is involved in several adult diseases, including traumatic brain injury, stroke, Huntington’s disease, and Parkinson’s disease. Although the research is less robust in pediatrics, there is emerging evidence that aberrations in cholesterol metabolism may also be involved in the pathophysiology of neonatal NE. This narrative review provides an overview of cholesterol metabolism in the brain along with several examples from the adult literature where pathologic alterations in cholesterol metabolism have been associated with inflammatory and ischemic brain injury. Using those data as a background, the review then discusses the current preclinical data supporting the involvement of cholesterol in the pathogenesis of NE as well as how brain-specific cholesterol metabolites may serve as serum biomarkers for brain injury. Lastly, we review the potential for using the cholesterol metabolic pathways as therapeutic targets. Further investigation of the shifts in cholesterol synthesis and metabolism after hypoxia–ischemia may prove vital in understanding NE pathophysiology as well as providing opportunities for rapid diagnosis and therapeutic interventions.

Impact

  • This review summarizes emerging evidence that aberrations in cholesterol metabolism may be involved in the pathophysiology of NE.

  • Using data from NE as well as analogous adult disease states, this article reviews the potential for using cholesterol pathways as targets for developing novel therapeutic interventions and using cholesterol metabolites as biomarkers for injury.

  • When possible, gaps in the current literature were identified to aid in the development of future studies to further investigate the interactions between cholesterol pathways and NE.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: Current understanding of central nervous system cholesterol metabolism.
Fig. 2: Cholesterol synthesis and transport during development.

References

  1. 1.

    Kurinczuk, J. J., White-Koning, M. & Badawi, N. Epidemiology of neonatal encephalopathy and hypoxic-ischaemic encephalopathy. Early Hum. Dev. 86, 329–338 (2010).

    PubMed  Article  PubMed Central  Google Scholar 

  2. 2.

    Allen, K. A. & Brandon, D. H. Hypoxic ischemic encephalopathy: pathophysiology and experimental treatments. Newborn Infant Nurs. Rev. 11, 125–133 (2011).

    PubMed  PubMed Central  Article  Google Scholar 

  3. 3.

    Douglas-Escobar, M. & Weiss, M. D. Hypoxic-ischemic encephalopathy: a review for the clinician. JAMA Pediatr. 169, 397–403 (2015).

    PubMed  Article  PubMed Central  Google Scholar 

  4. 4.

    Yu, Z. et al. Hypoxia-ischemia brain damage disrupts brain cholesterol homeostasis in neonatal rats. Neuropediatrics 40, 179–185 (2009).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  5. 5.

    Bruns, N. et al. Application of an Amplitude-integrated EEG Monitor (Cerebral Function Monitor) to neonates. J. Vis. Exp. 127, (2017).

  6. 6.

    Chandrasekaran, M., Chaban, B., Montaldo, P. & Thayyil, S. Predictive value of amplitude-integrated EEG (aEEG) after rescue hypothermic neuroprotection for hypoxic ischemic encephalopathy: a meta-analysis. J. Perinatol. 37, 684–689 (2017).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  7. 7.

    Del Río, R. et al. Amplitude integrated electroencephalogram as a prognostic tool in neonates with hypoxic-ischemic encephalopathy: a systematic review. PLoS ONE 11, e0165744 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  8. 8.

    Hackam, D. G. & Hegele, R. A. Cholesterol lowering and prevention of stroke. Stroke 50, 537–541 (2019).

    PubMed  Article  PubMed Central  Google Scholar 

  9. 9.

    Kay, A. D. et al. Remodeling of cerebrospinal fluid lipoprotein particles after human traumatic brain injury. J. Neurotrauma 20, 717–723 (2003).

    PubMed  Article  PubMed Central  Google Scholar 

  10. 10.

    Björkhem, I. & Hansson, M. Cerebrotendinous xanthomatosis: an inborn error in bile acid synthesis with defined mutations but still a challenge. Biochem. Biophys. Res. Commun. 396, 46–49 (2010).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  11. 11.

    Fitzky, B. U. et al. Mutations in the Delta7-sterol reductase gene in patients with the Smith–Lemli–Opitz syndrome. Proc. Natl Acad. Sci. USA 95, 8181–8186 (1998).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  12. 12.

    Lu, F. et al. Upregulation of cholesterol 24-hydroxylase following hypoxia-ischemia in neonatal mouse brain. Pediatr. Res. 83, 1218–1227 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  13. 13.

    Ramirez, M. R. et al. Neonatal hypoxia-ischemia reduces ganglioside, phospholipid and cholesterol contents in the rat hippocampus. Neurosci. Res. 46, 339–347 (2003).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  14. 14.

    Zhang, J. & Liu, Q. Cholesterol metabolism and homeostasis in the brain. Protein Cell 6, 254–264 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  15. 15.

    Alphonse, P. A. S. & Jones, P. J. H. Revisiting human cholesterol synthesis and absorption: the reciprocity paradigm and its key regulators. Lipids 51, 519–536 (2016).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  16. 16.

    Dietschy, J. M. Central nervous system: cholesterol turnover, brain development and neurodegeneration. Biol. Chem. 390, 287–293 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  17. 17.

    Sun, M.-Y. et al. 24(S)-Hydroxycholesterol as a modulator of neuronal signaling and survival. Neurosci. Rev. J. Bringing Neurobiol. Neurol. Psychiatry 22, 132–144 (2016).

    CAS  Google Scholar 

  18. 18.

    Genaro-Mattos, T. C. et al. Cholesterol biosynthesis and uptake in developing neurons. ACS Chem. Neurosci. 10, 3671–3681 (2019).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  19. 19.

    Zerenturk, E. J., Sharpe, L. J., Ikonen, E. & Brown, A. J. Desmosterol and DHCR24: unexpected new directions for a terminal step in cholesterol synthesis. Prog. Lipid Res. 52, 666–680 (2013).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  20. 20.

    Jansen, M. et al. What dictates the accumulation of desmosterol in the developing brain? FASEB J. 27, 865–870 (2013).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  21. 21.

    Hernández-Jiménez, M. et al. Seladin-1/DHCR24 is neuroprotective by associating EAAT2 glutamate transporter to lipid rafts in experimental stroke. Stroke 47, 206–213 (2016).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  22. 22.

    Nguyen, A. D., McDonald, J. G., Bruick, R. K. & DeBose-Boyd, R. A. Hypoxia stimulates degradation of 3-hydroxy-3-methylglutaryl-coenzyme A reductase through accumulation of lanosterol and hypoxia-inducible factor-mediated induction of insigs. J. Biol. Chem. 282, 27436–27446 (2007).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  23. 23.

    Dorszewska, J. & Adamczewska-Goncerzewicz, Z. Patterns of free and esterified sterol fractions of the cerebral white matter in severe and moderate experimental hypoxia. Med. Sci. Monit. Int. Med. J. Exp. Clin. Res. 6, 227–231 (2000).

    CAS  Google Scholar 

  24. 24.

    Wender, M., Adamczewska-Goncerzewicz, Z., Doroszewska, J. & Szczech, J. Free sterols in the rat white matter following experimental global ischemia. Exp. Toxicol. Pathol. 49, 57–59 (1997).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  25. 25.

    Cartagena, C. M. et al. Cortical injury increases cholesterol 24S hydroxylase (Cyp46) levels in the rat brain. J. Neurotrauma 25, 1087–1098 (2008).

    PubMed  PubMed Central  Article  Google Scholar 

  26. 26.

    Cartagena, C. M., Burns, M. P. & Rebeck, G. W. 24S-hydroxycholesterol effects on lipid metabolism genes are modeled in traumatic brain injury. Brain Res. 1319, 1–12 (2010).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  27. 27.

    Lu, F. et al. Serum 24S-hydroxycholesterol predicts long-term brain structural and functional outcomes after hypoxia-ischemia in neonatal mice. J. Cereb. Blood Flow Metab. 271678X20911910 (2020).

  28. 28.

    Björkhem, I. et al. Cholesterol homeostasis in human brain: turnover of 24S-hydroxycholesterol and evidence for a cerebral origin of most of this oxysterol in the circulation. J. Lipid Res. 39, 1594–1600 (1998).

    PubMed  Article  PubMed Central  Google Scholar 

  29. 29.

    Emnett, C. M. et al. Interaction between positive allosteric modulators and trapping blockers of the NMDA receptor channel. Br. J. Pharm. 172, 1333–1347 (2015).

    CAS  Article  Google Scholar 

  30. 30.

    Grayaa, S. et al. Plasma oxysterol profiling in children reveals 24-hydroxycholesterol as a potential marker for Autism Spectrum Disorders. Biochimie 153, 80–85 (2018).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  31. 31.

    Björkhem, I. et al. Oxysterols and Parkinson’s disease: evidence that levels of 24S-hydroxycholesterol in cerebrospinal fluid correlates with the duration of the disease. Neurosci. Lett. 555, 102–105 (2013).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  32. 32.

    Leoni, V. et al. Changes in human plasma levels of the brain specific oxysterol 24S-hydroxycholesterol during progression of multiple sclerosis. Neurosci. Lett. 331, 163–166 (2002).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  33. 33.

    Ye, J. & DeBose-Boyd, R. A. Regulation of cholesterol and fatty acid synthesis. Cold Spring Harb. Perspect. Biol. 3, 7. https://cshperspectives.cshlp.org/content/3/7/a004754.long (2011).

  34. 34.

    Eberlé, D. et al. SREBP transcription factors: master regulators of lipid homeostasis. Biochimie 86, 839–848 (2004).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  35. 35.

    Vergnes, L. et al. SREBP-2-deficient and hypomorphic mice reveal roles for SREBP-2 in embryonic development and SREBP-1c expression. J. Lipid Rs. 57, 410–421 (2016).

    CAS  Article  Google Scholar 

  36. 36.

    Ferris, H. A. et al. Loss of astrocyte cholesterol synthesis disrupts neuronal function and alters whole-body metabolism. Proc. Natl Acad. Sci. USA 114, 1189–1194 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  37. 37.

    Woollett, L. A. Review: Transport of maternal cholesterol to the fetal circulation. Placenta 32, S218–S221 (2011).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  38. 38.

    Woollett, L. A. Maternal cholesterol in fetal development: transport of cholesterol from the maternal to the fetal circulation. Am. J. Clin. Nutr. 82, 1155–1161 (2005).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  39. 39.

    McConihay, J. A., Horn, P. S. & Woollett, L. A. Effect of maternal hypercholesterolemia on fetal sterol metabolism in the Golden Syrian hamster. J. Lipid Res. 42, 1111–1119 (2001).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  40. 40.

    Tint, G. S. et al. The use of the Dhcr7 knockout mouse to accurately determine the origin of fetal sterols. J. Lipid Res. 47, 1535–1541 (2006).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  41. 41.

    Tint, G. S. et al. Desmosterol in brain is elevated because DHCR24 needs REST for robust expression but REST is poorly expressed. Dev. Neurosci. 36, 132–142 (2014).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  42. 42.

    Jurevics, H. A., Kidwai, F. Z. & Morell, P. Sources of cholesterol during development of the rat fetus and fetal organs. J. Lipid Res. 38, 723–733 (1997).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  43. 43.

    Pfrieger, F. W. & Ungerer, N. Cholesterol metabolism in neurons and astrocytes. Prog. Lipid Res. 50, 357–371 (2011).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  44. 44.

    Nägler, K., Mauch, D. H. & Pfrieger, F. W. Glia-derived signals induce synapse formation in neurones of the rat central nervous system. J. Physiol. 533, 665–679 (2001).

    PubMed  PubMed Central  Article  Google Scholar 

  45. 45.

    Ullian, E. M., Sapperstein, S. K., Christopherson, K. S. & Barres, B. A. Control of synapse number by glia. Science 291, 657–661 (2001).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  46. 46.

    Hinse, C. H. & Shah, S. N. The desmosterol reductase activity of rat brain during development. J. Neurochem. 18, 1989–1998 (1971).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  47. 47.

    Nie, S., Chen, G., Cao, X. & Zhang, Y. Cerebrotendinous xanthomatosis: a comprehensive review of pathogenesis, clinical manifestations, diagnosis, and management. Orphanet J. Rare Dis. 9, 179 (2014).

    PubMed  PubMed Central  Article  Google Scholar 

  48. 48.

    Ben Hamida, M. et al. Peripheral neuropathy in a sporadic case of cerebrotendinous xanthomatosis. Rev. Neurol. 147, 385–388 (1991).

    PubMed  PubMed Central  Google Scholar 

  49. 49.

    Tint, G. S. et al. Defective cholesterol biosynthesis associated with the Smith-Lemli-Opitz syndrome. N. Engl. J. Med. 330, 107–113 (1994).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  50. 50.

    Tint, G. S. et al. Correlation of severity and outcome with plasma sterol levels in variants of the Smith-Lemli-Opitz syndrome. J. Pediatr. 127, 82–87 (1995).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  51. 51.

    Nowaczyk, M. J. M. & Irons, M. B. Smith-Lemli-Opitz syndrome: phenotype, natural history, and epidemiology. Am. J. Med. Genet. C 160C, 250–262 (2012).

    Article  Google Scholar 

  52. 52.

    Tierney, E., Conley, S. K., Goodwin, H. & Porter, F. D. Analysis of short-term behavioral effects of dietary cholesterol supplementation in Smith-Lemli-Opitz syndrome. Am. J. Med. Genet. A 152A, 91–95 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  53. 53.

    Porter, F. D. Smith-Lemli-Opitz syndrome: pathogenesis, diagnosis and management. Eur. J. Hum. Genet. 16, 535–541 (2008).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  54. 54.

    Fitzky, B. U. et al. 7-Dehydrocholesterol-dependent proteolysis of HMG-CoA reductase suppresses sterol biosynthesis in a mouse model of Smith-Lemli-Opitz/RSH syndrome. J. Clin. Invest. 108, 905–915 (2001).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  55. 55.

    Sodero, A. O. et al. Cholesterol loss during glutamate-mediated excitotoxicity. EMBO J. 31, 1764–1773 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  56. 56.

    Catapano, A. L., Pirillo, A. & Norata, G. D. Vascular inflammation and low-density lipoproteins: is cholesterol the link? A lesson from the clinical trials. Br. J. Pharm. 174, 3973–3985 (2017).

    CAS  Article  Google Scholar 

  57. 57.

    Martiskainen, H. et al. DHCR24 exerts neuroprotection upon inflammation-induced neuronal death. J. Neuroinflamm. 14, 215 (2017).

    Article  CAS  Google Scholar 

  58. 58.

    Yatsu, F. M. & Moss, S. A. Brain lipid changes following hypoxia. Stroke 2, 587–593 (1971).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  59. 59.

    Kacher, R. et al. CYP46A1 gene therapy deciphers the role of brain cholesterol metabolism in Huntington’s disease. Brain J. Neurol. 142, 2432–2450 (2019).

    Article  Google Scholar 

  60. 60.

    del Toro, D. et al. Altered cholesterol homeostasis contributes to enhanced excitotoxicity in Huntington’s disease. J. Neurochem. 115, 153–167 (2010).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  61. 61.

    Valenza, M. et al. Dysfunction of the cholesterol biosynthetic pathway in Huntington’s disease. J. Neurosci. J. Soc. Neurosci. 25, 9932–9939 (2005).

    CAS  Article  Google Scholar 

  62. 62.

    Hu, G. et al. Total cholesterol and the risk of Parkinson disease. Neurology 70, 1972–1979 (2008).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  63. 63.

    Hu, G. et al. Body mass index and the risk of Parkinson disease. Neurology 67, 1955–1959 (2006).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  64. 64.

    Doria, M. et al. Contribution of cholesterol and oxysterols to the pathophysiology of Parkinson’s disease. Free Radic. Biol. Med. 101, 393–400 (2016).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  65. 65.

    Lee, C.-Y. J. et al. Different patterns of oxidized lipid products in plasma and urine of dengue fever, stroke, and Parkinson’s disease patients: cautions in the use of biomarkers of oxidative stress. Antioxid. Redox Signal. 11, 407–420 (2009).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  66. 66.

    Choi, J.-Y., Jang, E.-H., Park, C.-S. & Kang, J.-H. Enhanced susceptibility to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine neurotoxicity in high-fat diet-induced obesity. Free Radic. Biol. Med. 38, 806–816 (2005).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  67. 67.

    Bousquet, M. et al. High-fat diet exacerbates MPTP-induced dopaminergic degeneration in mice. Neurobiol. Dis. 45, 529–538 (2012).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  68. 68.

    Lim, L. et al. Lanosterol induces mitochondrial uncoupling and protects dopaminergic neurons from cell death in a model for Parkinson’s disease. Cell Death Differ. 19, 416–427 (2012).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  69. 69.

    Xiong, Y., Zhang, Y., Mahmood, A. & Chopp, M. Investigational agents for treatment of traumatic brain injury. Expert Opin. Investig. Drugs 24, 743–760 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  70. 70.

    Morganti-Kossmann, M. C., Satgunaseelan, L., Bye, N. & Kossmann, T. Modulation of immune response by head injury. Injury 38, 1392–1400 (2007).

    PubMed  Article  PubMed Central  Google Scholar 

  71. 71.

    Wang, J. et al. Traumatic brain injury leads to accelerated atherosclerosis in apolipoprotein E deficient mice. Sci. Rep. 8, 5639 (2018).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  72. 72.

    Weiner, M. F. et al. Plasma 24S-hydroxycholesterol and other oxysterols in acute closed head injury. Brain Inj. 22, 611–615 (2008).

    PubMed  PubMed Central  Article  Google Scholar 

  73. 73.

    Saher, G. & Stumpf, S. K. Cholesterol in myelin biogenesis and hypomyelinating disorders. Biochim. Biophys. Acta 1851, 1083–1094 (2015).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  74. 74.

    Linsenbardt, A. J. et al. Different oxysterols have opposing actions at N-methyl-D-aspartate receptors. Neuropharmacology 85, 232–242 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  75. 75.

    Jun, J. C. et al. Thermoneutrality modifies the impact of hypoxia on lipid metabolism. Am. J. Physiol. 304, E424–E435 (2013).

    CAS  Google Scholar 

  76. 76.

    Denihan, N. M., Boylan, G. B. & Murray, D. M. Metabolomic profiling in perinatal asphyxia: a promising new field. BioMed. Res. Int. 2015, 254076 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  77. 77.

    Fabelo, N. et al. Severe alterations in lipid composition of frontal cortex lipid rafts from Parkinson’s disease and incidental Parkinson’s disease. Mol. Med. 17, 1107–1118 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  78. 78.

    Schönknecht, P. et al. Cerebrospinal fluid 24S-hydroxycholesterol is increased in patients with Alzheimer’s disease compared to healthy controls. Neurosci. Lett. 324, 83–85 (2002).

    PubMed  Article  PubMed Central  Google Scholar 

  79. 79.

    Papassotiropoulos, A. et al. Plasma 24S-hydroxycholesterol: a peripheral indicator of neuronal degeneration and potential state marker for Alzheimer’s disease. NeuroReport 11, 1959–1962 (2000).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  80. 80.

    Sato, Y. et al. Identification of a new plasma biomarker of Alzheimer’s disease using metabolomics technology. J. Lipid Res. 53, 567–576 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  81. 81.

    Wakamatsu, H. et al. Serum desmosterol and other lipids in myotonic dystrophy-a possible pathogenesis of myotonic dystrophy. Keio J. Med. 19, 145–149 (1970).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  82. 82.

    Berghoff, S. A. et al. Dietary cholesterol promotes repair of demyelinated lesions in the adult brain. Nat. Commun. 8, 14241 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  83. 83.

    Chong, A. J. et al. The neuroprotective effects of simvastatin on high cholesterol following traumatic brain injury in rats. World Neurosurg. 132, e99–e108 (2019).

    PubMed  Article  PubMed Central  Google Scholar 

  84. 84.

    Sikora, D. M. et al. Cholesterol supplementation does not improve developmental progress in Smith-Lemli-Opitz syndrome. J. Pediatr. 144, 783–791 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. 85.

    Ridker, P. M. et al. Measurement of C-reactive protein for the targeting of statin therapy in the primary prevention of acute coronary events. N. Engl. J. Med. 344, 1959–1965 (2001).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  86. 86.

    Wible, E. F. & Laskowitz, D. T. Statins in traumatic brain injury. Neurother. J. Am. Soc. Exp. Neurother. 7, 62–73 (2010).

    CAS  Google Scholar 

  87. 87.

    Xu, X. et al. Anti-inflammatory and immunomodulatory mechanisms of atorvastatin in a murine model of traumatic brain injury. J. Neuroinflamm. 14, 167 (2017).

    Article  CAS  Google Scholar 

  88. 88.

    He, X. et al. Lovastatin modulates increased cholesterol and oxysterol levels and has a neuroprotective effect on rat hippocampal neurons after kainate injury. J. Neuropathol. Exp. Neurol. 65, 652–663 (2006).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  89. 89.

    Wassif, C. A. et al. A placebo-controlled trial of simvastatin therapy in Smith-Lemli-Opitz syndrome. Genet. Med. 19, 297–305 (2017).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  90. 90.

    Jira, P. E. et al. Simvastatin. A new therapeutic approach for Smith-Lemli-Opitz syndrome. J. Lipid Res. 41, 1339–1346 (2000).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  91. 91.

    Verrips, A. et al. Effect of simvastatin in addition to chenodeoxycholic acid in patients with cerebrotendinous xanthomatosis. Metabolism 48, 233–238 (1999).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  92. 92.

    Balduini, W., De Angelis, V., Mazzoni, E. & Cimino, M. Simvastatin protects against long-lasting behavioral and morphological consequences of neonatal hypoxic/ischemic brain injury. Stroke 32, 2185–2191 (2001).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  93. 93.

    Carloni, S. & Balduini, W. Simvastatin preconditioning confers neuroprotection against hypoxia-ischemia induced brain damage in neonatal rats via autophagy and silent information regulator 1 (SIRT1) activation. Exp. Neurol. 324, 113117 (2020).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  94. 94.

    Li, A. et al. Simvastatin attenuates hypomyelination induced by hypoxia-ischemia in neonatal rats. Neurol. Res. 32, 945–952 (2010).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  95. 95.

    Rufini, S. et al. Cholesterol depletion inhibits electrophysiological changes induced by anoxia in CA1 region of rat hippocampal slices. Brain Res. 1298, 178–185 (2009).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  96. 96.

    Balduini, W. et al. Prophylactic but not delayed administration of simvastatin protects against long-lasting cognitive and morphological consequences of neonatal hypoxic-ischemic brain injury, reduces interleukin-1beta and tumor necrosis factor-alpha mRNA induction, and does not affect endothelial nitric oxide synthase expression. Stroke 34, 2007–2012 (2003).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank Dr. Zeljka Korade for her support and advice during the process of writing this review.

Author information

Affiliations

Authors

Contributions

A.M.D and E.S.P. both contributed substantially to the conception, design, drafting, and critical revisions of the article. Both authors reviewed and approved the final version.

Corresponding author

Correspondence to Eric S. Peeples.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Dave, A.M., Peeples, E.S. Cholesterol metabolism and brain injury in neonatal encephalopathy. Pediatr Res 90, 37–44 (2021). https://doi.org/10.1038/s41390-020-01218-3

Download citation

Search

Quick links