Ascorbate Deficiency Confers Resistance to Hippocampal Neurodegeneration After Asphyxial Cardiac Arrest in Juvenile Rats

Overview

Journal Pediatr Res

Specialties Biology
Pediatrics

Date 2021 Apr 13

PMID 33846553

Authors

Michael S Wolf

Mioara D Manole

Lee Ann New

Yaming Chen

Elif Soysal

Patrick M Kochanek

Hulya Bayir

Robert S B Clark

Affiliations

Soon will be listed here.

Abstract

Background: Asphyxial cardiac arrest (CA) is a significant cause of death and disability in children. Using juvenile Osteogenic disorder Shionogi (ODS) rats that, like humans, do not synthesize ascorbate, we tested the effect of ascorbate deficiency on functional and histological outcome after CA.

Methods: Postnatal day 16-18 milk-fed ODS and wild-type Wistar rats underwent 9-min asphyxial CA (n = 8/group) or sham surgery (n = 4/group). ODS mothers received ascorbate in drinking water to prevent scurvy. Levels of ascorbate and glutathione (GSH) were measured in plasma and hippocampus at baseline and after CA. Neurologic deficit score (NDS) was measured at 3, 24, and 48 h and hippocampal neuronal counts, neurodegeneration, and microglial activation were assessed at day 7.

Results: ODS rats showed depletion of plasma and hippocampal ascorbate, attenuated hippocampal neurodegeneration and microglial activation, and increased CA1 hippocampal neuron survival vs. Wistar rats while NDS were similar. Hippocampal GSH levels were higher in ODS vs. Wistar rats at baseline and 10 min, whereas hypoxia-inducible factor-1α levels were higher in Wistar vs. ODS rats at 24 , after CA.

Conclusion: Ascorbate-deficient juvenile ODS rats appear resistant to neurodegeneration produced by asphyxia CA, possibly related to upregulation of the endogenous antioxidant GSH in brain.

Impact: Like humans and unlike other rodents, osteogenic disorder Shionogi (ODS) rats do not synthesize ascorbate, and thus may serve as a useful model for studying the role of ascorbate in human disease. Conflicting evidence exists regarding ascorbate's protective versus detrimental effects in animal models and clinical studies. Ascorbate-deficient ODS rats are resistant to neurodegeneration after experimental cardiac arrest.

References

Tress E, Kochanek P, Saladino R, Manole M . Cardiac arrest in children. J Emerg Trauma Shock. 2010; 3(3):267-72. PMC: 2938492. DOI: 10.4103/0974-2700.66528. View

Moler F, Silverstein F, Holubkov R, Slomine B, Christensen J, Nadkarni V . Therapeutic hypothermia after out-of-hospital cardiac arrest in children. N Engl J Med. 2015; 372(20):1898-908. PMC: 4470472. DOI: 10.1056/NEJMoa1411480. View

Ichord R, Silverstein F, Slomine B, Telford R, Christensen J, Holubkov R . Neurologic outcomes in pediatric cardiac arrest survivors enrolled in the THAPCA trials. Neurology. 2018; 91(2):e123-e131. PMC: 6053110. DOI: 10.1212/WNL.0000000000005773. View

Harrison F, May J . Vitamin C function in the brain: vital role of the ascorbate transporter SVCT2. Free Radic Biol Med. 2009; 46(6):719-30. PMC: 2649700. DOI: 10.1016/j.freeradbiomed.2008.12.018. View

Spector R, Eells J . Deoxynucleoside and vitamin transport into the central nervous system. Fed Proc. 1984; 43(2):196-200. View

Bayir H, Kagan V, Tyurina Y, Tyurin V, Ruppel R, Adelson P . Assessment of antioxidant reserves and oxidative stress in cerebrospinal fluid after severe traumatic brain injury in infants and children. Pediatr Res. 2002; 51(5):571-8. DOI: 10.1203/00006450-200205000-00005. View

Hackenhaar F, Medeiros T, Heemann F, Behling C, Mahl C, Verona C . Mild Therapeutic Hypothermia Increases Glutathione Levels in Postcardiac Arrest Patients. Ther Hypothermia Temp Manag. 2018; 9(1):63-69. DOI: 10.1089/ther.2018.0012. View

Dezfulian C, Kenny E, Lamade A, Misse A, Krehel N, St Croix C . Mechanistic characterization of nitrite-mediated neuroprotection after experimental cardiac arrest. J Neurochem. 2016; 139(3):419-431. PMC: 5247267. DOI: 10.1111/jnc.13764. View

Katz L, Callaway C, Kagan V, Kochanek P . Electron spin resonance measure of brain antioxidant activity during ischemia/reperfusion. Neuroreport. 1998; 9(7):1587-93. DOI: 10.1097/00001756-199805110-00061. View

10.

Valls N, Gormaz J, Aguayo R, Gonzalez J, Brito R, Hasson D . Amelioration of persistent left ventricular function impairment through increased plasma ascorbate levels following myocardial infarction. Redox Rep. 2015; 21(2):75-83. PMC: 6837495. DOI: 10.1179/1351000215Y.0000000018. View

11.

Miura S, Ishida A, Nakajima W, Ohmura A, Kawamura M, Takada G . Intraventricular ascorbic acid administration decreases hypoxic-ischemic brain injury in newborn rats. Brain Res. 2006; 1095(1):159-66. DOI: 10.1016/j.brainres.2006.04.045. View

12.

Miura S, Ishida-Nakajima W, Ishida A, Kawamura M, Ohmura A, Oguma R . Ascorbic acid protects the newborn rat brain from hypoxic-ischemia. Brain Dev. 2008; 31(4):307-17. DOI: 10.1016/j.braindev.2008.06.010. View

13.

Tan S, Zhou F, Nielsen V, Wang Z, Gladson C, Parks D . Sustained hypoxia-ischemia results in reactive nitrogen and oxygen species production and injury in the premature fetal rabbit brain. J Neuropathol Exp Neurol. 1998; 57(6):544-53. DOI: 10.1097/00005072-199806000-00002. View

14.

Cheng B, Zhang Y, Wang A, Dong Y, Xie Z . Vitamin C Attenuates Isoflurane-Induced Caspase-3 Activation and Cognitive Impairment. Mol Neurobiol. 2014; 52(3):1580-1589. PMC: 4418956. DOI: 10.1007/s12035-014-8959-3. View

15.

Tsai M, Huang C, Tsai C, Chen H, Lee H, Cheng H . Ascorbic acid mitigates the myocardial injury after cardiac arrest and electrical shock. Intensive Care Med. 2011; 37(12):2033-40. DOI: 10.1007/s00134-011-2362-6. View

16.

Putzu A, Daems A, Lopez-Delgado J, Giordano V, Landoni G . The Effect of Vitamin C on Clinical Outcome in Critically Ill Patients: A Systematic Review With Meta-Analysis of Randomized Controlled Trials. Crit Care Med. 2019; 47(6):774-783. DOI: 10.1097/CCM.0000000000003700. View

17.

Wald E, Sanchez-Pinto L, Smith C, Moran T, Badke C, Barhight M . Hydrocortisone-Ascorbic Acid-Thiamine Use Associated with Lower Mortality in Pediatric Septic Shock. Am J Respir Crit Care Med. 2020; 201(7):863-867. DOI: 10.1164/rccm.201908-1543LE. View

18.

Aly H, Abd-Rabboh L, El-Dib M, Nawwar F, Hassan H, Aaref M . Ascorbic acid combined with ibuprofen in hypoxic ischemic encephalopathy: a randomized controlled trial. J Perinatol. 2009; 29(6):438-43. DOI: 10.1038/jp.2009.1. View

19.

Vergely C, Goirand F, Ecarnot-Laubriet A, Renard C, Moreau D, Guilland J . Vitamin C deficiency exerts paradoxical cardiovascular effects in osteogenic disorder Shionogi (ODS) rats. J Nutr. 2004; 134(4):729-35. DOI: 10.1093/jn/134.4.729. View

20.

Fink E, Alexander H, Marco C, Dixon C, Kochanek P, Jenkins L . Experimental model of pediatric asphyxial cardiopulmonary arrest in rats. Pediatr Crit Care Med. 2004; 5(2):139-44. PMC: 3235952. DOI: 10.1097/01.pcc.0000112376.29903.8f. View