Persistently Altered Metabolic Phenotype following Perinatal Excitotoxic Brain Injury

Abstract

Excitotoxicity plays a key role during insults to the developing brain such as neonatal encephalopathy, stroke, and encephalopathy of prematurity. Such insults affect many thousands of infants each year. Excitotoxicity causes frank lesions due to cell death and gliosis and disturbs normal developmental process, leading to deficits in learning, memory, and social integration that persist into adulthood. Understanding the underlying processes of the acute effects of excitotoxicity and its persistence during brain maturation provides an opportunity to identify mechanistic or diagnostic biomarkers, thus enabling and designing possible therapies. We applied mass spectrometry to provide metabolic profiles of brain tissue and plasma over time following an excitotoxic lesion (intracerebral ibotenate) to the neonatal (postnatal day 5) mouse brain. We found no differences between the plasma from the control (PBS-injected) and excitotoxic (ibotenate-injected) groups over time (on postnatal days 8, 9, 10, and 30). In the brain, we found that variations in amino acids (arginine, glutamine, phenylananine, and proline) and glycerophospholipids were sustaining acute and delayed (tertiary) responses to injury. In particular, the effect of the excitotoxic lesion on the normal profile of development was linked to alterations in a fingerprint of glycerophospolipids and amino acids. Specifically, we identified increases in the amino acids glutamine, proline, serine, threonine, tryptophan, valine, and the sphingolipid SM C26:1, and decreases in the glycerophospholipids, i.e., the arachidonic acid-containing phosphatidylcholine (PC aa) C30:2 and the PC aa C32:3. This study demonstrates that metabolic profiling is a useful approach to identify acute and tertiary effects in an excitotoxic lesion model, and generating a short list of targets with future potential in the hunt for identification, stratification, and possibly therapy.

Exposure to intrauterine inflammation alters metabolomic profiles in the amniotic fluid, fetal and neonatal brain in the mouse

“…Jaeger and coworkers demonstrated that the different regions of the mouse brain have unique metabolomic signatures and that excitotoxic injury results in an altered brain metabolome [ 51 ]. Similarly, utilizing an excitotoxic lesion model, Blaise and coworkers demonstrated an altered metabolomic fingerprint of the neonatal brain, post injury [ 52 ]. It is clear that defining the metabolomic profile of affected tissue is informative and may provide insight into the pathophysiology of brain injury.…”

Acylcarnitine profile in neonatal hypoxic-ischemic encephalopathy

“…Knowledge of how hypoxia-ischemia affects ACP is limited, [22–24] but evidence of alterations in different ischemic tissues such as the myocardium [25] underlines the need for a better understanding of how these metabolic pathways respond to hypoxic insult. The main aim of the current study was to characterize postnatal ACP in infants with HIE compared with a control group and to correlate results with clinical outcomes.…”

Blood Plasma Metabolic Profile of Newborns with Hypoxic‐Ischaemic Encephalopathy by GC‐MS

“…In terms of different species, compared with the finding in mouse [27,28], piglet [30,[43][44][45], and human primate [29], we found that only several coexpressed metabolites were present in the PB plasma of HIE. For the different biosample types, there were also few coexpressed metabolites among human PB, UCB, and urine [26,31,34,46].…”