A Metabolomic Approach in Search of Neurobiomarkers of Perinatal Asphyxia: A Review of the Current Literature

Abstract

Perinatal asphyxia and the possible sequelae of hypoxic-ischemic encephalopathy (HIE), are associated with high morbidity and mortality rates. The use of therapeutic hypothermia (TH) commencing within the first 6 h of life—currently the only treatment validated for the management of HIE—has been proven to reduce the mortality rate and disability seen at follow up at 18 months. Although there have been attempts to identify neurobiomarkers assessing the severity levels in HIE; none have been validated in clinical use to date, and the lack thereof limits the optimal treatment for these vulnerable infants. Metabolomics is a promising field of the “omics technologies” that may: identify neurobiomarkers, help improve diagnosis, identify patients prone to developing HIE, and potentially improve targeted neuroprotection interventions. This review focuses on the current evidence of metabolomics, a novel tool which may prove to be a useful in the diagnosis, management and treatment options for this multifactorial complex disease. Some of the most promising metabolites analyzed are the group of acylcarnitines: Hydroxybutyrylcarnitine (Malonylcarnitine) [C3-DC (C4-OH)], Tetradecanoylcarnitine [C14], L-Palmitoylcarnitine [C16], Hexadecenoylcarnitine [C16:1], Stearoylcarnitine [C18], and Oleoylcarnitine [C18:1]. A metabolomic “fingerprint” or “index,” made up of 4 metabolites (succinate × glycerol/(β-hydroxybutyrate × O-phosphocholine)), seems promising in identifying neonates at risk of developing severe HIE.

Metabolomics to Diagnose Oxidative Stress in Perinatal Asphyxia: Towards a Non-Invasive Approach

“…Oxidative stress markers glutathione [ 24 ], malondialdehyde [ 24 , 25 , 26 , 27 ] catalase, protein carbonyls, glutathione peroxidase, and 8-hydroxy-2′-deoxyguanosine [ 27 ], as well as isoprotanes, isofuranes, neuroprostanes, and neurofuranes [ 28 ] have all been measured in saliva from adults. However, although sporadically mentioned as an alternative [ 5 , 29 ], the evidence of metabolomics analysis of saliva in asphyxiated neonates is sparse, if not non-existing.…”

“…Superoxide dismutase, glutathione, catalase, and glutathione peroxidase are cellular antioxidants [ 49 ]. Debuf et al [ 29 ] performed a review of biomarkers of perinatal asphyxia and highlighted acylcarnitines as the most promising.…”

“…Several reviews, including one very recent [ 29 ], have addressed metabolomics biomarker analysis in perinatal asphyxia and HIE. However, they did not focus on oxidative stress the way our present review does.…”

“…Modern methods, e.g., LC-MS/MS have a turnaround time ranging from minutes to hours, opening for the possibility of integration into care. As stated by Debuf et al [ 29 ], despite a current lack of point-of-care methods to measure these metabolites, considering the increasing advances in metabolomics, a “bench to the bedside” approach may be realistic within a reasonable time frame. Mussap et al [ 5 ] suggested the translation of research results into the development of a low-cost device, e.g., a dipstick.…”

“…Table 2. Metabolites related to oxidative stress [29][30][31][32]. Reproduced with permission from Dr. Wishart, University of Alberta, Edmonton, Canada.…”