Exploring Perinatal Asphyxia by Metabolomics

Abstract

Brain damage related to perinatal asphyxia is the second cause of neuro-disability worldwide. Its incidence was estimated in 2010 as 8.5 cases per 1000 live births worldwide, with no further recent improvement even in more industrialized countries. If so, hypoxic-ischemic encephalopathy is still an issue of global health concern. It is thought that a consistent number of cases may be avoided, and its sequelae may be preventable by a prompt and efficient physical and therapeutic treatment. The lack of early, reliable, and specific biomarkers has up to now hampered a more effective use of hypothermia, which represents the only validated therapy for this condition. The urge to unravel the biological modifications underlying perinatal asphyxia and hypoxic-ischemic encephalopathy needs new diagnostic and therapeutic tools. Metabolomics for its own features is a powerful approach that may help for the identification of specific metabolic profiles related to the pathological mechanism and foreseeable outcome. The metabolomic profiles of animal and human infants exposed to perinatal asphyxia or developing hypoxic-ischemic encephalopathy have so far been investigated by means of 1 H nuclear magnetic resonance spectroscopy and mass spectrometry coupled with gas or liquid chromatography, leading to the identification of promising metabolomic signatures. In this work, an extensive review of the relevant literature was performed.trigger several changes at molecular and cellular levels, which may end in cell death and in local/systemic inflammation. The shortage of oxygen, which acts as final electron acceptor in the electron transport chain (ETC) during aerobic respiration, induced by hypoxia and by ischemia, boosts reactive oxygen species (ROS) generation at the cellular level. Generated ROS attack surrounds components at both the mitochondrial and cellular level, leading to mitochondrial dysfunction and permanent damage to cells. The pathogenesis of HIE is strongly influenced by the failure of several potent fetal compensatory mechanisms to cope with the 'physiological' hypoxia during pregnancy and delivery. The final clinical outcome of such an insult is a wide spectrum of neurological deficits, ranging from behavioral and motor impairments to general developmental delays to seizures related to structural brain damage.The severity of the clinical picture of HIE infants is the final result of an uneven combination of several factors, and among them the length and strength of hypoxic insult, together with fetal metabolic conditions before the hypoxia onset. For this reason, the pathological effects are complex to forecast, and they evolve over time. They may be related to two main pathological phases: A primary and a secondary energy failure. Primary energy failure is the first biological effect of both hypoxia and a reduction of cerebral blood flow and it mainly takes place before birth. While the impairment of blood flow is responsible for the progressive reduction of glucose availability needed to fuel brain cells' metabo...

Alzheimer’s Disease Associated Presenilin 1 and 2 Genes Dysregulation in Neonatal Lymphocytes Following Perinatal Asphyxia

“…The prevalence of perinatal asphyxia is ~2 per 1000 live births in developed countries, but the number of those affected rises to 26 per 1000 in developing countries [ 1 , 2 , 3 , 4 , 5 , 6 ]. Perinatal asphyxia occurs worldwide in approximately 4 million newborns annually [ 7 ] and is responsible for 23% of all infant deaths and 8% of child deaths [ 8 ].…”

“…Perinatal asphyxia occurs worldwide in approximately 4 million newborns annually [ 7 ] and is responsible for 23% of all infant deaths and 8% of child deaths [ 8 ]. Up to 25% of survivors have persistent neurological deficits [ 2 ], which is the second most common cause of neurological disability in the world [ 3 ]. Despite advances in treating the causes of perinatal asphyxia and asphyxia alone, the number of perinatal asphyxia cases has not decreased over the last decade [ 9 ], and its consequence is the development of hypoxic-ischemic encephalopathy diagnosed 1.8 per 1000 live births [ 10 , 11 , 12 ] with further deterioration the postpartum neurological status of newborns.…”

Metabolomics improves the histopathological diagnosis of asphyxial deaths: an animal proof-of-concept model

“…A wide body of literature on the impact of hypoxic-ischaemic conditions on different biofluids, and organs, metabolome in both animal models and human studies exists, among which an important part is devoted to the study of perinatal asphyxia 10 – 15 and sudden infant death syndrome 16 – 18 . Although scientifically remarkable, these models could not be translated to a mechanical asphyxia setup.…”

Pretreatment with mGluR2 or mGluR3 Agonists Reduces Apoptosis Induced by Hypoxia‐Ischemia in Neonatal Rat Brains

“…Hypoxic-ischemic encephalopathy (HIE) is one of the major causes of human infant mortality and morbidity, contributing to neuronal injury and impaired development [1], affecting up to 1.2 million infants annually [2].…”