Neonatal hypoxia-ischemia (HI) and the delayed injury cascade that follows involve excitotoxicity, oxidative stress and mitochondrial failure. The susceptibility to excitotoxicity of the neonatal brain may be related to the capacity of astrocytes for glutamate uptake. Furthermore, the neonatal brain is vulnerable to oxidative stress, and the pentose phosphate pathway (PPP) may be of particular importance for limiting this kind of injury. Also, in the neonatal brain, neurons depend upon de novo synthesis of neurotransmitters via pyruvate carboxylase in astrocytes to increase neurotransmitter pools during normal brain development. Several recent publications describing intermediary brain metabolism following neonatal HI have yielded interesting results: (1) Following HI there is a prolonged depression of mitochondrial metabolism in agreement with emerging evidence of mitochondria as vulnerable targets in the delayed injury cascade. (2) Astrocytes, like neurons, are metabolically impaired following HI, and the degree of astrocytic malfunction may be an indicator of the outcome following hypoxic and hypoxic-ischemic brain injury. (3) Glutamate transfer from neurons to astrocytes is not increased following neonatal HI, which may imply that astrocytes fail to upregulate glutamate uptake in response to the massive glutamate release during HI, thus contributing to excitotoxicity. (4) In the neonatal brain, the activity of the PPP is reduced following HI, which may add to the susceptibility of the neonatal brain to oxidative stress. The present review aims to discuss the metabolic temporal alterations observed in the neonatal brain following HI.

Perinatal hypoxic-ischemic brain injury is a major health problem. Adjuvant treatments that improve the neuroprotective effect of the current treatment, therapeutic hypothermia, are urgently needed. The growing knowledge about the complex pathophysiology of hypoxia-ischemia (HI) has led to the discovery of several important targets for neuroprotection. Early interventions should focus on the preservation of energy metabolism, the reduction of glutamate excitotoxicity and oxidative stress, the maintenance of calcium homeostasis, and the prevention of apoptosis. Delayed interventions should promote injury repair. The multiple metabolic changes following HI as well as the metabolic effects of potential treatments can be observed noninvasively by magnetic resonance spectroscopy (MRS). This mini-review provides an overview of the neuroprotective pharmacological agents that have been evaluated with ¹H/³¹P/¹³C MRS. A better understanding of how these agents influence cerebral metabolism and the use of relevant translational MRS biomarkers can guide future clinical trials.

Mitochondrial impairment is a key feature underlying neonatal hypoxic-ischemic (HI) brain injury and melatonin is potentially neuroprotective through its effects on mitochondria. In this study, we have used 1 H and 13 C NMR spectroscopy after injection of [1- 13C]glucose and [1,2-13 C]acetate to examine

Melatonin has potential neuroprotective capabilities after neonatal hypoxia-ischemia (HI), but long-term effects have not been investigated. We hypothesized that melatonin treatment directly after HI could protect against early and delayed brain injury. Unilateral HI brain injury was induced in postnatal day 7 rats. An intraperitoneal injection of either melatonin or vehicle was given at 0, 6 and 25 hours after hypoxia. In-vivo MRI was performed 1, 7, 20 and 43 days after HI, followed by histological analysis. Forelimb asymmetry and memory were assessed at 12–15 and at 36–43 days after HI. More melatonin treated than vehicle treated animals (54.5% vs 15.8%) developed a mild injury characterized by diffusion tensor values, brain volumes, histological scores and behavioral parameters closer to sham. However, on average, melatonin treatment resulted only in a tendency towards milder injury on T2-weighted MRI and apparent diffusion coefficient maps day 1 after HI, and not improved long-term outcome. These results indicate that the melatonin treatment regimen of 3 injections of 10 mg/kg within the first 25 hours only gave a transient and subtle neuroprotective effect, and may not have been sufficient to mitigate long-term brain injury development following HI.