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Review
. 2012 Apr;160(4):544-552.e4.
doi: 10.1016/j.jpeds.2011.12.052. Epub 2012 Feb 9.

Which neuroprotective agents are ready for bench to bedside translation in the newborn infant?

Nicola J Robertson  1 , Sidhartha Tan, Floris Groenendaal, Frank van Bel, Sandra E Juul, Laura Bennet, Matthew Derrick, Stephen A Back, Raul Chavez Valdez, Frances Northington, Alistair Jan Gunn, Carina Mallard
Affiliations
Review

Which neuroprotective agents are ready for bench to bedside translation in the newborn infant?

Nicola J Robertson et al. J Pediatr. 2012 Apr.
No abstract available

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure
Figure
Simplified schematic representation of putative neurotoxic cascade targets for some promising medications. After global hypoxia-ischemia, glutamate-induced excitotoxicity proceeds via NMDA receptor activation, producing Ca2+ influx and therefore activation of Ca2+-dependent NOS, particularly nNOS. At high concentrations, NO• reacts with superoxide (O•−) to produce peroxynitrite (ONOO−), which in turn induces lipid peroxidation and mitochondrial nitrosylation. Consequently, mitochondrial dysfunction and membrane depolarization develop with further release of O•− and decline in sulfhydryls, such as glutathione. Ca2+ also triggers other mechanisms including: (1) the irreversible proteolytic conversion of xanthine dehydrogenase to xanthine oxidase producing significant amounts of O•− and H2O2 in the process; and (2) the activation of cytosolic phospholipases, increasing eicosanoid release and inflammation. During the acute energy depletion, some cells undergo primary cell death, the magnitude of which will depend on the severity and duration of hypoxia-ischemia. After reperfusion, the initial hypoxia-induced cytotoxic edema and accumulation of excitatory amino acids typically resolve in 30 to 60 minutes, with apparent recovery of cerebral oxidative metabolism. It is thought that the neurotoxic cascade is largely inhibited during the latent phase and that this period provides a “therapeutic window.” Cerebral oxidative metabolism may then secondarily deteriorate 6 to 15 hours later (termed secondary energy failure in studies using phosphorus-31 or proton magnetic resonance spectroscopy). This phase is marked by the onset of seizures, secondary cytotoxic edema, accumulation of cytokines, and mitochondrial failure. Mitochondrial failure is a key step leading to delayed cell death. The degree of energy failure influences the type of cell death displayed by neurons during early and delayed stages, the degree of trophic support influences the angiogenesis and neurogenesis during the recovery phase after hypoxia-ischemia. Each treatment shown targets single or multiple points in the cascade initiated by hypoxia-ischemia, and many show potential effects by improving neuronal survival, regeneration, or both.
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