Novel treatments after experimental brain injury.
Perinatal hypoxic-ischaemic encephalopathy(HIE) is being studied in laboratory models that allow the delayed cascade of events triggered by the energetic insult to be examined in detail. The concept of the 'excitotoxic cascade' provides a conceptual framework for thinking about the pathogenesis of HIE. Major events in the cascade triggered by hypoxia-ischaemia include overstimulation of N-methyl-D-aspartate type glutamate receptors, calcium entry into cells, activation of calcium-sensitive enzymes such as nitric oxide synthase, production of oxygen free radicals, injury to mitochondria, leading in turn to necrosis or apoptosis. New experimental approaches to salvaging brain tissue from the effects of HIE include inhibition of neuronal nitric oxide synthase, administration of neuronal growth factors, and inhibition of the caspase enzymes that execute apoptosis. Recent experimental work suggests that these approaches may be effective during a longer 'therapeutic window' after the insult, because they are acting on events that are relatively delayed. Application of modest hypothermia may allow these agents to be neuroprotective at even longer intervals after hypoxia-ischaemia.
Johnston
M V
MV
Johns Hopkins University School of Medicine, Kennedy Krieger Institute, Baltimore, MD 21205, USA.
Trescher
W H
WH
Ishida
A
A
Nakajima
W
W
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001238:Asphyxia Neonatorum / Q000378:metabolism / Q000628:therapy*; D001923:Brain Chemistry / Q000187:drug effects; D001930:Brain Injuries / Q000151:congenital* / Q000378:metabolism / Q000628:therapy*; D003546:Cysteine Endopeptidases / Q000187:drug effects; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D005311:Fetal Hypoxia / Q000378:metabolism / Q000628:therapy*; D016166:Free Radical Scavengers / Q000627:therapeutic use; D006801:Humans; D007036:Hypothermia, Induced; D007231:Infant, Newborn; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology; D009414:Nerve Growth Factors / Q000627:therapeutic use; D018696:Neuroprotective Agents / Q000627:therapeutic use; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000502:physiology
D016166:Free Radical Scavengers; D009414:Nerve Growth Factors; D018696:Neuroprotective Agents; D016194:Receptors, N-Methyl-D-Aspartate; D019001:Nitric Oxide Synthase; D003546:Cysteine Endopeptidases