Astrocytic-inducible nitric oxide synthase in the ischemic developing human brain

Abstract

Variability in the expression of apoptotic and inflammatory mediators with time after an ischemic insult and their role in the expansion of cerebral infarcts are still controversial. This study examines DNA degradation and the expression of activated caspase-3 and iNOS, inducible nitric oxide (iNOS) in the human developing brain. Autopsy specimens from children with a neuropathologic diagnosis of focal ischemic infarct were included in the study. The specimens were classified based on the clinical history as acute (< 24 h, n = 5), subacute (24-72 h, n = 8), or old (> 72 h, n = 6) infarcts. Immunohistochemical staining for caspase-3, iNOS and TUNEL were then performed on all infarcts alongside age-matched controls. TUNEL staining was detected in regions of all infarcts. Expression of iNOS was significantly higher than that of caspase-3 in the penumbra of subacute infarcts (p = 0.02). Glial fibrillary acidic protein and iNOS staining co-localized in the penumbra of acute and subacute infarcts. These results suggest that cell death continues to occur for more than 3 d post ischemic insult. Cell death in the penumbra of subacute infarcts is partially caspase-3 independent and may be attributed to nitric oxide. Astrocytes are a source of iNOS and may play a role in the evolution of pediatric brain injury days after the initial insult.