Neuronal death and survival in two models of hypoxic-ischemic brain damage

Abstract

Two unilateral hypoxic-ischemia (HI) models (moderate and severe) in immature rat brain have been used to investigate the role of various transcription factors and related proteins in delayed neuronal death and survival. The moderate HI model results in an apoptotic-like neuronal death in selectively vulnerable regions of the brain while the more severe HI injury consistently produces widespread necrosis resulting in infarction, with some necrosis resistant cell populations showing evidence of an apoptotic type death. In susceptible regions undergoing an apoptotic-like death there was not only a prolonged induction of the immediate early genes, c-jun, c-fos and nur77, but also of possible target genes amyloid precursor protein (APP751) and CPP32. In contrast, increased levels of BDNF, phosphorylated CREB and PGHS-2 were found in cells resistant to the moderate HI insult suggesting that these proteins either alone or in combination may be of importance in the process of neuroprotection. An additional feature of both the moderate and severe brain insults was the rapid activation and/or proliferation of glial cells (microglia and astrocytes) in and around the site of damage. The glial response following HI was associated with an upregulation of both the CCAAT-enhancer binding protein alpha (microglia only) and NFkappaB transcription factors.