Nerve growth factor protects the neonatal brain against hypoxic–ischemic injury

Abstract

Nerve growth factor (NGF) has been shown to protect specific neurons that express its signaling receptor, trkA, from a variety of insults. There are some data, in particular in the developing brain, indicating that NGF has neuroprotective actions that extend beyond cells expressing trkA. In this study, we asked whether NGF would protect against brain injury in a neonatal model of hypoxia-ischemia. Postnatal day (PD) 7 rat pups received a right carotid ligation and were then exposed to hypoxic conditions. Prior to carotid ligation and 48 hours later, pups received an intracerebroventricular injection of NGF or denatured NGF dissolved in vehicle or vehicle alone. Brains were then assessed at PD21. In vehicle- and denatured NGF-treated animals, there was significant damage (30-40% volume loss) to both the striatum and cortex ipsilateral to the carotid ligation. In contrast, little damage (10% volume loss) was observed in most NGF-treated animals. NGF injection studies revealed that NGF stimulated tyrosine phosphorylation of trkA in multiple brain regions. These results show that NGF appears globally neuroprotective to the developing brain in a neonatal model of hypoxia-ischemia and that there may be novel mechanisms in vivo through which NGF exerts its protective actions.

A Novel Role for Vascular Endothelial Growth Factor as an Autocrine Survival Factor for Embryonic Stem Cells during Hypoxia

“…Indeed, a survival activity has been documented for bFGF, PDGF-B, VEGF, nerve growth factor, brain-derived neurotrophic factor, neurotrophin-3 and erythropoietin for hypoxic neurons (15,(35)(36)(37)(38)(39)(40)(41), acidic fibroblast growth factor, IGF-I and erythropoietin for hypoxic myocardial cells (42)(43)(44)(45)(46), VEGF for hypoxic chondrocytes (47), or hepatocyte growth factor and erythropoietin for hypoxic renal cells (48,49). Growth factors may also protect cells against apoptosis in response to other stimuli, as exemplified by the ability of erythropoietin, c-kit ligand, or interleukin-3 to block p53-mediated apoptosis of hematopoietic cell lines (50 -52) by the protective effect of IGF-I or EGF on epithelial cells or lymphocytes against Fas-induced apoptosis (53)(54)(55) or by the inhibition by IGF-I of glutamateinduced apoptosis of oligodendrocyte progenitors (56).…”

Vasoactive intestinal peptide prevents excitotoxic cell death in the murine developing brain.

“…Glutamate receptor antagonists and inhibitors of glutamate release (for review see reference 9), free radical scavengers (59), growth factors including nerve growth factor (60), and insulinlike growth factor 1 (61), have been shown to protect partially rodent brains against excitotoxic and/or hypoxic-ischemic damages. VIP derivatives could represent an alternate approach to treat these disorders in premature infants.…”

Selective, Reversible Caspase-3 Inhibitor Is Neuroprotective and Reveals Distinct Pathways of Cell Death after Neonatal Hypoxic-ischemic Brain Injury

“…Briefly, coronal sections from the genu of the corpus callosum to the end of the dorsal hippocampus were stained with cresyl violet as previously described (46). The cross-sectional areas of the striatum, cortex, and hippocampus in each of eight equally spaced reference planes were photo-scanned, and the area of each brain region was calculated using SigmaScan Pro (Jandel Scientific Software).…”