IGF-1 Can Either Protect Against or Increase LPS-Induced Damage in the Developing Rat Brain

Abstract

Periventricular leukomalacia (PVL) is a major form of brain damage in premature infants. The present study was to test whether Insulin-like growth factor-1 (IGF-1) can prevent PVL-like brain damage induced by lipopolysaccharide (LPS) in the neonatal rat. Intraventricular delivery of LPS resulted in an acute brain inflammatory response, i.e., rapid recruitment of polymorphonuclear leukocytes (PMNs), activation of microglia and astrocytes, and induction of interleukin-1β (IL1β) expression. Brain inflammation was associated with the loss of O4+ pre-oligodendrocytes (pre-OLs), a decrease of myelin basic protein (MBP) in the white matter and an increase of pyknotic cells in the cortex. IGF-1 at a low dose significantly prevented LPS-induced deleterious effects without alteration of IL-1β expression and microglia/astrocytes activation. On the other hand, the low dose of IGF-1 enhanced LPS-induced PMNs recruitment and blood-brain barrier (BBB) permeability, and caused intracerebral hemorrhage. At higher doses, co-application of IGF-1 with LPS resulted in a high mortality rate. Brains from the surviving rats showed massive PMN infiltration and intracerebral hemorrhage. However, these adverse effects were not found in rats treated with IGF-1 alone. This study provides the alarming evidence that in an acute inflammatory condition, IGF-1 may have severe, harmful effects on developing brain.

Combined Exercise and Insulin-Like Growth Factor-1 Supplementation Induces Neurogenesis in Old Rats, but Do Not Attenuate Age-Associated DNA Damage

“…33,34 However, the findings of a recent report suggest that IGF-1 could have beneficial as well as harmful effects on the developing brain. 35 This revelation supports the earlier observation that hyperactivated IGF-1 signaling shows accelerated aging and amyloid beta production in the brain. 36 Blockade of IGF-1 in nonexercising and exercising mice has revealed the complex role of IGF-1 in neurogenesis, dendritic spine density, CA1 pyramidal cells, and hippocampal structure.…”

Pathophysiology of glia in perinatal white matter injury

“…Post-transcriptional control by microRNAs regulates OL differentiation and OPCs that lack mature microRNAs display arrested maturation (Dugas et al 2010; Shin et al 2009). Insulin-like growth factors (IGFs) promote OL lineage cell survival and myelination and protect against OL progenitor loss in fetal and neonatal models of WMI (Guan et al 2001; Pang et al 2010b; Wood et al 2007). Bone morphogenetic proteins both repress OL differentiation and regulate myelin protein expression (See et al 2004; See and Grinspan 2009).…”

Safety aspects of longitudinal administration of IGF-I/IGFBP-3 complex in neonatal mice

“…Recently, Pang et al reported that IGF-I could have negative effects on the developing brain in an acute inflammatory condition [67]. On the one hand, a low dose of IGF-I prevented lipopolysaccharideinduced brain injury, but on the other hand the permeability of the blood-brain barrier was enhanced causing intracerebral hemorrhage.…”