Intranasal administration of insulin-like growth factor-1 protects against lipopolysaccharide-induced injury in the developing rat brain

Abstract

Our previous studies show that insulin-like growth factor-1 (IGF-1) can either protect against or increase lipopolysaccharide (LPS)-induced damage in the developing brain, depending on the dose, when it is co-administered with LPS through intracerebral injection. To further explore effects of IGF-1 on central inflammation associated brain injury, IGF-1 was administered through intranasal infusion in the current study. Postnatal day 5 (P5) rats were exposed to LPS at a dose of 1 μg/g body weight or sterile saline through intracerebral injection. Recombinant human insulin-like growth factor-1 (rhIGF-1) at a dose of 50 μg/pup or vehicle was administered intranasally 1 or 2 hr after the LPS injection. Neonatal LPS exposure resulted in oligodendrocyte (OL) and white matter injury in the P6 or P21 rat brain. The damages include dilatation of lateral ventricles, pyknotic cell death, loss of OL progenitor cells and mature OLs in the cingulum area, and impairment of myelination at the corpus callosum area. Neurological dysfunctions were observed in juvenile rats with neonatal LPS exposure. Intranasal IGF-1 treatment at either 1 or 2 hr after LPS exposure significantly attenuated LPS-induced brain injury and improved some behavioral deficits. Intranasal IGF-1 treatment also reduced infiltration of polymorphonuclear leukocytes and activation of microglia in the rat brain 24 hr after LPS exposure, but it did not prevent the elevation in concentrations of interleukin-1β (IL-1β) and tumor necrosis factor alpha (TNFα) in the LPS-exposed rat brain during the first 24 hr. This is an indication that direct anti-inflammation might not be the primary mechanism for the protection of IGF-1, and other mechanisms, such as anti-apoptotic effects, are likely involved in its protective effects.

Enhanced memory consolidation in mice lacking the circadian modulators Sharp1 and -2 caused by elevated Igf2 signaling in the cortex

“…Moreover, our analysis supports the hypothesis that the control of sleep and memory consolidation may be controlled by similar mechanisms including IGF2-dependent signaling. IGF2 seems to be a potent memory enhancer in the hippocampus (34,43,52) as well as in the cortex (our study) and factors of insulinlike signaling are under investigation as putative therapeutical agents to overcome cognitive decline upon aging and in neurodegenerative and psychiatric disease conditions (53)(54)(55)(56)(57). Recently, we could show that S1/2 −/− mice display an impaired working memory (20), whereas long-term memory consolidation is enhanced (this study), which may be explained by the fact that the CaMKII-cre display highly significantly reduced fear learning compared with Igf1R/InsR fl/fl control mice 1 d and 28 d after conditioning.…”

Circulatory insulin-like growth factor-I and brain volumes in relation to neurodevelopmental outcome in very preterm infants

“…Exogenous intranasal administration of IGF-I has protective effects in the developing rat brain after hypoxic or inflammatory insults, probably by interfering with antiapoptotic mechanisms (21,22). Very preterm infants are exposed to multiple hypoxic and inflammatory events during and after birth.…”

Traumatic Brain Injury Increased IGF-1B mRNA and Altered IGF-1 Exon 5 and Promoter Region Epigenetic Characteristics in the Rat Pup Hippocampus

“…IGF-1 administration improved histologic and functional outcomes in adult rodents after TBI (Kazanis et al, 2003;Lu et al, 2009;Rubovitch et al, 2010;Saatman et al, 1997), and in adult and neonatal rats after hypoxic-ischemic brain injury Lin et al, 2005Lin et al, ,2009. Similarly, IGF-1 administration improved neurologic outcome in 21-day-old rat pups after lipopolysaccharide-induced brain injury (Cai et al, 2011). Thus, brain IGF-1 upregulation appears to be a neuroprotective response in the mature and immature brain.…”