Background/Objectives: Repeated exposure to postnatal inflammation plays an important role in the pathogenesis of preterm brain injury, and is characterised by abnormalities in white matter development, manifesting as fine motor deficits, cognitive/learning impairments, behavioural disturbances, and sensory deficits. Importantly, these deficits have been associated with long-term reductions in circulating levels of insulin-like growth factor-1 (IGF-1), which are further reduced in preterm infants with perinatal inflammation. Given the key role of IGF-1 in normal brain development, we examined the hypothesis that restoring IGF-1 signalling may be a therapeutic approach to promote normal brain development following early postnatal infection/inflammation.
Methods: Neonatal rats received intraperitoneal injections of lipopolysaccharide (LPS; 0.3 mg/kg) or saline, and subcutaneous injections of recombinant human IGF-1 (rhIGF-1; 0.5 mg/kg), (ii) cyclic glycine-proline (cGP; 0.01 mg/kg), or saline, on postnatal days (PND) 1-3. Animals were recovered to a range of time points to determine the pharmacokinetic and safety profile of rhIGF-1 and cGP, as well as pathological and behavioural outcomes at PND21.
Results: LPS exposure was associated with persisting alterations in IGF-1 bioavailability in the brain from PND2-21, which coincided with the period of oligodendrocyte cell death, and myelination deficits. Repeated administration of either rhIGF-1 or cGP following LPS exposure provided acute protection against LPS-induced oligodendrocyte cell death, with cGP exhibiting neuroprotection over a wider range of doses than rhIGF-1 (cGP: 0.01-0.1mg/kg; rhIGF-1 0.5mg/kg). Further, peak brain rhIGF-1 concentrations occurred at 1h post drug administration, and was associated increased brain glucose concentrations. By contrast, cGP administration was associated with decreased brain glucose concentrations.
Conclusions: Repeated postnatal inflammation impairs IGF-1 signalling in the brain, which may impact oligodendrocyte survival and white matter development. Further, targeting IGF-1 signalling directly (rhIGF-1) or indirectly (cGP) can promote normal brain development following repeated postnatal inflammatory insult, despite differential effects on brain glucose utilization.