# Neuroprotection of IGF-1 in neonatal hypoxic-ischemic brain injury through downregulation of FoXO3a-PUMA pathway

## TL;DR

This study shows that IGF-1 protects the brains of newborn mice from injury by blocking a pathway that causes cell death.

## Contribution

The study reveals a new mechanism by which IGF-1 protects neurons through suppression of the FoXO3a-PUMA pathway.

## Key findings

- IGF-1 expression increases in astrocytes after hypoxic-ischemic injury.
- IGF-1 reduces brain damage and improves behavior in neonatal mice.
- IGF-1 inhibits neuronal apoptosis by blocking the FoXO3a-PUMA pathway.

## Abstract

Insulin-like growth factor-1 (IGF-1) is a single chain polypeptide hormone that plays an essential role in intrauterine and postnatal growth. Recent studies suggest that IGF-1 and its receptor IGF-1R are involved in the pathogenesis of neurological diseases. Here, we explore the effect of IGF-1 signaling in neonatal hypoxic-ischemic (HI) brain injury and elucidate the underlying mechanisms of action. We found that the expression levels of IGF-1 were markedly enhanced in astrocytes post HI. Delivery of IGF-1 significantly alleviates neonatal brain insult and improves neurobehavioral disorders in neonatal mice after HI challenge. Through binding to IGF-1 receptor (IGF-1R), IGF-1 inhibited the apoptosis of neuronal cells following HI exposure. IGF-1 improved neuronal cell survival and proliferation through activation of phosphorylated AKT signaling. Of note, the protective property of IGF-1 against ischemic neuronal insults was dependent on suppression of the FoXO3a-PUMA signaling pathway. Taken together, these findings suggest that IGF-1 may represent a new neuroprotectant for newborns with hypoxic-ischemic encephalopathy.

IGF-1, by binding to IGF-1R, activates AKT to inhibit FoXO3a nuclear translocation, thereby preventing its binding to the PUMA promoter and subsequent neuronal apoptosis.Diagram illustrating a cellular signaling pathway where IGF-1 binds to IGF-1R, activating Akt which phosphorylates to p-Akt. This inhibits FoxO3a in the cytoplasm. In the nucleus, FoxO3a activates PUMA, leading to apoptosis.

IGF-1, by binding to IGF-1R, activates AKT to inhibit FoXO3a nuclear translocation, thereby preventing its binding to the PUMA promoter and subsequent neuronal apoptosis.