Protective mechanisms of cGP in hypoxic-ischemic brain injury

Abstract

Cyclo-glycyl-proline (cGP) is an endogenous diketopiperazine (DKP) derived from Insulin-like growth factor-1 (IGF-1) and has shown neuroprotective effect after hypoxic-ischemic (HI) brain injury. Central administration of cGP showed neuroprotection in hippocampus, striatum and lateral cortex following unilateral HI brain injury. As a derivative of IGF-1, however, cGP does not interact with IGF-1 receptors (IGF-1R) and its natural role and mechanism of action in neuroprotection have been largely unknown. Our previous study showed that after unilateral HI brain injury in rats, the intracerebroventricular administration of 0.2μg of cGP reduced brain damage in hippocampus, striatum and lateral cortex. The present study explores the possible protective mechanisms of cGP after HI brain injury by analysing blood vessel density, astrocyte density, the expression and distributions of IGF-1R, phosphorylated IGF-1R and IGFBP-2 in hippocampus, striatum and lateral cortex in brain tissues generated from the previous study. In this study, it was found that HI brain injury can lead to loss of blood vessels and astrocytes in the injured areas and suppression of IGF-1R and IGFBP-2 expression. The central administration of cGP after HI brain injury showed injury dependent upregulation of IGF-1R and IGFBP-2 expression, enhanced astrocyte survival and vascular remodelling. IGF-1R and IGFBP-2 have been suggested to be involved in IGF-1 mediated astrocyte proliferation and vascular remodelling, which can lead to neuroprotection in brain injury. Therefore, the neuroprotective effects of cGP could be mediated through promoting astrocyte survival and proliferation and vascular remodelling and protection by stimulating IGF-1 signalling pathway.