Delayed peripheral administration of a GPE analogue induces astrogliosis and angiogenesis and reduces inflammation and brain injury following hypoxia-ischemia in the neonatal rat

Dev Neurosci. 2007;29(4-5):393-402. doi: 10.1159/000105480.


Glycine 2-methyl proline glutamate (G-2mPE) is a proline-modified analogue to the naturally existing N-terminal tripeptide glycine-proline-glutamate that is a cleaved product from insulin-like growth factor-1. G-2mPE is designed to be more enzymatically resistant than glycine-proline-glutamate and to increase its bioavailability. The current study has investigated the protective effects of G-2mPE following hypoxic-ischemic brain injury in the neonatal brain. On postnatal day 7, Wistar rats were exposed to hypoxia-ischemia (HI). HI was induced by unilateral ligation of the left carotid artery followed by hypoxia (7.7% O2, 36 degrees C) for 60 min. The drug treatment started 2 h after the insult, and the pups were given either 1.2 mg/kg (bolus), 1.2 mg/ml once a day for 7 days, or vehicle. The degree of brain damage was determined histochemically by thionin/acid fuchsin staining. G-2mPE's anti-inflammatory properties were investigated by IL-1beta, IL-6, and IL-18 ELISA, and effects on apoptosis by caspase 3 activity. Vascularization was determined immunohistochemically by the total length of isolectin-positive blood vessels. Effect on astrocytosis was also determined in the hippocampus. Animals treated with multiple doses of G-2mPE demonstrated reduced overall brain injury 7 days after HI, particularly in the hippocampus and thalamus compared to vehicle-treated rats. The expression of IL-6 was decreased in G-2mPE-treated animals compared to vehicle-treated pups, and both the capillary length and astrogliosis were increased in the drug-treated animals. There was no effect on caspase 3 activity. This study indicates that peripheral administration of G-2mPE, starting 2 h after a hypoxic-ischemic insult, reduces the degree of brain injury in the immature rat brain. The normalization of IL-6 levels and the promotion of both neovascularization and reactive astrocytosis may be potential mechanisms that underlie its protective effects.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Apoptosis / drug effects
  • Apoptosis / physiology
  • Astrocytes / drug effects
  • Astrocytes / physiology
  • Birth Injuries / drug therapy*
  • Birth Injuries / pathology
  • Birth Injuries / physiopathology
  • Brain / blood supply
  • Brain / drug effects
  • Brain / physiopathology
  • Caspase 3 / drug effects
  • Caspase 3 / metabolism
  • Cerebral Arteries / drug effects
  • Cerebral Arteries / growth & development
  • Disease Models, Animal
  • Drug Administration Schedule
  • Encephalitis / drug therapy*
  • Encephalitis / pathology
  • Encephalitis / physiopathology
  • Gliosis / drug therapy
  • Gliosis / pathology
  • Gliosis / physiopathology
  • Hypoxia-Ischemia, Brain / drug therapy*
  • Hypoxia-Ischemia, Brain / pathology
  • Hypoxia-Ischemia, Brain / physiopathology
  • Interleukins / metabolism
  • Neovascularization, Physiologic / drug effects
  • Neovascularization, Physiologic / physiology
  • Nerve Degeneration / drug therapy*
  • Nerve Degeneration / pathology
  • Nerve Degeneration / physiopathology
  • Neuroprotective Agents / pharmacology*
  • Neuroprotective Agents / therapeutic use
  • Oligopeptides / pharmacology*
  • Oligopeptides / therapeutic use
  • Rats
  • Rats, Wistar
  • Time Factors
  • Treatment Outcome


  • Interleukins
  • Neuroprotective Agents
  • Oligopeptides
  • glycine 2-methyl proline glutamate
  • Caspase 3
  • glycyl-prolyl-glutamic acid