Insulin-like growth factor-1 and its derivatives: potential pharmaceutical application for ischemic brain injury.
Brain ischemia induces the IGF-1 system in damaged regions, and exogenous administration of IGF-1 after injury is neuroprotective and improves long-term neurological function. The short treatment window can be extended by mild hypothermia, probably due to delayed apoptosis. Nevertheless, the poor central uptake of IGF-1 and its mitogenic potential preclude clinical application. The N-terminal tripeptide of IGF-1 (glycine-proline-glutamate, GPE) is neuroprotective after central administration. Central uptake of GPE is injury dependent, and it is rapidly degraded in the plasma. Intravenous infusion of GPE prevents brain injury and improves long-term functional recovery, with a broad effective dose range and a 3-7 hour therapeutic window. GPE does not interact with IGF receptors. G-2meth-PE, a GPE analogue with improved stability, has a prolonged plasma half life and is neuroprotective after ischemic injury. Neuroprotection by GPE and its analogue may involve modulating inflammation, promoting astrocytosis and inhibiting apoptosis, and the analogue may have a vascular effect. Cyclo-glycyl-proline (cGP) is an endogenous diketopiperazine possibly derived from GPE. Cyclic GP and its analogue cyclo-L-glycyl-L-2-allylproline (cG-2allylP) are neuroprotective after ischemic injury. cG-2allylP crosses the BBB independent of injury and remains detectable several hours after a single administration. Repeated peripheral administration of cG-2allyP improves somatosensory-motor function and long-term histological outcome.
Liggins Institute, The University of Auckland, New Zealand. j.guan@auckland.ac.nz
Jian
J
Guan
D000818:Animals; D001930:Brain Injuries / Q000209:etiology* / Q000378:metabolism / Q000517:prevention & control*; D002545:Brain Ischemia / Q000150:complications* / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism* / Q000627:therapeutic use; D009842:Oligopeptides / Q000627:therapeutic use; D010446:Peptide Fragments / Q000627:therapeutic use
D009842:Oligopeptides; D010446:Peptide Fragments; C058957:insulin-like growth factor 1, des-(1-3)-; D007334:Insulin-Like Growth Factor I; C062053:glycyl-prolyl-glutamic acid