Insulin-like growth factor -1 (IGF-1) derived neuropeptides, a novel strategy for the development of pharmaceuticals for managing ischemic brain injury.
Insulin-Like Growth Factor-1 (IGF-1) is neuroprotective and improves long-term function after brain injury. However, its clinical application to neurological disorders is limited by its large molecular size, poor central uptake, and mitogenic potential. Glycine-proline-glutamate (GPE) is naturally cleaved from the IGF-1 N-terminal and is also neuroprotective after ischemic injury, thus providing a potential novel strategy of drug discovery for management of neurological disorders. GPE is not enzymatically stable, thus intravenous infusion of GPE becomes necessary for stable and potent neuroprotection. The broad effective dose range and treatment window of 3-7 h after the lesion suggest its potential for treating acute brain injuries. The neuroprotective action of GPE is not age selective, is not dependent on cerebral reperfusion, plasma glucose concentrations, and core body temperature. G-2mPE, a GPE analogue designed to be more resistant to enzymatic activity, has a prolonged plasma half-life and is more potent in neuroprotection. Neuroprotection by GPE and its analogue may be involved in modulation of inflammation, promotion of astrocytosis, inhibition of apoptosis, and in vascular remodeling. Small neuropeptides have advantages over growth factors in the treatment of brain injury, and modified neuropeptides, designed to overcome the limitations of their endogenous counterparts, represent a novel strategy of pharmaceutical discovery for neurological disorders.
Liggins Institute, The University of Auckland, New Zealand. j.guan@auckland.ac.nz
Jian
J
Guan
D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism; D001930:Brain Injuries / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D002545:Brain Ischemia / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000031:analogs & derivatives* / Q000378:metabolism / Q000627:therapeutic use; D009479:Neuropeptides / Q000493:pharmacokinetics / Q000627:therapeutic use*; D018696:Neuroprotective Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D010446:Peptide Fragments / Q000627:therapeutic use; D051381:Rats
D009479:Neuropeptides; D018696:Neuroprotective Agents; D010446:Peptide Fragments; D007334:Insulin-Like Growth Factor I