title: Insulin-like growth factor-1 and its derivatives: potential pharmaceutical application for treating neurological conditions.
abstract: Ischemic brain damage remains a major cause of disability at all ages. This review examines the efficacy, mode of action and mechanisms of insulin-like growth factor (IGF)-1 and its derivatives in animal models of acute brain injury and neurodegenerative conditions, their potential in pharmaceutical developments. IGF-1 reduces cell loss and improves long-term neurological function in animal models. IGF-1 needs to be given within a few hours of the insult. However, the therapeutic window can be extended by mild hypothermia, likely by delaying apoptosis. Nevertheless, the poor central uptake of IGF-1 and its mitogenic potential limit clinical translation. Thus, recent studies have examined related compounds. For example, intravenous infusion of the N-terminal tripeptide of IGF-1 (glycine- proline-glutamate, GPE) can alleviate brain injury and improve long-term function in rats, with a broad effective dose range and a 3-7 hour therapeutic window, but has a short half-life. G-2meth-PE(G-2mPE), a GPE analogue with a longer half-life, is also neuroprotective. GPE/G-2mPE do not interact with IGF receptors and may act by modulating postinjury inflammation, astrogliosis and vascular remodeling. Cyclo-glycyl-proline (cGP), an endogenous diketopiperazine possibly derived from GPE is also neuroprotective. An analogue, cyclo-L-glycyl-L-2-allylproline (NNZ-2591) improves long-term somatosensory-motor function and histology after ischemic injury. Treatment with NNZ-2591 after 6-hypdroxydopamine injection in adult rats improves neurogenesis and long-term motor function. Further, oral administration of NNZ-2591 also prevents scopolamine-induced acute memory impairment. These beneficial effects may mediated by improved neuroplasticity. This review is an updated version of a previous publication in Recent Pat CNS Drug Discov.
authors.affiliation: The Liggins Institute, the University of Auckland, New Zealand. j.guan@auckland.ac.nz
authors.forename: Jian
authors.initials: J
authors.lastname: Guan
authors.forename: Sam
authors.initials: S
authors.lastname: Mathai
authors.forename: Hua-ping
authors.initials: HP
authors.lastname: Liang
authors.forename: Alistair J
authors.initials: AJ
authors.lastname: Gunn
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D007334:Insulin-Like Growth Factor I / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use*; D009422:Nervous System Diseases / Q000188:drug therapy*; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use; D020127:Recovery of Function / Q000187:drug effects
chemical_list: D018696:Neuroprotective Agents; D007334:Insulin-Like Growth Factor I