Frontiers in CNS Drug Discovery

Volume: 1

Indexed in: Scopus, EMBASE, Book Citation Index, Science Edition, BIOSIS

“Frontiers in CNS Drug Discovery” is an eBook series devoted to publishing the latest and the most important advances in Central Nervous System (CNS) drug design and discovery. Eminent scientists ...
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Insulin-Like Growth Factor-1 and its Derivatives: Potential Pharmaceutical Application for Ischemic Brain Injury

Pp. 51-75 (25)

Jian Guan

Abstract

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. Its neuroprotective effects are also independent of cerebral reperfusion and not age selective. 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 vascular remodeling

Cyclo-glycyl-proline (cGP) is an endogenous diketopiperazine possibly derived from GPE. Cyclic GP and its analogue cyclo-L-glycyl-L-2-allylproline (NNZ 2591) are neuroprotective after ischemic injury. NNZ 2591 crosses the BBB independent of injury and remains detectable several hours after a single administration. Repeated peripheral administration of NNZ 2591 improves somatosensorymotor function and long-term histological outcome.

Keywords:

IGF-1, GPE, diketopiperazine, pharmaceuticals, pharmacology, clinical applications and ischemic brain injury

Affiliation:

Liggins Institute, The University of Auckland, New Zealand