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.