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 it is also neuroprotective after ischemic injury, which provided a novel strategy of
drug discovery for
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. G-2meth-PE, a GPE analogue designed to be more enzymatic resistant, has a prolonged plasma half-life and is more potent in neuroprotection. Neuroprotection by GPE and its analogue may involve modulation of
inflammation, promotion of
astrocytosis, inhibition of apoptosis and vascular remodelling. Acute administration of GPE also prevents 6-OHDA-induced nigrostrial
dopamine depletion.
Delayed treatment with GPE does not prevent
dopamine loss, but improves long-term function. Cyclo-glycyl-
proline (cyclic
Gly-Pro) is an endogenous DKP that may be derived from GPE. Cyclic
Gly-Pro and its analogue
cyclo-L-glycyl-L-2-allylproline (NNZ 2591) are both neuroprotective after ischaemic injury. NNZ2591 is highly enzymatic resistant and centrally accessible. Its peripheral administration improves somatosensory-motor function and long-term histological outcome after
brain injury. Our research suggests that small
neuropeptides have advantages over
growth factors in the treatment of
brain injury, and that modified
neuropeptides designed to overcome the limitations of their endogenous counterparts represent a novel strategy of
pharmaceutical discovery for
neurological disorders.