IGF‐1 derived small neuropeptides and analogues: a novel strategy for the development of pharmaceuticals for neurological conditions

Abstract

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.

Growth Hormone Receptors in the Brain and their Potential as Therapeutic Targets in Central Nervous System Disorders

“…In a more recent study it was suggested that smaller peptide fragments, derived from IGF-1, could have advantages over growth factors in the treatment of brain injury. These fragments could be modified and designed with suitable properties to overcome many of the limitations associated with the native endogenous peptides regarding their potential role as medical drugs [68].…”

The role for IGF-1-derived small neuropeptides as a therapeutic target for neurological disorders

“…While the neuroprotective effect of IGF-1 is clearly mediated by IGF-1 receptors [16], the mode of action of GPE and cGP remains unclear as GPE does not bind to the IGF-1 receptor [32,34,68,73]. Despite the failure to identify a specific receptor, the neuroprotective effects of GPE and cGP after central (ICV) administration are clearly dose-dependent, consistent with receptor-mediated pharmacodynamics [73].…”

“…Inhibition of injuryinduced inflammation responses has also been suggested by the association of neuroprotection with these derivatives, and subsequently reduced levels of pro-inflammatory cytokines (IL-6 and TNF-a) and numbers of reactive microglia [60][61][62][63]. Furthermore, there was evidence of improved vascular remodeling, probably through either elevation in and/or protection of activation of astrocytes [73].…”

“…Despite the failure to identify a specific receptor, the neuroprotective effects of GPE and cGP after central (ICV) administration are clearly dose-dependent, consistent with receptor-mediated pharmacodynamics [73]. It is also known that the neuroprotective effects of IGF-1 [74] and GPE [48,59] involve reduced vascular damage and improved vascular remodeling.…”

“…Neuroprotection with IGF-1 derivatives are clearly involved in preventing necrotic and apoptotic neuronal death as shown by reduced area of tissue infarction and numbers of cleaved caspase-3-positive neurons [60][61][62][63]73]. Inhibition of injuryinduced inflammation responses has also been suggested by the association of neuroprotection with these derivatives, and subsequently reduced levels of pro-inflammatory cytokines (IL-6 and TNF-a) and numbers of reactive microglia [60][61][62][63].…”