Insulin-Like Growth Factor -1 (IGF-1) Derived Neuropeptides, a Novel Strategy for the Development of Pharmaceuticals for Managing Ischemic Brain Injury

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 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.

Bone marrow mesenchymal stem cells repair the hippocampal neurons and increase the expression of IGF‑1 after cardiac arrest in rats

“…Previous studies showed that IGF-1 can enhance the activity of BDNF and VEGF ( 30 , 31 ), and there were no growth factors can enhance the activity of IGF-1. Peripherally administered IGF-1 is not easily to pass BBB because of its big molecular weight, and direct injection to brain can cause twice trauma, so the clinical application of IGF-1 is limited ( 32 ). However, BMSCs can secrete the IGF-1 homing to the ischemia areas, and it provides an appropriate administration route to avoid BBB.…”

IGFBP2 Produces Rapid-Acting and Long-Lasting Effects in Rat Models of Posttraumatic Stress Disorder via a Novel Mechanism Associated with Structural Plasticity

“…Future studies will be needed to determine which binding domain(s) of IGFBP2 are responsible for its therapeutic-like effects, and the site(s) of action responsible for these effects. In addition, other IGFBPs should be examined given that some of them have been shown to have protective effects in stress as well as hypoxia-ischemia, which could be relevant to PTSD ( Guan, 2011 ; Basta-Kaim et al, 2014 ). Thus, IGFBP2 and mimetics offer the potential for a new generation of therapeutics for PTSD.…”

A systematic review of neuroprotective strategies after cardiac arrest: from bench to bedside (part II-comprehensive protection)

“…GPE is a bioactive cleavage product from N-terminal IGF-1 and is also protective against ischemic brain injury [ 20 ]. The multiple mechanisms of GPE may be modulation of inflammation, promotion of astrocytosis, inhibition of apoptosis and vascular remodeling [ 20 ]. The effects of IGF-1 and GPE were compared in a rat model of CA and CPR [ 21 ].…”

“…From a translational point of view, GPE is a small neuropeptide that can pass BBB easily, thus giving advantages over growth factors in the treatment of brain injury. Nevertheless, it requires a continuous IV infusion to maintain stable central uptake due to the extremely short half-life of GPE [ 20 ].…”