Neuroprotective effects of Gly-Pro-Glu, the N- terminal tripeptide of IGF-1, in the hippocampus in vitro

Abstract

Insulin-like growth factor 1 (IGF-1) plays a critical role in CNS development. IGF-1 can block neuronal apoptosis in vitro and in vivo. IGF-1 is thought to be cleaved into des-N-(1-3)-IGF-1 and an amino terminal glycine-proline-glutamate (GPE tripeptide). Here we report a neuroprotective role for GPE tripeptide, with enhanced survival of the CA1-2 hippocampal neurons following an excitotoxic insult in vitro. Binding and displacement studies suggest uniquely distributed sites of action within the rat including the hippocampal CA1-2, pyriform cortex, amygdala, choroid plexus, blood vessels and to a lesser extent in the cortical regions. A similar pattern of binding was seen in the human. This finding could lead to new strategies to reduce neuronal death after injury and in disease.

GPE Promotes the Proliferation and Migration of Mouse Embryonic Neural Stem Cells and Their Progeny In Vitro

“…Although GPE was initially considered to be a non-bioactive by-product of IGF-1, it was later found that this small peptide was able to significantly increase the release of ACh from rat cortical slices [11,12]. Consequently, several neuroprotective effects of GPE have been unveiled since that discovery (see [13,14,15] for review). Thus, GPE has been shown to protect hippocampal neurons from NMDA-induced toxicity in vitro [11], and to reduce brain injury after hypoxia-ischemia [16,17,18].…”

NNZ-2566: A Gly–Pro–Glu analogue with neuroprotective efficacy in a rat model of acute focal stroke

“…Despite a lack of affinity for the IGF-1 receptor [2], these effects include stimulation of K + -evoked acetylcholine release from rat cortical slices [2,3], and considerable neuroprotective efficacy in multiple models. In vitro, Glypromate ® has been shown to protect hippocampal neurons from glutamate-mediated excitotoxicity [4,5] and protects cerebellar and striatal cells from both oxidative stress and excitotoxicity at low nanomolar concentrations (F. Sieg, personal communication). These in vitro neuroprotective effects have been shown to translate to efficacy in various animal models of acute brain injury and chronic neurodegeneration, including hypoxic-ischaemic injury in juvenile and adult rats [6][7][8], quinolinic-acid induced lesions of the striatum as a model of Huntington's disease [9], 6-hydroxydopamine lesions as a model of Parkinson's disease [10,11], the experimental autoimmune encephalomyelitis model of multiple sclerosis [12] and β-amyloid-induced somatostatin depletion, of relevance to Alzheimer's disease [13].…”

Combining Insulin-Like Growth Factor Derivatives Plus Caffeinol Produces Robust Neuroprotection After Stroke in Rats

“…9 When administered acutely after ischemia, GPE reduced both cortical damage and neuronal loss in CA1-2 subregions of the hippocampus. 5,10,11 Protease-resistant analogues (G2MePE) have been developed that prolong the half-life of GPE (usually 1 to 2 minutes).…”