Glucagon-like peptide 1 receptor stimulation as a means of neuroprotection

Abstract

Glucagon-like peptide 1 (GLP-1) is a relatively recently discovered molecule originating in the so-called L-cells of the intestine. The peptide has insulinotrophic properties and it is this characteristic that has predominantly been investigated. This has led to the use of the GLP-1-like peptide exendin-4 (EX-4), which has a much longer plasma half-life than GLP-1 itself, being used in the treatment of type II diabetes. The mode of action of this effect appears to be a reduction in pancreatic apoptosis, an increase in beta cell proliferation or both. Thus, the effects of GLP-1 receptor stimulation are not based upon insulin replacement but an apparent repair of the pancreas. Similar data suggest that the same effects may occur in other peripheral tissues. More recently, the roles of GLP-1 and EX-4 have been studied in nervous tissue. As in the periphery, both peptides appear to promote cellular growth and reduce apoptosis. In models of Alzheimer's disease, Parkinson's disease and peripheral neuropathy, stimulation of the GLP-1 receptor has proved to be highly beneficial. In the case of Parkinson's disease this effect is evident after the neurotoxic lesion is established, suggesting real potential for therapeutic use. In the present review we examine the current status of the GLP-1 receptor and its potential as a therapeutic target.

Figure 1

Intracellular events associated with stimulation of glucagon-like peptide 1 receptors (GLP-1Rs). The receptor is G-protein coupled with a consequent rise in cyclic adenosine monophosphate (cAMP). Further intracellular events lead to nuclear changes and alterations in transcription. EX-4, exendin-4; GLP-1R, GLP-1 receptor; PLC, phospholipase C; IP₃, inositol triphosphate; DAG, diacylglycerol; PKC, protein kinase C; NF-kB, nuclear factor kappa B; PI3 kinase, phosphoinositide 3 kinase; PKB, protein kinase B; PKCζ, protein kinase C-zeta; AC, adenylate cylase; Epac, exchange proteins directly activated by cAMP; MAPK, mitogen-activated protein kinase; ERK, extracellular signal-regulated kinase; PKA, protein kinase A; PDX-1, pancreatic duodenal homeobox-1; CREB, cyclic AMP response element binding protein.

Figure 3

Photomicrographs of selected nigral sections from rats treated with fluorogold and visualized under UV light. Rats were lesioned with 6-hydroxydopamine (6-OHDA) as indicated in the text and either treated with vehicle (upper panel; twice daily for 7 days) starting 7 days post toxin or 0.5 µg·kg⁻¹ exendin-4 (EX-4) (lower panel). Massive loss of retrograde staining by 6-OHDA and retention or reversal of this is apparent. The extent of cell loss in the 6-OHDA only group suggests that treatment with EX-4 effects a restoration of nigrostriatal neurons. Bar is 100 µm.

Figure 2

Neuroprotection by exendin-4 (EX-4) in the 6-hydroxydopamine (6-OHDA) rat model of Parkinson's disease. (A) EX-4 shows clear restoration of motor behaviour; (B) tissue dopamine (DA) content; (C) striatal tyrosine hydroxylase (TH) activity; (D) nigral TH immunoreactivity shown as a qualitative index of TH staining. In all groups, EX-4 or vehicle was given twice daily for 7 days after the initial 6-OHDA insult. In each case groups are made up of six rats per group and were subjected to one-way analysis of variance (anova) followed by a post hoc Bonferonni's Multiple Comparison Test (A–C). One-way anova revealed significant differences between treatments in for all of the parameters studied (A–C; P < 0.001). Bonferonni's Multiple Comparison Test revealed significant differences (*) from all other groups (A) and from sham or EX-4 treated groups (B and C). Data adapted from (Harkavyi et al., 2008). L-DOPA, L-3,4-dihydroxyphenylalanine; EX-9-39, exendin-(9,39).