Protection and Reversal of Excitotoxic Neuronal Damage by Glucagon-Like Peptide-1 and Exendin-4

Abstract

Glucagon-like peptide-1 (7-36)-amide (GLP-1) is an endogenous insulinotropic peptide that is secreted from the L cells of the gastrointestinal tract in response to food. It has potent effects on glucose-dependent insulin secretion, insulin gene expression, and pancreatic islet cell formation. In type 2 diabetes, GLP-1, by continuous infusion, can normalize blood glucose and is presently being tested in clinical trials as a therapy for this disease. More recently, GLP-1 has been found to have central nervous system (CNS) effects and to stimulate neurite outgrowth in cultured cells. We now report that GLP-1, and its longer-acting analog exendin-4, can completely protect cultured rat hippocampal neurons against glutamate-induced apoptosis. Extrapolating these effects to a well defined rodent model of neurodegeneration, GLP-1 and exendin-4 greatly reduced ibotenic acid-induced depletion of choline acetyltransferase immunoreactivity in basal forebrain cholinergic neurons. These findings identify a novel neuroprotective/neurotrophic function of GLP-1 and suggest that such peptides may have potential for halting or reversing neurodegenerative processes in CNS disorders, such as Alzheimer's disease, and in neuropathies associated with type 2 diabetes mellitus.Although GLP-1 is produced by cells in the intestines and was discovered because of its effects on glucose metabolism (Doyle and Egan, 2001), recent studies have shown that GLP-1 can decrease feeding by acting on specific receptors in the brain. When injected intracerebroventricularly, GLP-1 dramatically reduces food and water intake (Gunn et al

GLP-1 receptor stimulation preserves primary cortical and dopaminergic neurons in cellular and rodent models of stroke and Parkinsonism

“…GLP-1Rs are present in rodent cultured CC and VM primary neurons, as well as hippocampal neurons (14), and also in SH-SY5Y cells. Adding GLP-1 to primary neurons induced a time-dependent elevation in cAMP, indicative of a functional receptor.…”

“…Our previous studies have established that a 50% GLP-1R occupancy in primary neurons is achieved by 14 nM GLP-1 (14), a value similar to that for ␤-cells. Here we show that administration of GLP-1 and Ex-4 to primary CC and VM neurons or SH-SY5Y cells proved to be neuroprotective against insults that modeled stroke and PD.…”

Exendin-4-Loaded PLGA Microspheres Relieve Cerebral Ischemia/Reperfusion Injury and Neurologic Deficits through Long-Lasting Bioactivity-Mediated Phosphorylated Akt/eNOS Signaling in Rats

“…11 GLP-1R is widely located throughout the brain; and GLP-1 and Ex-4 provide neuroprotection against neuronal damage through GLP-1R activation. 12,13 Several neurovascular protective mechanisms are involved in the effects of GLP-1R activation, including activation of phosphorylated Akt/endothelial nitric oxide synthase (p-Akt/p-eNOS) protective signaling, 11 protein kinase A-mediated inhibition of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity-induced oxidative stress, 14 and inhibition of translocation of the p65 subunit of nuclear factor-κB (NF-κB) and mitochondrial pro-apoptotic Bax. 15 Ex-4 attenuates stroke injury in patients with Type 2 diabetes by arresting microglia infiltration, increasing neural stem cell proliferation, and depressing metabolic insults.…”

International Union of Pharmacology. XXXV. The Glucagon Receptor Family

“…GLP-1, and its longer-acting analog exendin-4, completely protected cultured rat hippocampal neurons against glutamate-induced apoptosis (Perry et al, 2002a), and GLP-1 promotes nerve growth factormediated differentiation in PC12 cells (Perry et al, 2002b). Activation of GLP-1 receptor signaling also promotes proliferative and anti-apoptotic actions in the endocrine pancreas, providing a potential opportunity for interventions directed at expanding ␤-cell mass in subjects with diabetes (Li et al, 2003;Drucker, 2003).…”