alexa Protection and reversal of excitotoxic neuronal damage by glucagon-like peptide-1 and exendin-4
Biomedical Sciences

Biomedical Sciences

Journal of Biomolecular Research & Therapeutics

Author(s): TracyAnn Perry, Norman J

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lucagon-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., 1996; Tang-Christensen et al., 1996; Turton et al., 1996; Wang et al., 1998) and body weight (Donahey et al., 1998;Meeran et al., 1999) in rats. The GLP-1 receptor antagonist exendin (9–39) inhibits the effects of GLP-1 on food and water intake, suggesting that GLP-1 receptors are involved in satiety (Turton et al., 1996). However, the effects of GLP-1 on feeding are not sustained, and mice lacking GLP-1 receptors are lean, eat normally, and do not develop obesity either with aging or after several months of high-fat intake (Scrocchi et al., 1996; Scrocchi and Drucker, 1998). Several studies have demonstrated GLP-1 receptor expression in both the rodent (Goke et al., 1995; Shughrue et al., 1996) and human (Wei and Mojsov, 1995; Satoh et al., 2000) brain. GLP-1 receptors appear to be distributed primarily in the hypothalamus, thalamus, brainstem, lateral septum, subfornical organ, and the area postrema. However, specific binding sites for GLP-1 have also been detected in neurons in the caudate-putamen, cerebral cortex, hippocampus, and cerebellum (Campos et al., 1994; Calvo et al., 1995; Goke et al., 1995). It remains to be established whether GLP-1 is produced by neural cells, but it has been shown that GLP-1 present in the bloodstream can enter the brain (Orskov et al., 1996). We have recently shown that GLP-1 receptor activation induces neurite outgrowth in PC12 cells and SK-N-SH human neuroblastoma cells by a mechanism involving the second messenger cyclic AMP (Perry et al., 2002). Signals that stimulate cyclic AMP production can protect neurons against death in various paradigms. For example, corticotropin-releasing hormone and urocortin can protect cultured hippocampal neurons against death induced by glutamate and amyloid β-peptide (Pedersen et al., 2001, 2002). In the present study, we have further examined the neurotrophic properties of GLP-1 and its longer-acting analog exendin-4 (Greig et al., 1999; see Perry et al., 2002 for amino acid sequences of GLP-1 and exendin-4) in cultured hippocampal neurons and in a well established rodent model of neurodegeneration. Exendin-4 has been shown to bind to the known GLP-1 receptor in pancreatic β cells (Goke et al., 1993;Thorens et al., 1993) and has several advantages over GLP-1: it has a higher potency than GLP-1, its half-life is approximately 120 min, and it maintains higher plasma levels of insulin over a longer time duration than GLP-1 (Ryan et al., 1998; Greig et al., 1999; Egan et al., 2002). In line with our demonstration that rat hippocampal neurons express functional GLP-1 receptors, we have tested the hypothesis that GLP-1 and exendin-4 can protect against glutamate-induced apoptosis and restore cholinergic marker activity in adult rats following nonselective excitotoxic basal forebrain damage. For several decades, lesion models of Alzheimer's disease in the rat have encompassed one aspect of the human condition, that is, the loss of cholinergic neurons found in the medial septum and nucleus basalis of Meynert (or basal nucleus in rodents). Such models have relied on immunohistochemical correlates of cholinergic phenotype to identify lesion- and treatment-induced changes. Although treatment with growth factors is well documented to protect against lesion-induced cholinergic cell death (Haroutunian et al., 1986; Mandel et al., 1989), recent observations suggest that such neurons may simply down-regulate their phenotype, rather than die, and that treatment with such growth factors may rescue cholinergic neurons (Haas and Frotscher, 1998; Weis et al., 2001). We propose that GLP-1 and exendin-4 possess neurotrophic capabilities and, as such, offer the possibility for restoring the cholinergic phenotype following partial excitotoxic damage within the basal nucleus of the rat. Although originally developed for their insulinotropic properties, GLP-1 and exendin-4 may have potential for reversing or halting neurodegenerative processes observed in central nervous system disorders such as severe epileptic seizures and Alzheimer's disease and in neuropathies associated with type 2 diabetes mellitus. This article was published in J Pharmacol Exp Ther and referenced in Journal of Biomolecular Research & Therapeutics

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