Exendin-4 protects dopaminergic neurons by inhibition of microglial activation and matrix metalloproteinase-3 expression in an animal model of Parkinson's disease

Abstract

Exendin-4 is a naturally occurring more potent and stable analog of glucagon-like peptide-1 (GLP-1) that selectively binds at the GLP-1 receptor. It has been recently demonstrated that GLP-1 receptor stimulation preserves dopaminergic neurons in cellular and rodent models of Parkinson's disease (PD). 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) causes nigrostriatal dopaminergic neurotoxicity in rodents; previous studies suggest that activated microglia actively participate in the pathogenesis of PD neurodegeneration. However, the role of microglia in the neuroprotective properties of exendin-4 is still unknown. Here, we show that, in the mouse MPTP PD model, systemic administration of exendin-4 significantly attenuates the loss of substantia nigra pars compacta (SNpc) neurons and the striatal dopaminergic fibers. Exendin-4 prevents MPTP-induced microglial activation in the SNpc and striatum, and the expression of matrix metalloproteinase-3. In addition, exendin-4 also suppressed MPTP-induced expression of pro-inflammatory molecules and tumor necrosis factor a and interleukin-1b. Our data indicate that exendin-4 may act as a survival factor for dopaminergic neurons by functioning as a microgliadeactivating factor and suggest that exendin-4 may be a valuable therapeutic agent for neurodegenerative diseases such as PD.

Anti-inflammatory action of exendin-4 in human islets is enhanced by phosphodiesterase inhibitors: potential therapeutic benefits in diabetic patients

“…Antiinflammatory action of GLP-1 has been suggested by Iwai et al (2006), who reported the inhibition of lipopolysaccharideinduced IL-1β production in cultured rat astrocytes by GLP-1 through generation of cyclic AMP [27]. Exendin-4 has also been reported to decrease microglia-derived TNF-α and IL-1β in mouse brain [28]. Several in vivo studies have reported the beneficial effects of exendin-4 in NOD mice.…”

Effects of glucagon-like peptide-1 receptor agonists on non-alcoholic fatty liver disease and inflammation

“…The levels of the pro-inflammatory cytokines IL-6 (P < 0.01), IL-12p70 (P < 0.01), and IL-1β (P < 0.05) were reduced in the brains of animals treated with liraglutide for 30 d [65] . Exendin-4 also suppressed MPTPinduced expression of pro-inflammatory molecules and IL-1β [60] .…”

“…This effect of GLP-1RAs is due to an increased level of adiponectin mRNA through the GLP-1R. Exendin-4 decreased MCP-1 mRNA levels in 3T3-L1 adipocytes [60,64] . In vitro treatment of mouse macrophages with exendin-4 suppressed lipopolysaccharide-induced mRNA expression of MCP-1 [52] .…”

“…Chen et al [59] injected female SD rats with exendin-4 for 9 wk and found that the level of TNF-α mRNA was significantly reduced in the liver of the mice. Exendin-4 also suppressed MPTP (1-Methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine)-induced expression of pro-inflammatory molecules and TNF-α [60] . Real-time quantitative PCR analysis showed that the expression of TNF-α mRNA was significantly reduced in the exendin-4 treatment group [60] .…”

“…Exendin-4 also suppressed MPTP (1-Methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine)-induced expression of pro-inflammatory molecules and TNF-α [60] . Real-time quantitative PCR analysis showed that the expression of TNF-α mRNA was significantly reduced in the exendin-4 treatment group [60] . Exendin-4 also inhibited TNF-α production by peritoneal macrophages in response to inflammatory stimulation [61] , and exendin-4 changed the expression of inflammatory cytokines via the c-AMP signaling pathway in vitro [61] .…”