Neuroprotection by Exendin-4 Is GLP-1 Receptor Specific but DA D3 Receptor Dependent, Causing Altered BrdU Incorporation in Subventricular Zone and Substantia Nigra
Glucagon-like peptide-1 receptor (GLP-1R) activation by exendin-4 (EX-4) is effective in preclinical models of Parkinson’s disease (PD) and appears to promote neurogenesis even in severely lesioned rats. In the present study, we determined the effects of EX-4 on cellular BrdU incorporation in the rat subventricular zone (SVZ) and substantia nigra (SN). We also determined the specificity of this effect with the GLP-1R antagonist EX-(9-39) as well as the potential role of dopamine (DA) D3 receptors. Rats were administered 6-OHDA and 1 week later given EX-4 alone, with EX-(9-39) or nafadotride (D3 antagonist) and BrdU. Seven days later, rats were challenged with apomorphine to evaluate circling. Extracellular DA was measured using striatal microdialysis and subsequently tissue DA measured. Tyrosine hydroxylase and BrdU were verified using immunohistochemistry. Apomorphine circling was reversed by EX-4 in lesioned rats, an effect reduced by EX-4, while both EX-(9-39) and NAF attenuated this. 6-OHDA decreased extracellular and tissue DA, both reversed by EX-4 but again attenuated by EX-(9-39) or NAF. Analysis of BrdU+ cells in the SVZ revealed increases in 6-OHDA-treated rats which were reversed by EX-4 and antagonised by either EX-(9-39) or NAF, while in the SN the opposite profile was seen. 1. Introduction Evidence suggests that the glucagon-like peptide-1 receptor (GLP-1R) agonist exendin-4 (EX-4), used in the treatment of type 2 diabetes mellitus, also displays neuroprotective properties in multiple cellular and in vivo models of neurodegenerative disorders. Evidence of its potential for the treatment of these neuropathologies has been accumulated rapidly [1–5]. The drug appears to be well tolerated and its use in the clinic, albeit for a different indication, obviates many of the obstacles seen with other putative treatments for PD. A key factor with EX-4 is that despite being a relatively large peptide it readily enters the CNS [6]. EX-4 is a potent agonist at mammalian GLP-1Rs and promotes insulin secretion from beta islet cells. Additionally, EX-4 protects beta cells from cytotoxic insults [7] and also promotes their proliferation and neogenesis from precursors [8, 9]. This suggests that similar mechanisms could be responsible for neuronal cell survival in animal models of neurodegenerative disorders in which EX-4 has been shown to be effective. Neuroprotective effects have been shown in vitro to be GLP-1R dependent by the use of the GLP-1R selective antagonist EX-(9-39) and also more recently in GLP-1R knockout mice [5]. A possible mechanism of
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