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A novel dual-glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide receptor agonist is neuroprotective in transient focal cerebral ischemia in the rat

Han, Linga; Hölscher, Christianb; Xue, Guo-Fanga; Li, Guanglaia; Li, Dongfanga

doi: 10.1097/WNR.0000000000000490
DEGENERATION AND REPAIR
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Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptor agonists have been shown to be neuroprotective in previous studies in animal models of Alzheimer’s or Parkinson’s disease. Recently, novel dual-GLP-1/GIP receptor agonists that activate both receptors (DA) were developed to treat diabetes. We tested the protective effects of a novel potent DA against middle cerebral artery occlusion injury in rats and compared it with a potent GLP-1 analog, Val(8)-GLP-1(glu-PAL). Animals were evaluated for neurologic deficit score, infarct volume, and immunohistochemical analyses of the brain at several time points after ischemia. The Val(8)-GLP-1(glu-PAL)-treated and DA-treated groups showed significantly reduced scores of neurological dysfunction, cerebral infarction size, and percentage of TUNEL-positive apoptotic neurons. Furthermore, the expression of the apoptosis marker Bax, the inflammation marker iNOS, and the survival marker Bcl-2 was significantly increased. The DA-treated group was better protected against neurodegeneration than the Val(8)-GLP-1(glu-PAL) group, and the scores of neurological dysfunction, cerebral infarction size, and expression of Bcl-2 were higher, whereas the percentage of TUNEL-positive neurons and the levels of Bax and iNOS were lower in the DA group. DA treatment reduced the infarct volume and improved the functional deficit. It also suppressed the inflammatory response and cell apoptosis after reperfusion. In conclusion, the novel GIP and GLP-1 dual-receptor agonist is more neuroprotective than a GLP-1 receptor agonist in key biomarkers of neuronal degeneration.

aDepartment of Neurology, the Second Affiliated Hospital of Shanxi Medical University, Taiyuan, China

bDivision of Biomedical and Life Sciences, Faculty of Health and Medicine, Lancaster University, Lancaster, UK

Correspondence to Guo-Fang Xue, MD, Department of Neurology, The Second Affiliated Hospital of Shanxi Medical University, Taiyuan 030001, China Tel: +86 135 4631 3726; e-mail: xueguofangty@163.com

Received September 14, 2015

Accepted October 12, 2015

© 2016 Wolters Kluwer Health | Lippincott Williams & Wilkins