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Sci Rep. 2018 Jun 12;8(1):8961. doi: 10.1038/s41598-018-27121-w.

Dual Therapy with Liraglutide and Ghrelin Promotes Brain and Peripheral Energy Metabolism in the R6/2 Mouse Model of Huntington's Disease.

Author information

1
CNC - Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal. ana.duarte@cnc.uc.pt.
2
Institute for Interdisciplinary Research (IIIUC), University of Coimbra, Coimbra, Portugal. ana.duarte@cnc.uc.pt.
3
Brain Disease Biomarker Unit, Department of Experimental Medical Sciences, Wallenberg Neuroscience Center, Lund University, Lund, Sweden. ana.duarte@cnc.uc.pt.
4
Brain Disease Biomarker Unit, Department of Experimental Medical Sciences, Wallenberg Neuroscience Center, Lund University, Lund, Sweden.
5
CNC - Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.
6
Life Sciences Department, Faculty of Sciences and Technology, University of Coimbra, Coimbra, Portugal.
7
Laboratory of Biochemistry, Faculty of Medicine, University of Coimbra, Coimbra, Portugal.
8
Laboratory of Physiology, Faculty of Medicine, University of Coimbra, Coimbra, Portugal.

Abstract

Neuronal loss alongside altered energy metabolism, are key features of Huntington's disease (HD) pathology. The orexigenic gut-peptide hormone ghrelin is known to stimulate appetite and affect whole body energy metabolism. Liraglutide is an efficient anti-type 2 diabetes incretin drug, with neuroprotective effects alongside anorectic properties. Combining liraglutide with the orexigenic peptide ghrelin may potentially promote brain/cognitive function in HD. The R6/2 mouse model of HD exhibits progressive central pathology, weight loss, deranged glucose metabolism, skeletal muscle atrophy and altered body composition. In this study, we targeted energy metabolism in R6/2 mice using a co-administration of liraglutide and ghrelin. We investigated their effect on brain cortical hormone-mediated intracellular signalling pathways, metabolic and apoptotic markers, and the impact on motor function in HD. We here demonstrate that liraglutide, alone or together with ghrelin (subcutaneous daily injections of 150 µg/kg (ghrelin) and 0.2 mg/kg (liraglutide), for 2 weeks), normalized glucose homeostatic features in the R6/2 mouse, without substantially affecting body weight or body composition. Liraglutide alone decreased brain cortical active GLP-1 and IGF-1 levels in R6/2 mice, alongside higher ADP levels. Liraglutide plus ghrelin decreased brain insulin, lactate, AMP and cholesterol levels in R6/2 mice. Taken together, our findings encourage further studies targeting energy metabolism in HD.

PMID:
29895889
PMCID:
PMC5997749
DOI:
10.1038/s41598-018-27121-w
[Indexed for MEDLINE]
Free PMC Article

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