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L23 Effects of peripheral (co-)administration of liraglutide and ghrelin in the R6/2 mouse brain function
  1. Ana I Duarte1,2,3,
  2. Marie Sjögren3,
  3. Maria S Santos1,4,
  4. Catarina R Oliveira1,5,
  5. Paula I Moreira1,6,
  6. Maria Björkqvist3
  1. 1CNC – Centre for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal
  2. 2Institute for Interdisciplinary Research (IIIUC), University of Coimbra, Coimbra, Portugal
  3. 3Brain Disease Biomarker Unit, Department of Experimental Medical Sciences, Wallenberg Neuroscience Centre, Lund Medical School, Lund University, Lund, Sweden
  4. 4Life Sciences Department, Faculty of Sciences and Technology, University of Coimbra, Coimbra, Portugal
  5. 5Laboratory of Biochemistry, Faculty of Medicine, University of Coimbra, Coimbra, Portugal
  6. 6Laboratory of Physiology, Faculty of Medicine, University of Coimbra, Coimbra, Portugal

Abstract

Background Huntington’s disease (HD) is a polyglutamine expansion disease associated with striatal and cortical neuronal loss, and with type 2 diabetes (T2D) features. Thus, an efficient anti-T2D drug – liraglutide - may protect against HD. But, as cachexia may occur in HD and liraglutide is also anorectic, a peripheral (co-) administration of liraglutide with the orexigenic ghrelin may protect against brain/cognitive dysfunction in HD.

Aims We studied the role of subcutaneous (sc) (co-)injection of liraglutide plus ghrelin in brain metabolic markers and motor/cognitive dysfunction in HD.

Methods Brain cortices from 12 week-old R6/2 and WT mice sc-treated with liraglutide and/or ghrelin (2 weeks) were used to measure cAMP, insulin, glucose, cholesterol, free-fatty acids (FFA), triglycerides and caspase-3 activity. Motor/exploratory activity was given by open-field test.

Results Liraglutide alone or plus ghrelin rescued body weight loss, lowered fat mass and peripheral T2D features in HD mice.

Brains from saline-treated R6/2 mice had higher cAMP and insulin, and lower glucose levels, suggesting either a brain insulin/GLP-1 resistance and/or a local stimulation of glucose metabolism (e.g. towards triglyceride synthesis). They may be also using FFA as alternative fuels (via degradation by Krebs cycle or β-oxidation) and cholesterol to maintain lipid rafts within brain. Though brain caspase-3 was slightly inhibited, exploratory activity was lower in R6/2 mice.

Liraglutide alone increased whereas together with ghrelin decreased brain cAMP levels in R6/2 mice. Liraglutide alone or plus ghrelin lowered their brain insulin levels, suggesting a recovery from insulin resistance. Liraglutide alone slightly increased R6/2 mouse brain glucose and lowered triglycerides and FFA, whereas liraglutide plus ghrelin slightly lowered their brain glucose, triglycerides, FFA and cholesterol levels. This suggested a liraglutide induction of glucose (energy) metabolism, protecting R6/2 mice from caspase-3 activation and restoring their exploratory behaviour. When added with ghrelin, liraglutide’s beneficial effects were not potentiated.

Conclusions Liraglutide plus ghrelin had anti-T2D effects in HD. Liraglutide alone rescued brain insulin resistance, caspase-related apoptosis and motor impairment.

This work was supported by European funds from FEDER, through the Programa Operacional Factores de Competitividade – COMPETE 2020; by a Seed Fund from European Huntington’s Disease Network; by Portuguese funds from FCT – Fundação para a Ciência e a Tecnologia (PTDC/SAU-TOX/117481/2010); and by European Social Fund: Fellowship SFRH/BPD/84473/2012 to A. I. Duarte).

  • Liraglutide and ghrelin
  • Neuroprotection

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