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The glucagon-like peptide-1 agonist Liraglutide improves memory and learning in obese-diabetic mice
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Abstracts / Regulatory Peptides 164 (2010) 35–51
Regional Regulatory Peptide Laboratory, RVH, Belfast and Obstetrics & Gynaecology, ICS, Queen's University Belfast, Northern Ireland, UK Leptin is produced mainly by adipocytes. Other sources include the placenta and ovaries. Although leptin is known to signal adiposity, it also influences the reproductive and immune systems. Adequate leptin is required for reproduction and leptin increases in pregnancy. At 5 time points leptin and other placental markers were measured in 106 non-smoking primiparous women. Placental histopathology examination was performed. Three groups included: controls, n = 47, with natural conception; those who required artificial reproductive techniques (ART), n = 38; and those who conceived naturally after at least one year of untreated infertility (INF) n = 21. As expected, those with a normal BMI (recorded at 14 weeks) had significantly lower leptin than those who were obese (p < 0.001). While the ART group showed significant differences in other placental markers, only the INF group showed significantly higher leptin levels at all time points (p < 0.001). There was no difference in mean BMI for controls (24.9 ± 0.5), ART (26.5 ± 0.9) and INF groups (26.97 ± 1.1). The difference in leptin between controls (43.7 ± 4.8 ng/ml) and the INF group (72.71 ± 10.5 ng/ml) was significant and remained so after adjustment for BMI. Leptin to BMI ratio was 1.7 ± 0.17 and 2.7 ± 0.4 respectively. Placental lesions suggesting possible immunodysregulatory response were more prevalent in the INF group, but the difference did not reach significance. Higher leptin concentrations in the group with a prolonged phase of infertility before natural conception may suggest leptin resistance. This may contribute to attenuation of the signal that all is physiologically well for conception.
doi:10.1016/j.regpep.2010.07.100
A017 The glucagon-like peptide-1 agonist Liraglutide improves memory and learning in obese-diabetic mice W.D. Porter, B.D. Kerr, P.R. Flatt, C. Holscher, V.A. Gault The SAAD Centre for Pharmacy and Diabetes, School of Biomedical Sciences, University of Ulster, Coleraine, Northern Ireland, UK Introduction: Liraglutide is a long-acting GLP-1 agonist which is a treatment option for type 2 diabetes. GLP-1 peptides, including Liraglutide, cross the blood–brain-barrier and GLP-1 receptors are expressed in brain areas responsible for memory and learning. Aims: This study tested the hypothesis that, in addition to its glucose-lowering actions, peripheral administration of Liraglutide exerts positive actions on learning and memory in obese-diabetic mice. Methods: Swiss TO mice maintained on a high-fat diet for 20 weeks received twice-daily injections of Liraglutide (200 μg/kg bw; sc) or saline vehicle over 28 days. An additional group of mice on standard diet received twice-daily saline injections. Energy intake, bodyweight, non-fasting plasma glucose and insulin concentrations were monitored regularly. Glucose tolerance, open field assessment, object recognition testing and electrophysiological hippocampal long-term potentiation (LTP) were performed at termination of the study. Results: Liraglutide treatment resulted in time-dependent reduction in bodyweight and energy intake (p < 0.05 to p < 0.01), whilst improving non-fasting glucose (1.5 to 2.3-fold; p < 0.01 to p < 0.001) and normalising glucose tolerance (1.5-fold decrease; p < 0.05). Although Liraglutide did not alter general behaviour, treated mice exhibited marked increase (1.4-fold; p < 0.05) in recognition index during object recognition testing, indicative of enhanced learning and
memory ability. Furthermore, Liraglutide rescued the deleterious effects of high fat diet on hippocampal LTP of neurotransmission. Discussion: Liraglutide not only improves metabolic parameters but exerts additional beneficial effects on learning and memory and hippocampal synaptic plasticity. Whether therapy with GLP-1 mimetics has similar effects in humans with type 2 diabetes needs to be established. doi:10.1016/j.regpep.2010.07.101
A018 The novel GLP-1 analogue liraglutide has neuroprotective properties in a mouse model of Alzheimer's disease P.L. McClean, V. Parthsarathy, E. Faivre, C. Hölscher School of Biomedical Sciences, University of Ulster, Coleraine, Northern Ireland, UK Introduction: Type 2 diabetes is a risk factor for Alzheimer's disease. The incretin hormone glucagon-like peptide-1 (GLP-1) facilitates insulin signaling, and novel long-lasting analogues such as liraglutide (Victoza®) are on the market as treatment for diabetes. Aims: Liraglutide was chronically administered i.p. to an Alzheimer mouse model (APP/PS1 DeltaE9), aged six months, to test whether memory impairments and the reduction of synaptic plasticity in the brain may be prevented. The effect of treatment on plaque formation and inflammatory response in the brain was also analysed. Methods: Liraglutide was injected for 8 weeks at 25 nmol/kg bw i. p. once daily in wild type (C57Bl/6) or APP/PS1 mice. Learning ability of animals was analysed by object recognition and water maze tasks. Evoked fEPSPs were recorded in vivo in the CA1 region of the hippocampus. A wt group was also injected with the GLP-1 antagonist exendin(9–36) at 25 nmol/kg i.p. once daily. Plaque load and inflammation response in the brain was evaluated. Data were analysed by ANOVA with post-hoc tests. Results: Liraglutide prevented the learning impairment of APP/ PS1 mice in both memory tasks (p < 0.001). Furthermore, decay of synaptic plasticity was rescued by the drug (p < 0001). In wild type mice, exendin(9–36) impaired learning in both memory tasks (p < 0.01). LTP was enhanced by liraglutide (p < 0.001) and impaired by exendin(9–36) (p < 0.01). Plaque numbers and inflammation was strongly reduced in brain (p < 0.0001). Discussion: The results show that liraglutide crosses the blood brain barrier and has neuroprotective properties. It may be effective in preventing neurodegenerative processes in Alzheimer's disease. doi:10.1016/j.regpep.2010.07.102
A019 Effects of GIP analogues in neuronal signalling, cell proliferation and learning and memory E. Faivre, A. Hamilton, C. Holscher School of Biomedical Sciences, University of Ulster, Coleraine, Northern Ireland, UK Introduction: Type 2 diabetes mellitus is a risk factor for Alzheimer's disease (AD). Glucose-dependent insulinotropic polypeptide (GIP) normalizes insulin signalling by facilitating insulin release, and the GIP receptor is widely expressed in the brain. GIP acts as a growth factor and possesses neuroprotective effects. We previously showed that GIP analogues modulate synaptic plasticity and protect synapses from the detrimental effects of beta-amyloid fragments on long term potential (LTP) formation.
Abstracts / Regulatory Peptides 164 (2010) 35–51
Regional Regulatory Peptide Laboratory, RVH, Belfast and Obstetrics & Gynaecology, ICS, Queen's University Belfast, Northern Ireland, UK Leptin is produced mainly by adipocytes. Other sources include the placenta and ovaries. Although leptin is known to signal adiposity, it also influences the reproductive and immune systems. Adequate leptin is required for reproduction and leptin increases in pregnancy. At 5 time points leptin and other placental markers were measured in 106 non-smoking primiparous women. Placental histopathology examination was performed. Three groups included: controls, n = 47, with natural conception; those who required artificial reproductive techniques (ART), n = 38; and those who conceived naturally after at least one year of untreated infertility (INF) n = 21. As expected, those with a normal BMI (recorded at 14 weeks) had significantly lower leptin than those who were obese (p < 0.001). While the ART group showed significant differences in other placental markers, only the INF group showed significantly higher leptin levels at all time points (p < 0.001). There was no difference in mean BMI for controls (24.9 ± 0.5), ART (26.5 ± 0.9) and INF groups (26.97 ± 1.1). The difference in leptin between controls (43.7 ± 4.8 ng/ml) and the INF group (72.71 ± 10.5 ng/ml) was significant and remained so after adjustment for BMI. Leptin to BMI ratio was 1.7 ± 0.17 and 2.7 ± 0.4 respectively. Placental lesions suggesting possible immunodysregulatory response were more prevalent in the INF group, but the difference did not reach significance. Higher leptin concentrations in the group with a prolonged phase of infertility before natural conception may suggest leptin resistance. This may contribute to attenuation of the signal that all is physiologically well for conception.
doi:10.1016/j.regpep.2010.07.100
A017 The glucagon-like peptide-1 agonist Liraglutide improves memory and learning in obese-diabetic mice W.D. Porter, B.D. Kerr, P.R. Flatt, C. Holscher, V.A. Gault The SAAD Centre for Pharmacy and Diabetes, School of Biomedical Sciences, University of Ulster, Coleraine, Northern Ireland, UK Introduction: Liraglutide is a long-acting GLP-1 agonist which is a treatment option for type 2 diabetes. GLP-1 peptides, including Liraglutide, cross the blood–brain-barrier and GLP-1 receptors are expressed in brain areas responsible for memory and learning. Aims: This study tested the hypothesis that, in addition to its glucose-lowering actions, peripheral administration of Liraglutide exerts positive actions on learning and memory in obese-diabetic mice. Methods: Swiss TO mice maintained on a high-fat diet for 20 weeks received twice-daily injections of Liraglutide (200 μg/kg bw; sc) or saline vehicle over 28 days. An additional group of mice on standard diet received twice-daily saline injections. Energy intake, bodyweight, non-fasting plasma glucose and insulin concentrations were monitored regularly. Glucose tolerance, open field assessment, object recognition testing and electrophysiological hippocampal long-term potentiation (LTP) were performed at termination of the study. Results: Liraglutide treatment resulted in time-dependent reduction in bodyweight and energy intake (p < 0.05 to p < 0.01), whilst improving non-fasting glucose (1.5 to 2.3-fold; p < 0.01 to p < 0.001) and normalising glucose tolerance (1.5-fold decrease; p < 0.05). Although Liraglutide did not alter general behaviour, treated mice exhibited marked increase (1.4-fold; p < 0.05) in recognition index during object recognition testing, indicative of enhanced learning and
memory ability. Furthermore, Liraglutide rescued the deleterious effects of high fat diet on hippocampal LTP of neurotransmission. Discussion: Liraglutide not only improves metabolic parameters but exerts additional beneficial effects on learning and memory and hippocampal synaptic plasticity. Whether therapy with GLP-1 mimetics has similar effects in humans with type 2 diabetes needs to be established. doi:10.1016/j.regpep.2010.07.101
A018 The novel GLP-1 analogue liraglutide has neuroprotective properties in a mouse model of Alzheimer's disease P.L. McClean, V. Parthsarathy, E. Faivre, C. Hölscher School of Biomedical Sciences, University of Ulster, Coleraine, Northern Ireland, UK Introduction: Type 2 diabetes is a risk factor for Alzheimer's disease. The incretin hormone glucagon-like peptide-1 (GLP-1) facilitates insulin signaling, and novel long-lasting analogues such as liraglutide (Victoza®) are on the market as treatment for diabetes. Aims: Liraglutide was chronically administered i.p. to an Alzheimer mouse model (APP/PS1 DeltaE9), aged six months, to test whether memory impairments and the reduction of synaptic plasticity in the brain may be prevented. The effect of treatment on plaque formation and inflammatory response in the brain was also analysed. Methods: Liraglutide was injected for 8 weeks at 25 nmol/kg bw i. p. once daily in wild type (C57Bl/6) or APP/PS1 mice. Learning ability of animals was analysed by object recognition and water maze tasks. Evoked fEPSPs were recorded in vivo in the CA1 region of the hippocampus. A wt group was also injected with the GLP-1 antagonist exendin(9–36) at 25 nmol/kg i.p. once daily. Plaque load and inflammation response in the brain was evaluated. Data were analysed by ANOVA with post-hoc tests. Results: Liraglutide prevented the learning impairment of APP/ PS1 mice in both memory tasks (p < 0.001). Furthermore, decay of synaptic plasticity was rescued by the drug (p < 0001). In wild type mice, exendin(9–36) impaired learning in both memory tasks (p < 0.01). LTP was enhanced by liraglutide (p < 0.001) and impaired by exendin(9–36) (p < 0.01). Plaque numbers and inflammation was strongly reduced in brain (p < 0.0001). Discussion: The results show that liraglutide crosses the blood brain barrier and has neuroprotective properties. It may be effective in preventing neurodegenerative processes in Alzheimer's disease. doi:10.1016/j.regpep.2010.07.102
A019 Effects of GIP analogues in neuronal signalling, cell proliferation and learning and memory E. Faivre, A. Hamilton, C. Holscher School of Biomedical Sciences, University of Ulster, Coleraine, Northern Ireland, UK Introduction: Type 2 diabetes mellitus is a risk factor for Alzheimer's disease (AD). Glucose-dependent insulinotropic polypeptide (GIP) normalizes insulin signalling by facilitating insulin release, and the GIP receptor is widely expressed in the brain. GIP acts as a growth factor and possesses neuroprotective effects. We previously showed that GIP analogues modulate synaptic plasticity and protect synapses from the detrimental effects of beta-amyloid fragments on long term potential (LTP) formation.