Treatment with a GLP−1R agonist over four weeks promotes weight loss-moderated changes in frontal-striatal brain structures in individuals with mood disorders

Mansur, Rodrigo B.; Zugman, André; Ahmed, Juhie; Danielle, S.; Subramaniapillai, Mehala; Lee, Yena; Lovshin, Julie A.; Lee, Jung G.; Lee, Jae-Hon; Drobinin, Vladislav; Newport, Jason; Brietzke, Elisa; Reininghaus, Eva; Sim, Kang; Vinberg, Maj; Rasgon, Natalie; Hájek, Tomáš; McIntyre, Roger S.

doi:10.1016/j.euroneuro.2017.08.433

Cited by 50 publications

(33 citation statements)

References 91 publications

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“…The study demonstrated that the disease‐induced decrease in glucose utilization in the brain was stopped by liraglutide (Gejl et al, ). Another pilot study in patients with mood disorders showed improvements in cognitive tasks and also in MRI brain scans, where cortical and subcortical brain areas were found to increase in volume (Mansur, Ahmed, et al, ; Mansur, Zugman et al, ). A phase II clinical trial in AD patients testing liraglutide is currently ongoing (Hölscher, ).…”

Section: Discussionmentioning

confidence: 99%

A novel GLP‐1/GIP/Gcg triagonist reduces cognitive deficits and pathology in the 3xTg mouse model of Alzheimer's disease

Jiao

Hölscher

et al. 2018

Hippocampus

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Type 2 diabetes mellitus (T2DM) is an important risk factor for Alzheimer's disease (AD). Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) have been identified to be effective in T2DM treatment and neuroprotection. In this study, we further explored the effects of a novel unimolecular GLP-1/GIP/Gcg triagonist on the cognitive behavior and cerebral pathology in the 7-month-old triple transgenic mouse model of AD (3xTg-AD), and investigated its possible electrophysiological and molecular mechanisms. After chronic administration of the GLP-1/GIP/Gcg triagonist (10 nmol/kg bodyweight, once daily, i.p.) for 30 days, open field, Y maze and Morris water maze tests were performed, followed by in vivo electrophysiological recording, immunofluorescence and Western blotting experiments. We found that the chronic treatment with the triagonist could improve long-term spatial memory of 3xTg-AD mice in Morris water maze, as well as the working memory in Y maze task. The triagonist also alleviated the suppression of long-term potentiation (LTP) in the CA1 region of hippocampus. In addition, the triagonist significantly reduced hippocampal pathological damages, including amyloid-β (Aβ) and phosphorylated tau aggregates, and upregulated the expression levels of p-CREB, p-CAMKII and p-GSK3β in the hippocampus of the 3xTg-AD mice. These results demonstrate for the first time that the novel GLP-1/GIP/Gcg triagonist is efficacious in ameliorating cognitive deficits and pathological damages of 3xTg-AD mice, suggesting that the triagonist might be potentially beneficial in the treatment of AD.

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Section: Discussionmentioning

confidence: 99%

A novel GLP‐1/GIP/Gcg triagonist reduces cognitive deficits and pathology in the 3xTg mouse model of Alzheimer's disease

Jiao

Hölscher

et al. 2018

Hippocampus

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“…In addition, liraglutide has shown neuroprotective effects in a range of preclinical studies of other neurodegenerative disorders [76], such as Alzheimer's disease [33][34][35], Parkinson's disease [36,37], traumatic brain injury [38,39], motor neurone disease / ALS [40], or stroke [41,42]. A pilot clinical trial has shown protective effects of liraglutide in patients with Alzheimer's disease [45], and another pilot study showed clear improvements in cognitive function and in MRI brain scans of key brain areas [46,47]. Importantly, exendin-4, a different GLP-1R agonist with good neuroprotective effects has been tested in Parkinson's patients with good results [48,49].…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, liraglutide has anti-inflammatory properties in models of chronic inflammation of the brain [33,35,43,44]. A pilot clinical trial has shown protective effects in patients with Alzheimer's disease [45], and another pilot study has shown improvements in cognitive performance and in MRI brain scans of people with mood disorders [46,47]. In addition, the GLP-1 receptor agonist exendin-4 has shown good protective effects in a pilot study in Parkinson's patients [48,49].…”

Section: Glp-1 Receptors (Glp-1r) Are Widely Expressed In the Brain Omentioning

confidence: 99%

Post-treatment with the GLP-1 analogue liraglutide alleviate chronic inflammation and mitochondrial stress induced by Status epilepticus

et al. 2018

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Glucagon-like peptide-1(GLP-1) is a growth factor that has neuroprotective and anti-inflammatory properties. The protease resistant GLP-1 analogue liraglutide has been shown to be neuroprotective in previous studies in animal models of Alzheimer's disease or Parkinson's disease. Status epilepticus (SE) is a complex disorder, involving many underlying pathological processes, including excitotoxic and chronic inflammatory events. The present pilot study aims to investigate whether liraglutide alleviates the chronic inflammation response and mitochondrial stress induced by SE in the lithium-pilocarpine animal model. We found that treatment with 25nmol/kg. i.p. once-daily after the induction of SE for 7 days reduced chronic inflammation as shown by reduced numbers of activated microglia and astrocytes, and reduced levels of TNF-α and IL-1ß in the hippocampus. The mitochondrial stress marker BAX was reduced and the survival factor Bcl-2 was enhanced by liraglutide. Blood glucose levels were not affected by liraglutide. We show for the first time that liraglutide can reduce the chronic inflammation and mitochondrial stress induced by SE, and the results suggest that GLP-1 receptor agonists such as liraglutide have restorative and protective effects in the brain after SE and could serve as a potential treatment.

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“…Data were derived from completed clinical trials conducted by the same group of investigators (RBM, EB and RSM) [13][14][15][16][17][18][19][20][21] or the Comprehensive Assessment of Long-Term Effects of Reducing Intake of Energy (CALERIE) [22][23][24][25][26][27] (Table 1). The clinical cohorts (studies 1-7) were comprised of individuals with MDD or BD, in a depressive episode or euthymic, recruited for clinical trials or observational studies.…”

Section: Study Populationsmentioning

confidence: 99%

“…The specific inclusion and exclusion criteria can be found in previously published articles. [13][14][15][16][17]22 Individuals that reported receiving treatment for diabetes and/or using anti-diabetic medications were excluded (n = 20). Details of each study are described in Table 1.…”

Section: Study Populationsmentioning

confidence: 99%

Parsing metabolic heterogeneity in mood disorders: A hypothesis‐driven cluster analysis of glucose and insulin abnormalities

et al. 2019

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Objectives Metabolically based distinctions for disturbances in glucose and insulin may provide meaningful insights both clinically and mechanistically. Methods Data were derived from 352 subjects of previously completed clinical studies with a mood disorder (MD) (bipolar disorder: n = 179, major depressive disorder: n = 173) and 218 healthy controls from the Comprehensive Assessment of Long‐Term Effects of Reducing Intake of Energy. We conducted a factor analysis to replicate a priori dissociable factors informed by glucose and insulin levels and indices of insulin resistance and beta‐cell function: elevated insulin and insulin resistance (“insulin‐IR”), and increased fasting glucose and reduced insulin secretion (“glucotoxicity”). Cluster analyses were conducted, separately in men and women, to evaluate the clinical relevance of subtyping individuals with MDs using insulin‐IR and glucotoxicity (GT) factor scores. Results Factors insulin‐IR and GT explained 92.64% and 92.09% of the variance in men and women respectively. Three clusters were replicated in men and women separately: metabolically healthy (MH), high GT, and insulin‐resistant (IR). After adjusting for age, gender, study cohort, MD diagnosis, and antipsychotics use, body mass index (BMI) and mean arterial pressure were higher in IR‐ vs GT‐ or MH‐clustered individuals; GT‐clustered individuals had more metabolic syndrome components and higher C‐reactive protein. Glucotoxic‐clustered subjects reported greater impairments in cognitive function and global functioning when compared to MH‐ or IR‐clustered subjects. Conclusions Using simple, cost‐effective, and accessible measures, we identified stable, gender‐convergent, subgroups of individuals that significantly diverged on measures of cognitive dysfunction, self‐reported anhedonia, functional disability, BMI, and blood pressure.

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Treatment with a GLP−1R agonist over four weeks promotes weight loss-moderated changes in frontal-striatal brain structures in individuals with mood disorders

Cited by 50 publications

References 91 publications

A novel GLP‐1/GIP/Gcg triagonist reduces cognitive deficits and pathology in the 3xTg mouse model of Alzheimer's disease

A novel GLP‐1/GIP/Gcg triagonist reduces cognitive deficits and pathology in the 3xTg mouse model of Alzheimer's disease

Post-treatment with the GLP-1 analogue liraglutide alleviate chronic inflammation and mitochondrial stress induced by Status epilepticus

Parsing metabolic heterogeneity in mood disorders: A hypothesis‐driven cluster analysis of glucose and insulin abnormalities

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