A Phase II, Randomized, Double-Blinded, Placebo-Controlled Trial of Liraglutide in Parkinson's Disease

Hogg, Elliot; Wu, Tina; Bresee, Catherine; Wertheimer, Jeffrey; Malatt, Camille; Tan, Echo; Pomeroy, Hayley; Nuño, Miriam A; Wyse, Richard K.H.; Tagliati, Michele

doi:10.2139/ssrn.4212371

Cited by 12 publications

(9 citation statements)

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“…We also found that 20-hour Semaglutide treatment was associated with the significant downregulation of pathways associated with neurodegeneration. While these findings require validation and mechanistic follow-up, it has not escaped our attention that GLP1R agonists show neuroprotective and cognitive benefits to mice (During et al 2003; Li et al 2009; Panagaki, Gengler, and Hölscher 2018), and humans (Wu et al 2018; Vadini et al 2020), and are in numerous clinical trials for Alzheimer’s Disease (Michael Gejl et al 2017; M. Gejl et al 2016; Egefjord et al 2012), Parkinson’s Disease (Aviles-Olmos et al 2013, 2014; Hogg et al 2022) and other neurological conditions (Mitchell et al 2023; Glotfelty et al 2019). The mechanisms by which GLP1R agonists exert their neuroprotective effects remain largely obscure (Reich and Hölscher 2022; Kopp et al 2022), and our findings suggest that they could involve direct effects on neurons.…”

Section: Discussionmentioning

confidence: 99%

GLP1R agonists activate human POMC neurons

Mazzaferro,

Chen,

Cahn

et al. 2024

Preprint

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Drugs like Semaglutide (a.k.a. Ozempic/Wegovy) that activate the glucagon-like peptide-1 receptor (GLP1R) are a promising therapy for obesity and type 2 diabetes (T2D). Animal studies suggest that appetite-suppressing proopiomelanocortin (POMC) neurons in the arcuate nucleus of the hypothalamus are a likely target of these drugs, but the mechanisms by which they reduce food intake in humans are still unclear. We therefore generated POMC neurons from human pluripotent stem cells (hPSCs) to study their acute responses to GLP1R agonists by calcium imaging and electrophysiology. We found that hPSC-derived POMC neurons expressed GLP1R and many of them robustly responded to GLP1R agonists by membrane depolarization, increased action potential firing rate, and extracellular calcium influx that persisted long after agonist withdrawal and was likely mediated by L-type calcium channels. Prolonged administration of Semaglutide upregulated transcriptional pathways associated with cell survival in POMC neurons, and downregulated pathways associated with oxidative stress and neurodegeneration. These findings suggest that POMC neurons contribute to the long-term appetite-suppressive effects of GLP1R agonists in humans.

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Section: Discussionmentioning

confidence: 99%

GLP1R agonists activate human POMC neurons

Mazzaferro,

Chen,

Cahn

et al. 2024

Preprint

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“…A second phase 2 trial testing the GLP-1 analogue liraglutide (Victoza) showed meaningful improvements in everyday motor activities such as walking, chewing, talking, and getting out of a chair compared to placebo treatment. An improvement in the quality of life score was observed, too [ 21 ].…”

Section: Discussionmentioning

confidence: 99%

“…Our dual GLP-1/GIP receptor agonist DA5-CH (KP405) has better neuroprotective effects in the MPTP mouse model of PD when directly compared to liraglutide [ 25 , 28 ] and is furthermore more effective than exendin-4 in the 6-OHDA rat model of PD [ 63 ]. Both exendin-4 (Bydureon) and liraglutide (Victoza) have shown good protective effects in clinical trials in PD [ 14 , 16 , 21 ]. In the present study, we show that DA5-CH is superior to liraglutide in the A53T mouse model of PD, too.…”

Section: Discussionmentioning

confidence: 99%

“…As liraglutide has already shown meaningful improvements in a phase 2 clinical trial of PD patients [ 21 ], DA5-CH may be more effective than liraglutide. In addition, we recently finished a phase 2 clinical trial testing liraglutide in patients with Alzheimer's disease.…”

Section: Discussionmentioning

confidence: 99%

“…In a phase II clinical trial in PD patients, liraglutide showed clear improvements. Disease progression was much reduced and motor controlled, and the quality of life assessment was improved [ 21 ]. Glucose-dependent insulinotropic polypeptide (GIP) is a peptide hormone from the same family as GLP-1 [ 22 ].…”

Section: Introductionmentioning

confidence: 99%

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A Dual GLP-1/GIP Receptor Agonist Is More Effective than Liraglutide in the A53T Mouse Model of Parkinson’s Disease

Zhang,

Shi,

et al. 2023

Parkinson's Disease

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Parkinson’s disease (PD) is a complex syndrome with many elements, such as chronic inflammation, oxidative stress, mitochondrial dysfunction, loss of dopaminergic neurons, build-up of alpha-synuclein (α-syn) in cells, and energy depletion in neurons, that drive the disease. We and others have shown that treatment with mimetics of the growth factor glucagon-like peptide 1 (GLP-1) can normalize energy utilization, neuronal survival, and dopamine levels and reduce inflammation. Liraglutide is a GLP-1 analogue that recently showed protective effects in phase 2 clinical trials in PD patients and in Alzheimer disease patients. We have developed a novel dual GLP-1/GIP receptor agonist that can cross the blood-brain barrier and showed good protective effects in animal models of PD. Here, we test liraglutide against the dual GLP-1/GIP agonist DA5-CH (KP405) in the A53T tg mouse model of PD which expresses a human-mutated gene of α-synuclein. Drug treatment reduced impairments in three different motor tests, reduced levels of α-syn in the substantia nigra, reduced the inflammation response and proinflammatory cytokine levels in the substantia nigra and striatum, and normalized biomarker levels of autophagy and mitochondrial activities in A53T mice. DA5-CH was superior in almost all parameters measured and therefore may be a better drug treatment for PD than liraglutide.

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Liraglutide Reduces Alcohol Consumption, Anxiety, Memory Impairment, and Synapse Loss in Alcohol Dependent Mice

Liu,

Wang,

Wang

et al. 2024

Neurochem Res

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Glucagon-like peptide 1 (GLP-1) analogues have been commercialized for the management of type 2 diabetes. Recent studies have underscored GLP-1's role as a modulator of alcohol-related behavior. However, the role of the GLP-1 analogue liraglutide on alcohol-withdrawal responses have not been fully elucidated. Additionally, the underlying neurobiological mechanisms of liraglutide on alcohol withdrawal remains unknown. This study endeavored to explore the effects of liraglutide on synaptic morphology and transmission in the medial prefrontal cortex (mPFC) and the hippocampus (HP), and thus affects the emotion and memory ability of alcohol-withdrawal mice. Male C57BL/6J mice were exposed to a regimen of 20% alcohol and water for a duration of 6 weeks. This regimen established the two-bottle choice model of alcohol exposure. Learning capabilities, memory pro ciency, and anxiety-like behavior were evaluated using the water maze, open eld, and elevated plus maze paradigms. Synaptic morphology in the mPFC and HP were assessed via Golgi staining and Western Blot analysis. Our ndings indicate that liraglutide can substantially decrease alcohol consumption and preference (p < 0.05) and enhance learning and memory performance (p < 0.01), as well as alleviate anxiety-like behavior (p < 0.01). Alcohol consumption led to a reduction in dendritic spine density in the mPFC and HP, which was restored to normal levels by liraglutide (p < 0.001). Furthermore, liraglutide was found to augment the levels of synaptic transportrelated proteins in mice subjected to alcohol withdrawal (p < 0.01). The study ndings corroborate that liraglutide has the potential to mitigate alcohol consumption and ameliorate the memory impairments and anxietyinduced by alcohol withdrawal. The therapeutic e cacy of liraglutide might be attributed to its role in counteracting synapse loss in the mPFC and HP regions.

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A Phase II, Randomized, Double-Blinded, Placebo-Controlled Trial of Liraglutide in Parkinson's Disease

Cited by 12 publications

References 0 publications

GLP1R agonists activate human POMC neurons

GLP1R agonists activate human POMC neurons

A Dual GLP-1/GIP Receptor Agonist Is More Effective than Liraglutide in the A53T Mouse Model of Parkinson’s Disease

Liraglutide Reduces Alcohol Consumption, Anxiety, Memory Impairment, and Synapse Loss in Alcohol Dependent Mice

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