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GLP-1R activation for the treatment of stroke: Updating and future perspectives

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Abstract

Stroke is the leading cause of adult disability in Westernized societies with increased incidence along ageing and it represents a major health and economical threat. Inactive lifestyle, smoking, hypertension, atherosclerosis, obesity and diabetes all dramatically increase the risk of stroke. While preventive strategies based on lifestyle changes and risk factor management can delay or decrease the likelihood of having a stroke, post stroke pharmacological strategies aimed at minimizing stroke-induced brain damage are highly needed. Unfortunately, several candidate drugs that have shown significant preclinical neuroprotective efficacy, have failed in clinical trials and no treatment for stroke based on neuroprotection is available today. Glucagon-like peptide 1 (GLP-1) is a peptide originating in the enteroendocrine L-cells of the intestine and secreted upon nutrient ingestion. The activation of the GLP-1R by GLP-1 enhances glucose-dependent insulin secretion, suppresses glucagon secretion and exerts multifarious extrapancreatic effects. Stable GLP-1 analogues and inhibitors of the proteolytic enzyme dipeptidyl peptidase 4 (DPP-4) (which counteract endogenous GLP-1 degradation) have been developed clinically for the treatment of type 2 diabetes. Besides their antidiabetic properties, experimental evidence has shown neurotrophic and neuroprotective effects of GLP-1R agonists and DPP-4 inhibitors in animal models of neurological disorders. Herein, we review recent experimental data on the neuroprotective effects mediated by GLP-1R activation in stroke. Due to the good safety profile of the drugs targeting the GLP-1R, we also discuss the high potential of GLP-1R stimulation in view of developing a safe clinical treatment against stroke based on neuroprotection in both diabetic and non-diabetic patients.

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Acknowledgments

Work in our laboratories is supported by grants from the Novo Nordisk foundation, the European Foundation for the Study of Diabetes (EFSD)/Lillly, Diabetesfonden, the Swedish Heart and Lung Foundation, AFA Insurance, Konung Gustaf V:s och Drottning Victorias Frimurarestiftelse, Diabetes Research & Wellness Foundation, Avtal om Läkarutbildning och Forskning (ALF) and by the foundations Magnus Bergvall, Fredrik and Ingrid Thuring, Axel and Signe Lagerman’s Donation, Loo and Hans Osterman, Stohne, Åhlén, STROKE Riksförbundet, Tornspiran, Gamla Tjänarinnor and Syskonen Svensson.

Conflict of interest

Work in CP’s laboratory is supported by Boehringer Ingelheim Pharma GmbH & Co. Thomas Klein is an employee of Boehringer Ingelheim Pharma GmbH & Co. ÅS has received research grants, consultancy fees, lecture honoraria, and fees for expert testimony from most companies involved in incretin-based therapy, and is on the national/Nordic/European/global advisory boards of Eli Lilly, Merck, Boehringer Ingelheim, AstraZeneca, Sanofiaventis, and Novartis. No other potential conflicts of interest relevant to this article were reported.

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Authors and Affiliations

  1. Department of Clinical Science and Education, Södersjukhuset, Internal Medicine, Karolinska Institutet, SE-118 83, Stockholm, Sweden

    Vladimer Darsalia, David Nathanson, Thomas Nyström & Cesare Patrone

  2. Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany

    Thomas Klein

  3. Department of Biochemistry and Molecular Biology, College of Medicine, University of South Alabama, Mobile, AL, USA

    Åke Sjöholm

  4. Department of Internal Medicine, Diabetes Research Unit, Södertälje Hospital, Södertälje, Sweden

    Åke Sjöholm

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  1. Vladimer Darsalia
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  2. David Nathanson
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  4. Thomas Klein
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  6. Cesare Patrone
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Correspondence to Cesare Patrone.

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Darsalia, V., Nathanson, D., Nyström, T. et al. GLP-1R activation for the treatment of stroke: Updating and future perspectives. Rev Endocr Metab Disord 15, 233–242 (2014). https://doi.org/10.1007/s11154-014-9285-9

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