Endocrine Abstracts (2017) 50 OC3.3 | DOI: 10.1530/endoabs.50.OC3.3

The GLP-1R agonist exendin-4 reduces cerebrospinal fluid secretion and intracranial pressure

Hannah Botfield1,2, Maria Uldall3, Connar Westgate1,2, James Mitchell1,2,4, Snorre Hagen3, Ana Maria Gonzalez5, David Hodson1,6, Rigmor Jensen3 & Alexandra Sinclair1,2,4

1Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, UK; 2Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham, UK; 3Danish Headache Center, Clinic of Neurology, Rigshospitalet-Glostrup, University of Copenhagen, Glostrup, Denmark; 4Department of Neurology, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK; 5Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK; 6Centre of Membrane Proteins and Receptors (COMPARE), University of Birmingham, Birmingham, UK.

Background: Current therapies for reducing raised intracranial pressure (ICP) in conditions such as idiopathic intracranial hypertension have limited efficacy and tolerability. As such, there is a pressing need to identify novel drugs. Glucagon-like peptide-1 receptor (GLP-1R) agonists are used to treat diabetes and promote weight loss but have also been shown to affect fluid homeostasis in the kidney. Here, we investigate whether exendin-4, a GLP-1R agonist, is able to modulate cerebrospinal fluid (CSF) secretion at the choroid plexus and subsequently reduce ICP.

Methods: GLP-1R mRNA and protein was assessed in human and rat choroid plexus. The effect of exendin-4 on GLP-1R activation and CSF secretion was evaluated in cultured rat choroid plexus epithelial cells using cAMP assays and a Na+K+ ATPase activity assay. The effect of Exendin-4 on ICP was assessed in adult female rats with normal and raised ICP.

Results: We demonstrated that the GLP-1R is present in human and rat choroid plexus. Exendin-4 significantly increased cAMP levels (2.14±0.61 fold, P<0.01), part of the GLP-1R signalling pathway, and significantly reduced Na+K+ ATPase activity, a marker of CSF secretion (39.3±9.4% of control; P<0.05). In vivo ICP recording in adult rats demonstrated that subcutaneous administration of exendin-4 significantly reduced ICP in normal (65.2±6.6% of baseline; P<0.01) and raised ICP rats (56.6±5.7% of baseline; P<0.0001). In addition, the effects of a single subcutaneous injection of exendin-4 lasted for 24 hours and daily exendin-4 administration had a cumulative effect on reducing baseline ICP.

Conclusion: We demonstrate that Exendin-4 reduces CSF secretion by the choroid plexus and ICP in normal rats and rats with raised ICP. Repurposing existing GLP-1R agonists may represent a novel therapeutic strategy for conditions of raised ICP such as idiopathic intracranial hypertension.

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