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Current therapies for reducing raised intracranial pressure (ICP) under conditions such as idiopathic intracranial hypertension or hydrocephalus have limited efficacy and tolerability. Thus, there is a pressing need to identify alternative 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. We investigated whether exendin-4, a GLP-1R agonist, is able to modulate cerebrospinal fluid (CSF) secretion at the choroid plexus and subsequently reduce ICP in rats. We used tissue sections and cell cultures to demonstrate expression of GLP-1R in the choroid plexus and its activation by exendin-4, an effect blocked by the GLP-1R antagonist exendin 9-39. Acute treatment with exendin-4 reduced Na(+)- and K(+)-dependent adenosine triphosphatase activity, a key regulator of CSF secretion, in cell cultures. Finally, we demonstrated that administration of exendin-4 to female rats with raised ICP (hydrocephalic) resulted in a GLP-1R-mediated reduction in ICP. These findings suggest that GLP-1R agonists can reduce ICP in rodents. Repurposing existing GLP-1R agonist drugs may be a useful therapeutic strategy for treating raised ICP.

Original publication

DOI

10.1126/scitranslmed.aan0972

Type

Journal article

Journal

Sci Transl Med

Publication Date

2017

Volume

9

Keywords

Animals Choroid Plexus/drug effects/metabolism Consciousness/drug effects Cyclic AMP/metabolism Disease Models, Animal Exenatide Female Glucagon-Like Peptide-1 Receptor/*agonists/metabolism Humans Hydrocephalus/*drug therapy/*physiopathology *Intracranial Pressure/drug effects Peptides/pharmacology/*therapeutic use Postmortem Changes RNA, Messenger/genetics/metabolism Rats, Sprague-Dawley Sodium-Potassium-Exchanging ATPase/metabolism Venoms/pharmacology/*therapeutic use