A glucagon-like peptide-1 receptor agonist reduces intracranial pressure in a rat model of hydrocephalus

Research output: Contribution to journalJournal articlepeer-review

  • Hannah F Botfield
  • Maria S Uldall
  • Connar S J Westgate
  • James L Mitchell
  • Snorre M Hagen
  • Ana Maria Gonzalez
  • David J Hodson
  • Jensen, Rigmor Højland
  • Alexandra J Sinclair

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 languageEnglish
Article numbereaan0972
JournalScience Translational Medicine
Volume9
Issue number404
Number of pages11
ISSN1946-6234
DOIs
Publication statusPublished - 23 Aug 2017

ID: 196007274