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

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Science Translational Medicine  23 Aug 2017:
Vol. 9, Issue 404, eaan0972
DOI: 10.1126/scitranslmed.aan0972

Could a drug for diabetes help in the treatment of hydrocephalus?

Hydrocephalus is a life-threatening condition in babies caused by raised intracranial pressure due to an increase in cerebrospinal fluid volume. Now, Botfield et al. show that the glucagon-like peptide-1 receptor (GLP-1R), known to modulate fluid homeostasis in the kidney, is expressed in human and rodent choroid plexus, the brain area responsible for cerebrospinal fluid secretion. The authors show that treating a rat model of hydrocephalus with a GLP-1R agonist reduced intracranial pressure. This suggests that GLP-1R agonists, approved for treating diabetes, could be repurposed for treating hydrocephalus and potentially other conditions characterized by raised ICP.


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.

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