Background: Idiopathic intracranial hypertension (IIH) predominantly affects obese women of childbearing age. IIH is characterised by increased intracranial pressure (ICP) which results in visual loss and disabling headaches. ICP dis-regulation results from imbalance of cerebrospinal fluid (CSF) production rate (at the choroid plexus epithelial cells) and drainage. Treatments for IIH are limited but weight loss is established as disease modifying.
Glucagon like peptide-1 (GLP-1), an incretin with weight modifying properties, has been shown to have a natriuretic effect in the kidney through inhibition of the Na+H+ exchanger in proximal tubule cells. CSF secretion is controlled by ion channels and pumps akin to an inverted renal proximal tubule. The choroid plexus (CP) expresses GLP-1 receptor (GLP-1R). Therefore, we hypothesise that GLP-1 modulates CSF secretion at the choroid plexus and reduces ICP.
Results: GLP-1 receptor mRNA (QPCR) and protein (WB) were detected in the rat CP. Immunohistochemical analysis of CP explants showed that GLP-1R localised to the cytoplasm and apical surface of the epithelial cells. After Exendin-4 (GLP-1R agonist) treatment GLP-1R immunoreactivity was translocated to the apical cell surface. GLP-1R mRNA and protein levels were also increased. Evaluation of the downstream signalling pathway on primary CP epithelial cells identified a twofold increase in cAMP after Exendin-4 treatment (P<0.01). Exendin-4 also significantly reduced the activity of Na+K+ ATPase, a marker of CSF secretion (39.3±9.4% of control; P<0.05). In vivo ICP recording in adult rats (n=6) demonstrated that Exendin-4 significantly reduced ICP (58.3±5.0%, P<0.0001).
Conclusions: We have identified a novel GLP-1 signalling pathway in the CP. We demonstrate that treatment with a GLP-1 agonist significantly reduces CSF secretion in vitro and ICP in rats. GLP-1 therapy may represent a novel therapeutic avenue for conditions of raised ICP such as IIH and may have additional long term advantages of weight reduction.