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

Abstract

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.

Super-resolution microscopy compatible fluorescent probes reveal endogenous glucagon-like peptide-1 receptor distribution and dynamics

“…We also detected LUXendin645labelling in the CP, an epithelial-vascular structure that secretes cerebrospinal fluid (CSF). Rat CP has recently been shown to express GLP1R ex vivo, with Ex4 reducing intracranial pressure in hydrocephalic models 52 . Notably, super-resolution snapshots showed that GLP1R in the ARC, AP, and CP were organized as nanodomains at the membrane.…”

Glucagon-Like Peptide-1 Receptor Agonist Differentially Affects Brain Activation in Response to Visual Food Cues in Lean and Obese Individuals with Type 2 Diabetes Mellitus

“…Along with functional changes in the fusiform gyrus, lixisenatide injection also differentially altered the functional activation in the lateral ventricle, which appeared to occur in the region of the choroid plexus [56] in lean and obese individuals with T2DM. In adult mice, the choroid plexus supports the recruitment and proliferation of neural stem cells [57] and expresses receptors for several hormones, including GLP-1 [58] and leptin [59]. The GLP-1 receptors in the choroid plexus are involved in the modulation of CSF [58], but their metabolic role is unknown.…”

“…In adult mice, the choroid plexus supports the recruitment and proliferation of neural stem cells [57] and expresses receptors for several hormones, including GLP-1 [58] and leptin [59]. The GLP-1 receptors in the choroid plexus are involved in the modulation of CSF [58], but their metabolic role is unknown. The choroid plexus also plays a role as a barrier or transporter in the brain along with the blood-brain barrier.…”

Posttraumatic Headache: Basic Mechanisms and Therapeutic Targets

“…Rare cases of significant brain edema, elevated intracranial pressure, and alteration in brain metabolism have been reported to occur in in the setting of repetitive mild head trauma, 45,71 but there is no evidence that significant elevations in intracranial pressure occur in mild TBI in general. 73 These findings raise the possibility that brain swelling and its potential adverse consequences including PTH could be treated acutely and/or chronically with well tolerated oral or parental approaches. Based in part upon this hypothesis, one study evaluated the effects of hypertonic saline on headache and other symptoms following concussion in children.…”

“…72 Recent studies in animal models have identified a novel strategy for the reduction of intracranial hypertension based on targeting the GLP-1 receptor. 73 These findings raise the possibility that brain swelling and its potential adverse consequences including PTH could be treated acutely and/or chronically with well tolerated oral or parental approaches.…”