Exendin-4, a commonly used diabetes drug, shows promise in reducing intracranial pressure (ICP) in patients with idiopathic intracranial hypertension (IIH) and other conditions associated with elevated brain pressure, new animal research shows.
Researchers at the University of Birmingham, United Kingdom, studied the effect of exendin-4, a glucagon-like peptide-1 (GLP-1) receptor agonist (RA), in rats with elevated ICP.
They found that it reduced ICP by 44% within 10 minutes of dosing. Moreover, the treatment effects lasted at least 24 hours.
These findings could have clinical applicability to several neurologic conditions associated with elevated ICP, including hydrocephalus, IIH, stroke, and traumatic brain injury.
“This is a real breakthrough because it is a completely different way of reducing brain pressure,” said corresponding author, Alexandra Sinclair, MBChB, MCRP, PhD, National Institute for Health Research clinician scientist and neurological consultant, Institute of Metabolism and Systems Research, University of Birmingham.
“What we have shown is that this GLP-1 receptor agonist can actually reduce the amount of CSF [cerebrospinal fluid] production, thereby reducing brain pressure,” she told Medscape Medical News.
The study was published online August 23 in Science Translational Medicine.
New Approach Needed
ICP is caused by “alterations in the volume of either cerebral blood, CSF, or brain tissue,” the authors write. CSF volume is “tightly regulated” and consists of a delicate balance between CSF secretion, modulated mostly by the choroid plexus, and drainage through the arachnoid granulations and lymphatics.
In conditions such as IIH and hydrocephalus, both characterized by elevated ICP, CSF reduction is often accomplished through decreasing CSF secretion.
CSF is secreted in the choroid plexus by epithelial (CPe) cells and “driven by net movement of sodium ions (Na+) from the blood into the cerebral ventricles,” creating “an osmotic gradient” that drives water transport into the cerebral ventricles, the authors explain.
GLP-1 is a gut peptide that the distal small intestine secretes in response to food intake. One of several mechanisms of action is reducing Na+ reabsorption and increasing diuresis. GLP-1 receptor (GLP-1R) activation “stimulates the conversion of adenosine triphosphate to cyclic adenosine monophosphate (cAMP).” cAMP activates protein kinase A, which inhibits the Na+ H+ exchanger, which in turn prevents the reabsorption of Na+ into the bloodstream.
The researchers hypothesized that GLP-1 might also modulate Na+ transport in the choroid plexus and thereby modulating fluid movement.
“Stabilized GLP-1 mimetics are widely used to treat diabetes and obesity and therefore could be repurposed for treating raised ICP,” they note.
This may be particularly relevant in IIH, a condition caused by obesity and characterized by severe chronic disabling daily headaches and optic nerve swelling, leading to blindness in 25% of patients.
“We do not know the mechanism, why obesity causes IIH,” Dr Sinclair said. “In my laboratory, we are looking at different chemicals and hormones released by fat that could cause increased CSF production and increase brain pressure, but the current study focused on how to reduce ICP once it is elevated.”
Her team has “been looking for a new treatment for this condition for quite some time,” she continued. “I am particularly passionate about working with these young women who suffer from IIH” because of its debilitating effects.
Women with IIH are unable to work or look after their families, she explained. “We currently have no good treatment for them. The existing treatment, acetazolamide, is only mild to moderately effective, does not work for everyone, and patients feel unwell when they take it. So 48% stop taking the drug because of the side effects.”
“IIH has been regarded as a relatively rare condition, with an incidence of only 2 per 100,000 in the general population and 20 per 100,000 among young obese women,” said Dr Sinclair.
“But based on hospital data in the UK, we have found that the incidence is rising in tandem with the obesity epidemic, so these are old data.” A new treatment approach is needed, she emphasized.
Rapid, Long-Lasting Effects
To investigate the effect of exendin-4, a GLP-1RA, the researchers used tissue selections and cell cultures to demonstrate the expression of GLP-1R in the choroid plexus and its activation by exendin-4.
The researchers incubated whole rat choroid plexus in vitro with fluorescently tagged exendin-4 to “demonstrate the presence of the receptor in the choroid plexus.”
The GLP-1RA localized predominately in the cytoplasm, which is “consistent with agonist-induced receptor internalization and trafficking,” the authors report.
When the researchers grew monolayers of rat CPe cells in a culture, they found that exendin-4 treatment increased cAMP and reduced N+ K+ adenosine triphosphatase activity (which they proposed as a marker of CSF secretion from the choroid plexus).
To establish whether exendin-4 had the capacity to modulate ICP in vivo, they implanted healthy female adult rats with an ICP monitor (day 0) and then administered daily subcutaneous injections of saline or exendin-4 for 5 days (days 2 to 6). On days 2, 4, and 6, they measured ICE before and after the subcutaneous injection.
On day 2, exendin-4 significantly reduced ICP 10 minutes after the injection. By 30 minutes, ICP was 65.2% ± 6.6% of baseline, compared with 91.0% ± 3.9% in saline-treated rats (P < .01).
Thirty minutes after exendin-4 administration, similar reductions were seen on day 4 (50.4% ± 6.9% of baseline; P < .001) and day 6 (54.5% ± 8.2% of baseline; P < .001) 30 minutes after exendin-4 administration.
Exendin-4 had a cumulative effect on reducing ICP (which was measured before administration on day 2 (baseline, 100%) to day 4 (79.3% ± 7.3%; P < .05), and day 6 (72.5% ± 5.6%; P < .01). Similar reductions were not observed in saline-treated rats.
The researches assessed whether the reduction in ICP was specific to the brain by injecting exendin-4 into the lateral ventricle through an intracerebroventricular cannula in anesthetized rats.
They found that over the 60-minute ICP measurement, intracerebroventricular delivery of exendin-4 significantly reduced the area under the curve (AUC) of ICP compared with saline delivered via the same route (3852 ± 397 vs 4974 ± 262 AUC; P < .05).
Subcutaneous injection of exendin-4 lowered ICP (P < .0001) compared with a subcutaneous injection of exendin 9-39, a GLP-1 RA. “These data suggest that exendin-4 in part exerts its effects on ICP via the GLP-1R signaling pathway in the brain,” the authors write.
Exendin-4 also reduced IPC in a dose-dependent manner, with effects lasting for 24 hours. The researchers compared doses of 1, 3, and 5 mg/kg and found that all of the doses significantly reduced ICP compared with saline. However, exendin-4 at 5 mg/kg demonstrated the greatest reduction in ICP, and the effect was still present 3 hours after the treatment, compared with the lower doses, which had returned to baseline by 3 hours (P < .001).
During a 24-hour period, a single subcutaneous injection of exendin-4 (5 mg/kg) maintained lower ICP compared with saline and returned to the predose ICP baseline at 24 hours.
“The key finding of this study is that subcutaneous exendin-4 treatment is able to reduce ICP in vivo in normal rats and rats with raised ICP,” the authors note. “In addition, the effect on ICP of a single administration of exendin-4 lasted for 24 hours, and cumulative dosing reduced the pre-dose ICP,” suggesting that “exendin-4 may be able to maintain low ICP over a long period.”
“The GLP-1 RA we used in animal models is much more effective than anything we have tried in our laboratory,” said Dr Sinclair.
“Landmark Change”
Dr Sinclair said she is “excited to move this from animal models and rats to clinical trials.” She noted that her group has a clinical trial opening within the next month.
She cautioned that it is premature to prescribe GLP-1 RAs for patients with IIH in the clinical setting.
“We need proof of efficacy through proper routes of clinical trials first. We are very confident that it will translate to humans, but it would be wrong of me as a doctor to suggest starting to use it in the clinical setting without evidence in human trials.”
Nevertheless, she stated that their research “marks a landmark change” in IIH treatment.
“We have the opportunity to not only lower brain pressure but also obesity itself, which is important since the condition is caused by obesity.”
She added that findings of this study are “just the tip of the iceberg” and that her group “will aim to investigate this in other conditions of raised ICP,” including post-traumatic brain injury, post-stroke ICP, and hydrocephalus.
“The mechanisms of action should help all of these other conditions as well.”
Exenatide, a synthetic version of exendin-4, has received orphan drug designation for the treatment of IIH from the European Medicines Agency and the US Food and Drug Administration.
Dr Sinclair’s work was funded by a National Institute for Health Research Clinician Scientist AQ56 Fellowship and by the Medical Research Council (MRC), United Kingdom. Other researchers were supported by Diabetes UK R.D. Lawrence, European Foundation for the Study of Diabetes/Novo Nordisk Rising Star and Birmingham AQ58 Fellowships, a Wellcome Trust Institutional Support Award, an MRC Project Grant, and a European Research Council Starting Grant. This work was supported by an MRC confidence-in-concept grant, the West Midlands Neuroscience Teaching and Research Fund, and the University of Birmingham Research Development Fund. Dr Sinclair reports holding a patent related to this work, titled “Elevated Intracranial Pressure Treatment.” Dr Jensen, another study author, reported several interests. The other authors have disclosed no relevant financial relationships.
Sci Transl Med. Published online August 23, 2017. Abstract
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