Friday, August 25, 2017

Exendin-4 and increased intracranial pressure

Botfield HF, Uldall MS, Westgate CSJ, Mitchell JL, Hagen SM, Gonzalez AM, Hodson DJ, Jensen RH, Sinclair AJ. A glucagon-like peptide-1 receptor agonist reduces intracranial pressure in a rat model of hydrocephalus. Sci Transl Med.2017 Aug 23;9(404).

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.

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.

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…

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…

"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.

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