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Controlling circadian IOP fluctuation


Research shows circadian variations in IOP can be regulated by orexin-containing neurons located in the hypothalamus


Research shows circadian variations in IOP can be regulated by orexin-containing neurons located in the hypothalamus.

Dr. Samuels


Indianapolis-A possible role for a specific type of hypothalamic neuron in mediating circadian variations in IOP has been identified, according to research findings presented by Brian C. Samuels, MD, PhD.

The study, which was conducted in an animal model, was approached from the perspective that the condition is a neurologic disease, rather than one involving only the eye. The focus was on the effects of neurons containing orexin neuropeptides located in the dorsomedial/periformical hypothalamus (DMH/PeF).

Chemical stimulation of this region of the hypothalamus results in increases in heart rate, blood pressure, IOP, intracranial pressure (ICP), and the translaminar pressure gradient, said Dr. Samuels, assistant professor of ophthalmology, Indiana University School of Medicine, Indianapolis.

Examining the study

Knowing that the DMH/PeF is rich in orexin-containing neurons that have been shown to regulate circadian rhythmicity of various physiological processes-and that IOP displays circadian patterns-it was investigated to find if orexin-containing neurons may also regulate circadian fluctuations in IOP and ICP.

For the study, responses to chemical stimulation of the hypothalamus were evaluated when animals were pretreated with an orexin receptor antagonist or vehicle control.

Increases in IOP were found and ICP induced by chemical stimulation were significantly attenuated by orexin receptor antagonist pre-treatment in a dose-dependent fashion.

Vital sign monitoring showed no attenuation of the increases in the animals’ heart rate or blood pressure.

“We are excited about these initial findings, considering fluctuation in IOP is a known independent risk factor for glaucoma progression and because recent work has shown an aberrancy in the translaminar gradient in patients with glaucoma,” Dr. Samuels said.

“However, additional research is needed to establish the efficacy and safety of orexin antagonists as a clinical approach to stabilizing IOP, ICP, and the translaminar pressure gradient,” he said.

The orexin antagonist used in the study was supplied by Merck and is a derivative of a compound that has been investigated as a treatment for insomnia in a phase III study.

Because there is already clinical trial data demonstrating an acceptable safety profile for orexin receptor antagonists-together with their oral mode of administration-enhance interest in investigating this class of drugs as novel therapy for glaucoma.

“The availability of human safety data makes an orexin antagonist well-positioned for entering clinical trials as a potential treatment for glaucoma, assuming there are positive efficacy findings from further animal studies,” Dr. Samuels said. “Considering how poorly glaucoma patients comply with use of their topical medications, perhaps an orally administered drug would be beneficial.”

Looking to the future

The next step, Dr. Samuels said, will be to describe the afferent and efferent pathways for the orexin-containing neurons, as well as characterizing the pharmacology of orexin antagonists that are selective for type 1 or type 2 receptors.

“Like the parent molecule and other orexin antagonists in clinical trials, the compound we tested in this animal study was a dual orexin receptor antagonist that affects both type 1 and type 2 orexin receptors,” he said. “We would like to determine if there may be any efficacy and/or safety advantages of an agent that specifically targets just one receptor subtype.”


Brian C. Samuels, MD, PhD

E: bcsamuel@iupui.edu

Dr. Samuels receives speaking honoraria from Merck, but it is not related to this research. He holds a patent for the use of orexin antagonists for the treatment of glaucoma. The patent has not been optioned by outside companies and Dr. Samuels is not currently receiving payments for the patent.


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