Posts tagged orexin
Articles and news from the latest research reports.
Proteins causing daytime sleepiness tied to bone formation, providing target for osteoporosis
Orexin proteins, which are blamed for spontaneous daytime sleepiness, also play a crucial role in bone formation, according to findings by UT Southwestern Medical Center researchers. The findings could potentially give rise to new treatments for osteoporosis, the researchers say.
Orexins are a type of protein used by nerve cells to communicate with each other. Since their discovery at UT Southwestern more than 15 years ago, they have been found to regulate a number of behaviors, including arousal, appetite, reward, energy expenditure, and wakefulness. Orexin deficiency, for example, causes narcolepsy – spontaneous daytime sleepiness. Thus, orexin antagonists are promising treatments for insomnia, some of which have been tested in Phase III clinical trials.
UT Southwestern researchers, working with colleagues in Japan, now have found that mice lacking orexins also have very thin and fragile bones that break easily because they have fewer cells called osteoblasts, which are responsible for building bones.
“Osteoporosis is highly prevalent, especially among post-menopausal women. We are hoping that we might be able to take advantage of the already available orexin-targeting small molecules to potentially treat osteoporosis,” said Dr. Yihong Wan, Assistant Professor of Pharmacology, the Virginia Murchison Linthicum Scholar in Medical Research, and senior author for the study, published in the journal Cell Metabolism.
Osteoporosis, the most common type of bone disease in which bones become fragile and susceptible to fracture, affects more than 10 million Americans. The disease, which disproportionately affects seniors and women, leads to more than 1.5 million fractures and some 40,000 deaths annually. In addition, the negative effects impact productivity, mental health, and quality of life. One in five people with hip fractures, for example, end up in nursing homes.
Orexins seem to play a dual role in the process: they both promote and block bone formation. On the bones themselves, orexins interact with another protein, orexin receptor 1 (OX1R), which decreases the levels of the hunger hormone ghrelin. This slows down the production of new osteoblasts and, therefore, blocks bone formation locally. At the same time, orexins interact with orexin receptor 2 (OX2R) in the brain. In this case, the interaction reduces the circulating levels of leptin, a hormone known to decrease bone mass, and thereby promotes bone formation. Therefore, osteoporosis prevention and treatment may be achieved by either inhibiting OX1R or activating OX2R.
“We were very intrigued by this yin-yang-style dual regulation,” said Dr. Wan, a member of the Cecil H. and Ida Green Center for Reproductive Biology Sciences and UT Southwestern’s Harold C. Simmons Comprehensive Cancer Center. “It is remarkable that orexins manage to regulate bone formation by using two different receptors located in two different tissues.”
The central nervous system regulation through OX2R, and therefore promotion of bone formation, was actually dominant over regulation through OX1R. So when the group examined mice lacking both OX1R and OX2R, they had very fragile bones with decreased bone formation. Similarly, when they assessed mice that expressed high levels of orexins, those mice had increased numbers of osteoblasts and enhanced bone formation.
(Source: utsouthwestern.edu)
![A Sleep Aid Without the Side Effects
Insomniacs desperate for some zzzs may one day have a safer way to get them. Scientists have developed a new sleep medication that has induced sleep in rodents and monkeys without apparently impairing cognition, a potentially dangerous side effect of common sleep aids. The discovery, which originated in work explaining narcolepsy, could lead to a new class of drugs that help people who don’t respond to other treatments.
Between 10% and 15% of Americans chronically struggle with getting to or staying asleep. Many of them turn to sleeping pills for relief, and most are prescribed drugs, such as zolpidem (Ambien) and eszopiclone (Lunesta), that slow down the brain by binding to receptors for GABA, a neurotransmitter that’s involved in mood, cognition, and muscle tone. But because the drugs target GABA indiscriminately, they can also impair cognition, causing amnesia, confusion, and other problems with learning and memory, along with a number of strange sleepwalking behaviors, including wandering, eating, and driving while asleep. This has led many researchers to seek out alternative mechanisms for inducing sleep.
Neuroscientist Jason Uslaner of Merck Research Laboratories in West Point, Pennsylvania, and colleagues decided to tap into the brain’s orexin system. Orexin (also known as hypocretin) is a protein that controls wakefulness and is missing in people with narcolepsy. Past studies successfully induced sleep by inhibiting orexin, but had not looked into its effects on cognition. The researchers developed a new orexin-inhibiting compound called DORA-22 and confirmed that it could induce sleep in rats and rhesus monkeys as effectively as the GABA-modulating drugs.
Then the researchers went about testing the drugs’ effects on the animals’ cognition. They measured the rats’ cognition and memory by assessing the rodents’ ability to recognize objects. They presented the rats with a new object—say, a cone or a sphere—that the rats then sniffed and explored. Then they took the object away for an hour. After that hour, the rats were exposed to a new object and the one they’d already gotten to know; if the rats remembered, they spent less time checking out the familiar object. With the primates, Uslaner’s team tested their ability to match colors on a touchscreen and to pay attention to and identify the origin of a flashing light. In all the cases, the researchers found the GABA-modulating sleeping pills caused both the rats and the primates to respond more slowly and less accurately. Monkeys taking the memory and attention tests, for example, were 20% less accurate on the highest dose of each of the GABA-modulating drugs. But DORA-22 had no such effect on cognition, the team reports today in Science Translational Medicine.
"We were very excited," Uslaner says. "Folks who take sleep medications need to be able to perform cognitive tasks when they awake, and this [compound] could help them do so without impairment."
Although DORA-22 has not yet been tested in humans, it holds tremendous promise for helping people suffering from sleep disorders, says Emmanuel Mignot, a sleep researcher with the Stanford University School of Medicine in Palo Alto, California. “This study is encouraging and exciting, because there’s good reason to believe it would work differently from what we’ve used in the past,” says Mignot, who helped discover the link between orexin (or its absence) and narcolepsy. “Not every drug works for everyone, so it’s really, really good news to have a potential new drug on the horizon.”](http://41.media.tumblr.com/ec7d58bff47f9cfe77e5a11284a658a0/tumblr_mks52vgAk71rog5d1o1_500.jpg)
A Sleep Aid Without the Side Effects
Insomniacs desperate for some zzzs may one day have a safer way to get them. Scientists have developed a new sleep medication that has induced sleep in rodents and monkeys without apparently impairing cognition, a potentially dangerous side effect of common sleep aids. The discovery, which originated in work explaining narcolepsy, could lead to a new class of drugs that help people who don’t respond to other treatments.
Between 10% and 15% of Americans chronically struggle with getting to or staying asleep. Many of them turn to sleeping pills for relief, and most are prescribed drugs, such as zolpidem (Ambien) and eszopiclone (Lunesta), that slow down the brain by binding to receptors for GABA, a neurotransmitter that’s involved in mood, cognition, and muscle tone. But because the drugs target GABA indiscriminately, they can also impair cognition, causing amnesia, confusion, and other problems with learning and memory, along with a number of strange sleepwalking behaviors, including wandering, eating, and driving while asleep. This has led many researchers to seek out alternative mechanisms for inducing sleep.
Neuroscientist Jason Uslaner of Merck Research Laboratories in West Point, Pennsylvania, and colleagues decided to tap into the brain’s orexin system. Orexin (also known as hypocretin) is a protein that controls wakefulness and is missing in people with narcolepsy. Past studies successfully induced sleep by inhibiting orexin, but had not looked into its effects on cognition. The researchers developed a new orexin-inhibiting compound called DORA-22 and confirmed that it could induce sleep in rats and rhesus monkeys as effectively as the GABA-modulating drugs.
Then the researchers went about testing the drugs’ effects on the animals’ cognition. They measured the rats’ cognition and memory by assessing the rodents’ ability to recognize objects. They presented the rats with a new object—say, a cone or a sphere—that the rats then sniffed and explored. Then they took the object away for an hour. After that hour, the rats were exposed to a new object and the one they’d already gotten to know; if the rats remembered, they spent less time checking out the familiar object. With the primates, Uslaner’s team tested their ability to match colors on a touchscreen and to pay attention to and identify the origin of a flashing light. In all the cases, the researchers found the GABA-modulating sleeping pills caused both the rats and the primates to respond more slowly and less accurately. Monkeys taking the memory and attention tests, for example, were 20% less accurate on the highest dose of each of the GABA-modulating drugs. But DORA-22 had no such effect on cognition, the team reports today in Science Translational Medicine.
"We were very excited," Uslaner says. "Folks who take sleep medications need to be able to perform cognitive tasks when they awake, and this [compound] could help them do so without impairment."
Although DORA-22 has not yet been tested in humans, it holds tremendous promise for helping people suffering from sleep disorders, says Emmanuel Mignot, a sleep researcher with the Stanford University School of Medicine in Palo Alto, California. “This study is encouraging and exciting, because there’s good reason to believe it would work differently from what we’ve used in the past,” says Mignot, who helped discover the link between orexin (or its absence) and narcolepsy. “Not every drug works for everyone, so it’s really, really good news to have a potential new drug on the horizon.”