Depression, obesity, chronic pain could be treated by targeting the same key protein

April 1, 2019

Science Daily/American Chemical Society

Major depression, obesity and chronic pain are all linked to the effects of one protein, called "FK506-binding protein 51," or FKBP51. Until now, efforts to inhibit this target have been hampered by the difficulty of finding something specific enough to do the job and not affect similar proteins. Now a research group has developed a highly selective compound that can effectively block FKBP51 in mice, relieving chronic pain and having positive effects on diet-induced obesity and mood. The new compound also could have applications in alcoholism and brain cancer.

The researchers will present their results today at the American Chemical Society (ACS) Spring 2019 National Meeting & Exposition.

"The FKBP51 protein plays an important role in depression, obesity, diabetes and chronic pain states," says Felix Hausch, Ph.D., the project's principal investigator. "We developed the first highly potent, highly selective FKBP51 inhibitor, called SAFit2, which is now being tested in mice. Inhibition of FKBP51 could thus be a new therapeutic option to treat all of these conditions."

Hausch, who is at the Technical University of Darmstadt, started the project when studies were published linking the protein to depression. "I was intrigued by the peculiar regulatory role it seemed to play in cells," he says. "And there was a known natural product that could serve as a starting point. Collectively, this looked like an interesting protein to work on."

FKBP51 is expressed in multiple places throughout the body, such as the brain, skeletal muscle tissue and fat. It also has multiple effects. For example, the protein can restrict the uptake of glucose and the browning of fat, so that the body stores fat instead of burning it. It also affects stress responses. So, Hausch and his colleagues figured that blocking this protein could be the key to developing drugs to treat a variety of conditions.

But FKBP51 looks a lot like its closest protein cousin, FKBP52. "These two proteins are very similar in structure, but they are doing opposing things in cells," Hausch says. "We have this yin-yang situation. Selectivity between these two proteins is thought to be crucial, but this is hard to achieve since the two proteins are so similar. We discovered that FKBP51 can change its shape in a way that FKBP52 can't, and this allowed the development of highly selective inhibitors."

The researchers have now used nuclear magnetic resonance techniques to detect a previously hidden binding site in FKBP51. The approach could help other researchers identify similar "cryptic" binding sites in challenging drug targets in the future, Hausch says.

His team is now testing SAFit2, the lead FKBP51 inhibitor they developed from these studies, in animals. "It indeed helps mice cope better in stressful situations," Hausch says. In mice, SAFit2 reduced stress hormone levels, promoted more active stress coping, was synergistic with antidepressants, protected against weight gain, helped normalize glucose levels and reduced pain in three animal models.

According to Hausch, much more needs to be done to get FKBP1 inhibitors to the point where they could be used as a drug molecule in human testing. In the meantime, the team is also exploring FKBP51 inhibitors in other applications. So far, the group has conducted a number of mouse studies on the involvement of FKBP51 in alcoholism, but results are still preliminary. In addition, Hausch points out that certain types of glioblastoma tumors overexpress FKBP51. He hopes that this result indicates FKBP51 inhibitors could be used in cancer treatment, when patients' tumors mutate beyond current drugs' capacity to treat them. "We may be able to resensitize them to different types of chemotherapy using these specific inhibitors," he says.

https://www.sciencedaily.com/releases/2019/04/190401075208.htm

Meditation reduces the emotional impact of pain

June 2, 2010

Science Daily/University of Manchester

People who meditate regularly find pain less unpleasant because their brains anticipate the pain less, a new study has found.

Scientists from The University of Manchester recruited individuals into the study who had a diverse range of experience with meditation, spanning anything from months to decades. It was only the more advanced meditators whose anticipation and experience of pain differed from non-meditators.

The type of meditation practised also varied across individuals, but all included 'mindfulness meditation' practices, such as those that form the basis of Mindfulness-Based Cognitive Therapy (MBCT), recommended for recurrent depression by the National Institute for Health and Clinical Excellence (NICE) in 2004.

"Meditation is becoming increasingly popular as a way to treat chronic illness such as the pain caused by arthritis," said Dr Christopher Brown, who conducted the research. "Recently, a mental health charity called for meditation to be routinely available on the NHS to treat depression, which occurs in up to 50% of people with chronic pain. However, scientists have only just started to look into how meditation might reduce the emotional impact of pain."

The study, to be published in the journal Pain, found that particular areas of the brain were less active as meditators anticipated pain, as induced by a laser device. Those with longer meditation experience (up to 35 years) showed the least anticipation of the laser pain.

He said: "The results of the study confirm how we suspected meditation might affect the brain. Meditation trains the brain to be more present-focused and therefore to spend less time anticipating future negative events. This may be why meditation is effective at reducing the recurrence of depression, which makes chronic pain considerably worse."

Dr Brown said the findings should encourage further research into how the brain is changed by meditation practice. He said: "Although we found that meditators anticipate pain less and find pain less unpleasant, it's not clear precisely how meditation changes brain function over time to produce these effects.

"However, the importance of developing new treatments for chronic pain is clear: 40% of people who suffer from chronic pain report inadequate management of their pain problem."

http://www.sciencedaily.com/releases/2010/06/100602091315.htm

Half of adults with anxiety or depression report chronic pain

May 31, 2017

Science Daily/Columbia University's Mailman School of Public Health

In a survey of adults with anxiety or a mood disorder like depression or bipolar disorder, about half reported experiencing chronic pain, according to researchers.

"The dual burden of chronic physical conditions and mood and anxiety disorders is a significant and growing problem," said Silvia Martins, MD, PhD, associate professor of Epidemiology at the Mailman School of Public Health, and senior author.

The research examined survey data to analyze associations between DSM-IV-diagnosed mood and anxiety disorders and self-reported chronic physical conditions among 5,037 adults in São Paulo, Brazil. Participants were also interviewed in person.

Among individuals with a mood disorder, chronic pain was the most common, reported by 50 percent, followed by respiratory diseases at 33 percent, cardiovascular disease at 10 percent, arthritis reported by 9 percent, and diabetes by 7 percent. Anxiety disorders were also common for those with chronic pain disorder at 45 percent, and respiratory at 30 percent, as well as arthritis and cardiovascular disease, each 11 percent. Individuals with two or more chronic diseases had increased odds of a mood or anxiety disorder. Hypertension was associated with both disorders at 23 percent.

"These results shed new light on the public health impact of the dual burden of physical and mental illness," said Dr. Martins. "Chronic disease coupled with a psychiatric disorder is a pressing issue that health providers should consider when designing preventive interventions and treatment services -- especially the heavy mental health burden experienced by those with two or more chronic diseases."

https://www.sciencedaily.com/releases/2017/05/170531133242.htm