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Mice Study Finds Cancer Drug May Work on Common Brain Diseases
Georgetown University Medical Center researchers discovered the drug prevented the accumulation of toxic proteins linked to Parkinson’s disease in the brains of mice. Researchers will now develop a clinical trial to study the effects of the drug on humans.
Investigators say their study, published online in Human Molecular Genetics, is a new strategy to treat neurodegenerative diseases that feature abnormal buildup of proteins.
Common diseases that develop in association with the abnormal buildup of proteins include Parkinson’s disease, Alzheimer’s disease, amyotrophic lateral sclerosis (ALS), frontotemporal dementia, Huntington disease and Lewy body dementia, among others.
“This drug, in very low doses, turns on the garbage disposal machinery inside neurons to clear toxic proteins from the cell,” said the study’s senior investigator, neuroscientist Charbel E-H Moussa, M.B., Ph.D.
“By clearing intracellular proteins, the drug prevents their accumulation in pathological inclusions called Lewy bodies and/or tangles, and also prevents amyloid secretion into the extracellular space between neurons, so proteins do not form toxic clumps or plaques in the brain,” he said.
When the drug, nilotinib, is used to treat chronic myelogenous leukemia (CML), it forces cancer cells into autophagy — a biological process that leads to death of tumor cells in cancer.
“The doses used to treat CML are high enough that the drug pushes cells to chew up their own internal organelles, causing self-cannibalization and cell death,” Moussa said.
“We reasoned that small doses — for these mice, an equivalent to one percent of the dose used in humans — would turn on just enough autophagy in neurons that the cells would clear malfunctioning proteins, and nothing else.”
Moussa hypothesized that the cancer drugs could help to clean up diseased brains. “No one has tried anything like this before,” he said.
However, a unique characteristic of the brain is a membrane that separates circulating blood from the brain’s extracellular fluid (BECF) in the central nervous system (CNS).
This blood-brain barrier protects the brain from many common bacterial infections but also has historically limited the administration of medical and therapeutic agents.
To this end, Moussa and his team searched for cancer drugs that can cross the blood-brain barrier.
They discovered two candidates — nilotinib and bosutinib, which is also approved to treat CML. This study discusses experiments with nilotinib, but Moussa says that use of bosutinib is also beneficial.
The mice used in this study were genetically engineered to have the Lewy bodies that are found in Parkinson’s disease and dementia patients, and in many other neurodegenerative diseases.
The animals were given one milligram of nilotinib every two days. (By contrast, the FDA approved use of up to 1,000 milligrams of nilotinib once a day for CML patients.)
“We successfully tested this for several diseases models that have an accumulation of intracellular protein,” Moussa says. “It gets rid of alpha synuclein and tau in a number of movement disorders, such as Parkinson’s disease as well as Lewy body dementia.”
The team also showed that movement and functionality in the treated mice was greatly improved, compared with untreated mice.
In order for such a therapy to be as successful as possible in patients, the agent would need to be used early in neurodegenerative diseases, Moussa said. Later use might retard further extracellular plaque formation and accumulation of intracellular proteins in inclusions such as Lewy bodies.
Moussa is planning a phase II clinical trial in participants who have been diagnosed with disorders that feature build-up of alpha Synuclein, including Lewy body dementia, Parkinson’s disease, progressive supranuclear palsy (PSP) and multiple system atrophy (MSA).
Source: Georgetown University Medical Center
Abstract of the brain photo by shutterstock.
Generating Positive Emotions Can Better Physical Health
Barbara Fredrickson, Ph.D., of the University of North Carolina at Chapel Hill and Bethany Kok, Ph.D., of the Max Planck Institute for Human Cognitive and Brain Sciences in Germany also found that people can improve their emotional health by having more social connections.
“People tend to liken their emotions to the weather, viewing them as uncontrollable,” Fredrickson said. “This research shows not only that our emotions are controllable, but also that we can take the reins of our daily emotions and steer ourselves toward better physical health.”
In the study, published in Psychological Science, researchers evaluated the bodily effects of up-regulating positive emotions. To do this, they focused on vagal tone, an indicator of how a person’s vagus nerve is functioning.
The vagus nerve helps regulate heart rate and is also a central component of a person’s social-engagement system.
Because people who have higher vagal tone tend to be better at regulating their emotions, the researchers speculated that having higher vagal tone might lead people to experience more positive emotions, which would then boost perceived positive social connections.
Having more social connections would in turn increase vagal tone, thereby improving physical health and creating an “upward spiral.”
To see whether people might be able to harness this upward spiral to steer themselves toward better health, Kok, Fredrickson, and their colleagues conducted a longitudinal field experiment.
Half of the study participants were randomly assigned to attend a six-week loving-kindness meditation (LKM) course in which they learned how to cultivate positive feelings of love, compassion, and goodwill toward themselves and others.
They were asked to practice meditation at home, but how often they meditated was up to them. The other half of the participants remained on a waiting list for the course.
Each day, for 61 consecutive days, participants in both groups reported their “meditation, prayer, or solo spiritual activity,” their emotional experiences, and their social interactions within the last day. Their vagal tone was assessed twice, once at the beginning and once at the end of the study.
Researchers say the data provides clear evidence to support the concept of an “upward spiral,” with perceived social connections serving as the link between positive emotions and health.
Participants in the LKM group who entered the study with higher vagal tone showed steeper increases in positive emotions over the course of the study. As participants’ positive emotions increased, so did their reported social connections.
And, as social connections increased, so did vagal tone. In contrast, participants in the wait-list group showed virtually no change in vagal tone over the course of the study.
“The daily moments of connection that people feel with others emerge as the tiny engines that drive the upward spiral between positivity and health,” Fredrickson said.
Investigators believe the findings suggest that positive emotions may be an essential psychological nutrient that builds health, just like getting enough exercise and eating leafy greens.
“Given that costly chronic diseases limit people’s lives and overburden health care systems worldwide, this is a message that applies to nearly everyone – citizens, educators, health care providers, and policy-makers alike,” Fredrickson said.
Source: Association for Psychological Science
Happy young woman meditating photo by shutterstock.
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