Researchers identify potential treatment for cognitive effects of stress-related disorders

Columbia University Medical Center (CUMC) researchers have identified a potential medical treatment for the cognitive effects of stress-related disorders, including post-traumatic stress disorder (PTSD). The study, conducted in a PTSD mouse model, shows that an experimental drug called S107, one of a new class of small-molecule compounds called Rycals, prevented learning and memory deficits associated with stress-related disorders. The findings were published today in the online edition of Cell.

"With the dramatic rise in cases of PTSD among our combat veterans, and following common afflictions such as heart attacks, there is a pressing need for new and better therapies for this debilitating disorder," said study leader Andrew R. Marks, MD, chair and professor of physiology and , the Clyde and Helen Wu Professor of Medicine, and director of the Wu Center for Molecular Cardiology at CUMC. "Our study provides new insight regarding the mechanism of stress-related cognitive disorders, as well as a potential treatment based on the understanding of this mechanism."

PTSD is a disabling anxiety disorder triggered by a traumatic experience, ranging from a one-time event such as physical assault to chronic stresses such as those experienced during warfare. Patients are commonly treated with supportive therapies, including antipsychotics, antidepressants, anti-anxiety medications, and psychotherapy. However, there is currently no specific treatment for PTSD and related disorders.

Several studies have shown that could affect the structure and function of neurons in the brain. Researchers have proposed that these effects could contribute to , including PTSD, which involves symptoms of . However, exactly how the cognitive dysfunction arises (which manifests as impaired ) has not been clear.

Based on his earlier work in heart and muscle disorders, Dr. Marks reasoned that chronic stress could lead to PTSD by destabilizing type 2 ryanodine receptors (RyR2) in the hippocampus, the brain region that plays a central role in learning and memory. RyR2 are channels that regulate the level of calcium in neurons, which is vital to cell survival and function.

In earlier mouse studies, Dr. Marks and his team showed that stress can cause RyR2 channels in heart muscle to leak calcium resulting in heart failure and arrhythmias. Subsequent studies in mouse models conducted by Dr. Marks' lab showed that leaky RyR1 channels (a closely related calcium channel) in skeletal muscle can contribute to Duchenne muscular dystrophy, limb-girdle muscular dystrophy and age-related muscle weakness.

To ascertain whether leaky RyR2 channels are a factor in stress-related cognitive disorders, the researchers used a classic model for PTSD that involves subjecting mice to stressful conditions for three weeks. This raises their corticosteroid levels (a classic marker of stress) and activates genes known to be expressed in response to stress.

"When we examined the hippocampal neurons of the stressed mice, we found that their RyR2 channels had become destabilized and leaky compared with channels from normal non-stressed mice which were not leaky. There was a remodeling of the channels that we had previously seen in heart and skeletal muscles from animal models of chronic diseases including heart failure and muscular dystrophy. We found these same leaky channels in samples from patients with these disorders but not in those from healthy humans," said Dr. Marks.

"The next question was: Do the leaky channels affect memory and learning, two functions that are impaired in individuals with PTSD?" said Dr. Marks. "Using classic behavioral and cognitive function tests, including a water-maze and object-recognition tests, we found that the stressed mice developed profound cognitive abnormalities affecting both learning and memory."

The researchers confirmed that hippocampal RyR2 channels were involved in the cognitive decline of the mice in two ways. First, when the mice were given Rycal S107, a novel drug designed in Dr. Marks' lab that prevents the calcium leak by stabilizing RyR2 channels, cognitive function was not affected by exposure to chronic stress. Second, the researchers created a strain of mice in which stress signals cannot destabilize hippocampal RyR2 channels. When these mice were subjected to chronic stress, they showed no signs of cognitive impairment.

Dr. Marks expects that clinical trials with S107, or a similar Rycal, for the treatment of PTSD could begin within several years. Another Rycal is currently being tested in patients with heart failure and arrhythmias.

The researchers are also examining the role of these RyR2 channels in neurodegenerative diseases, including Alzheimer's.

More information: Dr. Marks' paper is titled, "Role of Leaky Neuronal Ryanodine Receptors in Stress-Induced Cognitive Dysfunction."

Related Stories

Weakness in aging tied to leaky muscles

Aug 02, 2011

There is a reason exercise becomes more difficult with age. A report in the August Cell Metabolism, a Cell Press publication, ties the weakness of aging to leaky calcium channels inside muscle cells. But there is some good n ...

PTSD linked to increase risk in heart disease

Jun 01, 2011

(Medical Xpress) -- New research by Dr. Ramin Ebrahimi and his team from the Greater Los Angeles Veterans Administration Medical Center was published in The American Journal of Cardiology and shows a link ...

Recommended for you

Clues to stopping teenage male aggression

7 hours ago

UNSW researchers are recruiting for a study that could reveal the drivers of aggression in boys, opening up new treatments to stem violent offenders in future generations.

User comments

Adjust slider to filter visible comments by rank

Display comments: newest first

Sinister1811
not rated yet Sep 02, 2012
It's not just PTSD, though. Cognitive dysfunction is also found in a variety of other psychiatric disorders; like depression, extreme anxiety and also schizophrenia. I've been suffering from depression for a while now, and it has taken a huge toll on my cognition. I just don't feel as intelligent as I used to be. And it's almost impossible to function, lately. I can't even keep up with a conversation anymore. I'm surprised that neither depression nor schizophrenia were even mentioned in this article as other sources of cognitive dysfunction. Hopefully, this research will translate across to other disorders as well.