Laboratory research with mice suggests a new drug may prevent learning and memory deficits associated with stress-related disorders.
Using a mouse model of post-traumatic stress disorder (PTSD), Columbia University Medical Center researchers discovered 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.
“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, M.D.
“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.
Despite the prevalence of PTSD, there is not a standard or specific treatment for the disorder. Several studies have shown that chronic stress could affect the structure and function of neurons in the brain.
Researchers have proposed that these effects could contribute to neuropsychiatric disorders, including PTSD, which involve symptoms of cognitive dysfunction. However, researchers do not understand the exact mechanisms that contribute to impaired learning and memory.
Based on his earlier work in heart and muscle disorders, 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, 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 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,” Marks said.
“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.”
Marks said the next question was do the leaky channels affect memory and learning, two functions that are impaired in individuals with PTSD.
“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,” he said
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.
Research will also continue to examine the implications of the leaky channel model in neurodegenerative diseases, including Alzheimer’s.
The findings are published in the online edition of the journal Cell.