Nature Medicine | Spoonful of Medicine

New drug protects memory against stress in mouse study

A drug previously tested against muscular dystrophy might offer protection against memory problems induced by stressful conditions, according to a preliminary mouse study. Researchers behind the study say the findings could one day contribute to treatments such as post-traumatic stress disorder (PTSD). However other scientists in the field say the mechanism of action is in need of further evidence, and as such the jury remains out on the clinical utility of the agent.

Although people with PTSD can receive help from psychotherapists and antidepressants, drugs to specifically treat the disorder are lacking, as a feature in Nature Medicine detailed. Moreover, doctors know that people who experience shocking violence or abuse and develop PTSD have trouble remembering and learning new things.

In the new experiment, mice were placed each night in a plastic tube without space to move around, creating chronic stress and providing a proxy for PTSD. Andrew Marks, a physiologist at Columbia University in New York, and his team gave half of the animals a daily dose of the drug S107 beginning two days before the stress regime and continuing for the remaining three weeks of research. In their study appearing today in the journal Cell, they report that those mice that received S107 remembered where to find a hidden platform in a water maze a little more than twice as fast as their control counterparts. The treated mice also explored new objects placed in their cages while their stressed-out, untreated counterparts showed less interest.

According to Marks, S107 works by binding to a type of calcium channel called RyR2, which is located in the endoplasmic reticulum within cells, thereby keeping the protein calstabin2 bound to the channel. When calstabin2 is bound to the channel it helps prevent calcium–an important chemical for neuron signaling–from leaking out.* Prior to the current study, Marks contributed two articles in this journal encouraging further exploration of the role protein plays in ion channels in patients with heart arrhythmias and muscular dystrophy.

S107 is similar to a drug called S36, which Marks helped develop and is now in phase 2 clinical trials being conducted by New York-based Armgo in Europe to target calcium channels in the heart cells of people with heart failure. He also helped collaborate on a 2010 study of a mouse model of Duchenne muscular dystrophy–often accompanied by heart arrhythmia–in which S107 prevented those irregular heart beats.

Other researchers are interested to see that this class of drugs affects calcium channels in brain cells, and that it improved memory in stressed mice. “To be able to use this compound to correct the dysfunction at the behavioral level is impressive, says Mark Nelson, a pharmacologist at the University of Vermont in Burlington. But, he adds, “There are a lot of steps that need to be linked up.” He notes that calcium controls everything from neuron excitability to gene expression to neurotransmission, and the current study does not untangle those relationships.

The study itself notes that the stress conditions the mice experienced do not mimic PTSD, as this is difficult in an animal trial. Marks says he is excited to move to the next step and pointed out that the drug needs many more animal studies before clinical trials could even be considered.

*CORRECTION: An earlier version of this post incorrectly stated that S107 binds to the protein calstabin2 and incorrectly described the calcium channels (RyR2) as being located on the plasma membranes of brain cells. This post also includes a link to an article co-authored by Marks that appeared in Nature Medicine in 2009 detailing the role calstabin1–a close relative of calstabin2–plays in muscular dystrophy. 

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