Memory Decline Reversed by New Molecule
Researchers have demonstrated that a drug candidate called CMS121 can reverse memory decline in mice. They published their research in the journal Redox Biology in July 2020. (1, 2)
The research team, from Salk Institute for Biological Studies, has worked with CMS121 before.
“This was a more rigorous test of how well this compound would work in a therapeutic setting than our previous studies on it,” Pamela Maher said in an interview published by Salk. Maher is a senior staff scientist in the lab of Salk Professor David Schubert and the senior author of the paper. “Based on the success of this study, we’re now beginning to pursue clinical trials.” (1)
CMS121 comes from a chemical called fisetin. It is found in fruits and vegetables. As early as 2014, Salk researchers found that fisetin can improve memory in mice and reverse the symptoms of the equivalent of Alzheimer’s disease in mice. (2, 3)
Salk researchers synthesized fisetin to separate its compounds. They learned that CMS121 was very effective at memory improvement in animals and slowing the degeneration of brain cells. (1)
Alzheimer’s-Like Disease Reversed in Mice
In the study published in July 2020, Maher and her colleagues tested CMS121 on mice who had developed an equivalent of Alzheimer’s disease. This happens after 9 months of age, which is comparable to middle age for mice. The mice in the study had begun to show issues with learning and memory. Some mice received daily doses of CMS121. Their treatment schedule was comparable to how a human with Alzheimer’s disease would be treated by their doctor. A control group of mice with the Alzheimer’s-like disease was untreated. Both groups were compared to a group of healthy mice. (1, 2)
The mice were treated with CMS121 for three months. At 12 months old, both groups of mice performed behavioral and memory tests. Mice with the Alzheimer’s-like disease who were treated with CMS121 performed as well as the healthy mice in both types of tests. The untreated mice with the Alzheimer’s-like disease performed worse than the other two groups. (1, 2)
The research team looked at the levels of specific molecules in the brains of the three groups of mice. They noticed a difference in the levels of lipids. Lipids are molecules made up of fats and oils. They have three jobs in the body: storing energy, acting as structural components of cell membranes, and doing important work as signaling molecules. (1, 2, 4)
Lipid Peroxidation
The untreated mice with the Alzheimer’s-like disease had a difference in lipids than the healthy mice and those treated with CMS121. The most important difference was with lipid peroxidation, which is the breakdown of lipids. This creates free radicals that can cause cell damage. The untreated mice with the mouse equivalent of Alzheimer’s had higher levels of lipid peroxidation than the healthy mice or the ones treated with CMS121. (1, 2)
“That not only confirmed that lipid peroxidation is altered in Alzheimer’s, but that this drug is actually normalizing those changes,” says Salk postdoctoral fellow Gamze Ates, first author of the July 2020 paper. (1)
The research group is seeking clinical trials. They hope that other research teams will explore compounds that target lipid peroxidation and likewise reverse memory decline. (1, 2)
“There has been a big struggle in the field right now to find targets to go after,” Maher said in an interview published on Salk’s website. “So, identifying a new target in an unbiased way like this is really exciting and opens lots of doors.” (1)
