Activation of a protein called SREBP-1 is linked to continued cell death, according to an online paper in Nature Medicine.
Following a stroke, many brain cells continue to die even after blood flow has been restored. This is due to a complicated cascade of cellular messages that lead to the “self-destruction” and death of brain cells. Now, using animal models, scientists have discovered that the overactivation of NMDA receptors on the surface of brain cells activates another protein, SREBP-1, which subsequently causes cell death. They also claim to have developed a drug that indirectly inhibits activity of SREBP-1, thus decreasing cell death.
The results of the study were published November 22 online in Nature Medicine in a paper titled “Role of NMDA receptor–dependent activation of SREBP1 in excitotoxic and ischemic neuronal injuries.” The research team is from the Brain Research Centre, a partnership of the University of British Columbia Faculty of Medicine and Vancouver Coastal Health Research Institute.
NMDA receptors control the movement of calcium in and out of brain cells, which is necessary for normal brain function. However, following a stroke, levels of glutamate—the most abundant chemical messenger in the brain—rise rapidly in cells, leading to overactivation of NMDA receptors, an excess of calcium entering cells, and the onset of cell death.
SREBP-1 is found naturally in cells throughout the body and is involved with cholesterol and other fat production. The researchers found that under normal conditions, SREBP-1 is largely kept in an inactive form by a protein known as Insig-1. After a stroke, overactivation of NMDA receptors leads to a rapid degradation of Insig-1, which increases the level of active form of SREBP-1.
“How overactivation of NMDA receptors caused cell death after a stroke has been a mystery,” says Yu Tian Wang, Ph.D., co-leader of the study. “We found that SREBP-1 was one of the missing key players in that process.”
While the detailed mechanisms by which activation of SREBP-1 leads to brain cell death remain to be established, the researchers discovered a way to inhibit SREBP-1 and thereby significantly reduce cell death. “We developed a drug that can stabilize Insig-1, which in turn inhibits the activity of SREBP-1,” says Max Cynader, Ph.D., another co-leader of the study. “By doing so, we were able to prevent cell death.”
The researchers also found that the drug works post-stroke in animal models. “When we administered it post-stroke, there was less brain cell damage 30 days later than compared to controls,” says Dr. Wang. “This is important because previous studies focused on blocking the NMDA receptors in order to prevent cell death, but this approach didn’t work because it affected normal cell function and had a relatively short therapeutic window. The drug we studied works downstream of NMDA receptors and appears to have less detrimental side effects with a much improved therapeutic window.”
Further investigations will help researchers understand how SREBP-1 causes cell death and to further determine efficacy of the drug. Because of the protein’s connection to cholesterol synthesis and other cellular functions, further investigations may reveal if it has a role in other neurological disorders, such as ALS, and whether the drug might be effective for those conditions as well.