Summary: According to researchers, lithium, a drug commonly used to treat bipolar disorder, and rapamycin can help to protect neurons from further damage in those with TBI.
A drug used to treat bipolar disorder and other forms of depression may help to preserve brain function and prevent nerve cells from dying in people with a traumatic brain injury, according to a new Rutgers University study.
In research published in Scientific Reports, Rutgers scientists discovered that lithium – used as a mood stabilizer and to treat depression and bipolar disorder – and rapamycin, a treatment for some forms of cancer, protected nerve cells in the brain and stopped the chemical glutamate from sending signals to other cells and creating further brain cell damage.
“Many medications now used for those suffering with traumatic brain injury focus on treating the symptoms and stopping the pain instead of protecting any further damage from occurring,” said lead author Bonnie Firestein, professor in the Department of Cell Biology and Neuroscience in the School of Arts and Sciences at Rutgers University-New Brunswick. “We wanted to find a drug that could protect the cells and keep them from dying.”
According to the Centers for Disease Control and Prevention, traumatic brain injury (TBI) is a major cause of death and disability in the United States with an estimated 1.7 people sustaining a TBI annually. About 30 percent of all deaths due to injury are due, in part, to a TBI.
The symptoms of a TBI can include impaired thinking or memory, personality changes and depression, as well as vision and hearing problems.
The CDC reports that every day 153 people in the U.S. die from injuries that include a TBI. Children and older adults are at the highest risk, according to the CDC.
When a TBI occurs, Firestein said, a violent blow to the head can result in the release of abnormally high concentrations of glutamate, which under normal circumstances is an important chemical for learning and memory. But an overproduction of glutamate, she said, causes toxicity which leads to cell damage and death.
In the Rutgers research, scientists discovered that when these two FDA-approved medications were added to damaged cell cultures in the laboratory, the glutamate was not able to send messages between nerve cells. This stopped cell damage and death, Firestein said.
Further research needs to be done, she said, in animals and humans to determine if these drugs could help prevent brain damage and nerve cell death in humans after a traumatic brain injury.
“The most common traumatic brain injury that people deal with every day is concussion which affects thousands of children each year,” said Firestein. “Concussions are often hard to diagnose in children because they are not as vocal, which is why it is critical to find drugs that work to prevent long-term damage.”
Funding: The Rutgers research was funded by a three-year grant from the New Jersey Commission on Brain Injury Research. The commission is funded, in part, by traffic tickets for moving violations like speeding, using a cell phone or driving without a license, and provides $1 to the fund from every ticket issued.
Source: Robin Lally – Rutgers
Image Source: NeuroscienceNews.com image is in the public domain.
Original Research: Full open access research for “Role of Akt-independent mTORC1 and GSK3β signaling in sublethal NMDA-induced injury and the recovery of neuronal electrophysiology and survival” by Przemyslaw Swiatkowski, Ina Nikolaeva, Gaurav Kumar, Avery Zucco, Barbara F. Akum, Mihir V. Patel, Gabriella D’Arcangelo & Bonnie L. Firestein in Scientific Reports. Published online May 8 2017 doi:10.1038/s41598-017-01826-w
Role of Akt-independent mTORC1 and GSK3β signaling in sublethal NMDA-induced injury and the recovery of neuronal electrophysiology and survival
Glutamate-induced excitotoxicity, mediated by overstimulation of N-methyl-D-aspartate (NMDA) receptors, is a mechanism that causes secondary damage to neurons. The early phase of injury causes loss of dendritic spines and changes to synaptic activity. The phosphatidylinositol-4,5-bisphosphate 3-kinase/Akt/ mammalian target of rapamycin (PI3K/Akt/mTOR) pathway has been implicated in the modulation and regulation of synaptic strength, activity, maturation, and axonal regeneration. The present study focuses on the physiology and survival of neurons following manipulation of Akt and several downstream targets, such as GSK3β, FOXO1, and mTORC1, prior to NMDA-induced injury. Our analysis reveals that exposure to sublethal levels of NMDA does not alter phosphorylation of Akt, S6, and GSK3β at two and twenty four hours following injury. Electrophysiological recordings show that NMDA-induced injury causes a significant decrease in spontaneous excitatory postsynaptic currents at both two and twenty four hours, and this phenotype can be prevented by inhibiting mTORC1 or GSK3β, but not Akt. Additionally, inhibition of mTORC1 or GSK3β promotes neuronal survival following NMDA-induced injury. Thus, NMDA-induced excitotoxicity involves a mechanism that requires the permissive activity of mTORC1 and GSK3β, demonstrating the importance of these kinases in the neuronal response to injury.
“Role of Akt-independent mTORC1 and GSK3β signaling in sublethal NMDA-induced injury and the recovery of neuronal electrophysiology and survival” by Przemyslaw Swiatkowski, Ina Nikolaeva, Gaurav Kumar, Avery Zucco, Barbara F. Akum, Mihir V. Patel, Gabriella D’Arcangelo & Bonnie L. Firestein in Scientific Reports. Published online May 8 2017 doi:10.1038/s41598-017-01826-w