Summary: Researchers report that lithium, a medication commonly used to treat bipolar disorder, and the drug rapamycin can help protect neurons and limit further damage after traumatic brain injury (TBI).
Source: Rutgers University
Lithium and Rapamycin Show Promise for Protecting Neurons after Traumatic Brain Injury
A new study from Rutgers University suggests that two existing, FDA‑approved medications—lithium, a mood stabilizer frequently used to treat bipolar disorder and depression, and rapamycin, an immunosuppressant and anti‑cancer agent—may prevent further nerve cell loss and preserve brain function following traumatic brain injury (TBI).
Published in the journal Scientific Reports, the research found that both lithium and rapamycin interfere with an excitotoxic signaling cascade triggered by excessive glutamate release after brain trauma. Under normal conditions, glutamate is an essential neurotransmitter for learning and memory. However, a severe blow to the head can cause abnormal, sustained increases in glutamate that overstimulate NMDA receptors on neurons, causing cellular stress, dysfunction, and ultimately cell death.
“Many current treatments for traumatic brain injury focus on symptom management and pain relief rather than preventing additional cell damage,” said Bonnie Firestein, lead author and professor in the Department of Cell Biology and Neuroscience at Rutgers University–New Brunswick. “We set out to identify drugs that could stop the process of cell death and preserve neuronal function.”
Laboratory Findings: Blocking Glutamate-Induced Signaling Protects Neurons
In laboratory experiments using damaged neuron cell cultures, researchers added lithium and rapamycin after inducing sublethal NMDA receptor activation to mimic the excitotoxic conditions that follow TBI. The treatments limited the ability of glutamate-driven signals to propagate between nerve cells, which in turn prevented further cellular injury and death.
Electrophysiological tests showed that NMDA-induced injury reduced spontaneous excitatory synaptic activity at both two and twenty‑four hours post‑exposure. Importantly, inhibiting two downstream signaling components—mTORC1 and GSK3β—preserved synaptic activity and promoted neuronal survival. In contrast, manipulating Akt did not prevent the excitotoxic effects. These results indicate that the permissive activity of mTORC1 and GSK3β is required for NMDA-induced excitotoxicity and that targeting these kinases can protect neuronal structure and function.
Implications for Concussion and Other TBIs
Traumatic brain injury is a leading cause of death and disability. According to the Centers for Disease Control and Prevention, TBI affects millions each year in the United States and contributes to approximately 30 percent of injury-related deaths. Common TBI symptoms include impaired thinking and memory, personality changes, depression, and sensory problems such as vision or hearing loss. Children and older adults face higher risk profiles for TBI, and concussions—often underdiagnosed in children—are among the most frequent forms of brain injury.
Firestein emphasized the potential clinical value of an approach that protects neurons immediately after injury. “Concussions and other TBIs can have long‑term consequences, especially when early damage is not prevented,” she said. “Identifying drugs that can preserve neuronal viability and limit secondary injury could reduce lasting disability.”
Next Steps: From Cells to Animals and Humans
While the findings are promising, the researchers caution that further work is needed. These results were obtained in controlled cell culture models, and additional studies in animal models and clinical trials will be required to determine whether lithium, rapamycin, or related strategies can safely and effectively prevent brain damage and neuronal loss in people after TBI.
Funding: This Rutgers research was supported by a three‑year grant from the New Jersey Commission on Brain Injury Research. The commission’s funding is partially sourced from moving violation penalties such as speeding and distracted driving infractions; a portion of each ticket contributes to the brain injury fund.
Reporting: Robin Lally, Rutgers University. The results were published in Scientific Reports and detail the role of mTORC1 and GSK3β in NMDA‑induced sublethal injury and the recovery of neuronal electrophysiology and survival.
Abstract
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 NMDA receptors, drives secondary neuronal damage after brain injury. Early phases of this injury include dendritic spine loss and altered synaptic function. The PI3K/Akt/mTOR signaling network has been implicated in synaptic regulation and axonal regeneration. This study examined how manipulating Akt and downstream effectors—including GSK3β, FOXO1, and mTORC1—affects neuronal physiology and survival following sublethal NMDA exposure. The analysis showed that sublethal NMDA did not change phosphorylation of Akt, S6, or GSK3β at two and twenty‑four hours after injury. Electrophysiological recordings revealed a marked decrease in spontaneous excitatory postsynaptic currents at both time points; this decline was prevented by inhibiting mTORC1 or GSK3β but not Akt. Inhibition of mTORC1 or GSK3β also promoted neuronal survival. These findings indicate that NMDA‑induced excitotoxicity requires permissive mTORC1 and GSK3β activity and highlight these kinases as critical mediators of the neuronal response to injury.
Study authors included Przemyslaw Swiatkowski, Ina Nikolaeva, Gaurav Kumar, Avery Zucco, Barbara F. Akum, Mihir V. Patel, Gabriella D’Arcangelo, and Bonnie L. Firestein.