After experiencing a traumatic brain injury (TBI), patients may develop fatal brain edema. This type of brain swelling dramatically increases the risk of death and affects the prospects for recovery of brain function. In extreme cases, doctors need to remove a portion of the skull to release the pressure, but such a procedure is extremely risky and is only available to a small percentage of TBI patients. To this day, cerebral edema remains a common cause of in-hospital death and is associated with long-term neurological deficits.
Recently, a study published in the journal Nature promises a solution to the problem. The study found that a cocktail of therapies based on drugs already approved for treating high blood pressure was able to rapidly alleviate cerebral edema and ameliorate brain damage in an animal model.
This latest research was led by Maiken Nedergaard, Ph.D., co-director of the Center for Translational Neuromedicine at the University of Rochester.In 2012, Nedergaard's lab first discovered the lymphoid system in the brain, which removes waste products from the brain. Since then, with the aid of advanced imaging techniques and AI-driven hydrodynamic modeling, researchers have been able to more accurately predict, and manipulate, the movement of cerebrospinal fluid (CSF) in the central nervous system.
In the ensuing decade, understanding of the brain's lymphoid system has continued to grow. Now, new research has uncovered yet another potential role for the system: as a "valve" for releasing stress during emergencies.
"In other parts of the body, edema helps tissue repair. But because the brain's ability to expand is limited by the presence of a strong skull, increased intracranial pressure and reduced blood supply allow waste debris and toxic proteins to remain at the site of injury rather than being flushed away. As a result, injury recovery becomes more complicated." Rashad Hussain, the study's first author and an assistant professor at the University of Rochester's Center for Translational Neurology, said.
The research team has found a solution in the mechanism of brain edema. One of the main triggers of brain edema is norepinephrine. Immediately after a TBI, this neurotransmitter floods the brain. We are more familiar with norepinephrine's function in regulating the "flight or fight" response, but in TBI, this "adrenergic storm" blocks the flow of cerebrospinal fluid into and out of the brain.
The study noted that norepinephrine restricts the process of cerebrospinal fluid drainage from the brain into the meninges as well as into the cervical lymph nodes, thus hindering the function of the lymphatic system. Based on this phenomenon, the team hypothesized that reopening these "doors" in the lymph nodes might help flush excess cerebrospinal fluid away from the brain, thereby relieving stress.
To do this, the team used a cocktail of prazosin, atipamezole and propranolol. These three drugs are alpha 1-, alpha 2-, and beta-blockers, and together they inhibit different receptors used by cells to take up norepinephrine.Previous research in Nedergaard's lab has shown that this combination of drugs boosts the efficiency of the lymphoid system to the level of activity we experience when we are asleep, which is when the system is most effective at manipulating the flow of cerebrospinal fluid and removing waste.
In this study, the authors gave mice the cocktail of drugs described above shortly after TBI and tracked cerebrospinal fluid from the swollen area. The cerebrospinal fluid carried debris from the lymph node injury and flowed out of the brain in large quantities through the lymphatic vessels. As a result, the mice's cerebral edema resolved almost immediately and intracranial pressure returned to normal. At the same time, the treatment led to a significant recovery of cognitive, behavioral and motor functions in the mice.
Dr. Nedergaard said, "These findings suggest that the adrenergic storm, the resulting cerebral edema and intracranial pressure, as well as the debris that remains in the brain, can be reversed by adrenergic inhibitors, and that the mice's recovery is improved."
The authors noted that several clinical studies have confirmed the safety of the drug combination and observed neurologic benefits, and early evidence also suggests that this approach may be beneficial in humans. Atimezole reduced post-traumatic seizures, prazosin was effective in treating TBI-related post-traumatic stress, and propranolol, a beta-blocker, reduced in-hospital mortality and improved functional prognosis in patients with TBI.Dr. Nedergaard also said that because these drugs are already in clinical use, there is potential to move quickly into clinical studies to confirm these findings.