International Business Department           Liu Bojia           November 22, 2023

  After experiencing a traumatic brain injury (TBI), patients may develop fatal brain oedema. 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 oedema 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 therapy, based on drugs already approved to treat hypertension, was able to rapidly alleviate cerebral oedema and improve brain damage in animal models.

  This latest research was led by Maiken Nedergaard, PhD, co-director of the Center for Translational Neuromedicine at the University of Rochester.In 2012, Nedergaard's lab first identified the lymphoid system in the brain, which removes waste from the brain. Since then, with the aid of advanced imaging techniques and AI-driven hydrodynamic modelling, 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, the latest research has uncovered yet another potential role for the system: to act as a "valve" for releasing stress during emergencies.

  "In other parts of the body, oedema helps tissue repair. But the brain's ability to expand is limited by the presence of a strong skull, so increased intracranial pressure and reduced blood supply keep waste debris and toxic proteins at the site of injury, where they can't be flushed away. As a result, injury recovery becomes more complicated." Rashad Hussain, first author of the study and assistant professor at the University of Rochester's Centre for Translational Neurology, said.

  The research team found a solution in the mechanism of brain oedema. One of the main triggers of brain oedema is norepinephrine. Immediately after a TBI occurs, 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 hampering the function of the lymphatic system. Based on this phenomenon, the team hypothesised that reopening these "doors" in the lymph nodes might flush excess cerebrospinal fluid away from the brain, thereby relieving stress.

  To do this, the team used a cocktail of prazosin, atipamezole and propranolol. The three drugs are alpha 1-, alpha 2- and beta-blockers, and together the combination inhibits the 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 that we experience when we are asleep, which is precisely the stage at which the system is most effective at manipulating the flow of cerebrospinal fluid and removing waste.

  In this study, the authors gave mice the above cocktail of drugs shortly after TBI and tracked cerebrospinal fluid from the site of the swelling. Cerebrospinal fluid carries debris from lymph node damage and flows out of the brain in large quantities through lymphatic vessels. As a result, the mice's cerebral oedema resolved almost immediately and intracranial pressure returned to normal. At the same time, the treatment led to significant recovery of cognitive, behavioural and motor functions in the mice.

  Dr Nedergaard said, "These findings suggest that the adrenergic storm, the resulting cerebral oedema and intracranial pressure, as well as the debris that remains in the brain, can be reversed by an adrenergic inhibitor, and that the recovery of the mice was improved."

  The authors note that several clinical studies have confirmed the safety of the drug combination and observed neurological 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 since these drugs are already in clinical use, there is potential to move quickly into clinical studies to confirm these findings.