(Editor's Note: Paper is online.)

Most studies of traumatic brain injuries (TBI) focus on the pathology of the injured brain, but newly published research indicates that the liver plays an important role in TBI, and a soluble epoxide hydrolase (sEH) inhibitor discovered by UC Davis distinguished professor Bruce Hammock could lead to therapeutic treatment. 

The research, led by Professor Xinhong Zhu of the School of Biology and Biological Engineering, South China University of Technology, Guangzhou, and tested in the Zhu lab, appears in the Proceedings of the National Academy of Sciences (PNAS). Youngfeng Dai, PhD., is the first author. 

“Using animal models, we found that the liver has a neuroprotective effect in the pathophysiology of TBI, although its role was very weak,” Zhu said. “Our data suggest that enhancement of this neuroprotective role of the liver could provide novel strategies for developing treatment of TBI.” Plans call for “moving toward a clinical study to detect whether hepatic sEH manipulation benefits patients with TBI.”

Their results highlight the neuroprotective role of the liver in TBI and suggest that targeting this neuroprotective role may represent a promising therapeutic strategy for TBI. Earlier clinical studies report that the overall mortality in patients with TBI and cirrhosis is nearly twice that in patients without cirrhosis. 

In the paper, “Enhancement of the Liver's Neuroprotective Role Ameliorates Traumatic Brain Injury Pathology,” the authors describes TBI as a “pervasive problem worldwide, for which no effective treatment is currently available,” and “as a devastating injury that often results in long-term neurological deficits, including locomotor function and memory impairments.” 

“Blood–brain barrier (BBB) disruption is a hallmark feature of TBI and is associated with brain edema and neuronal death,” the authors wrote. “Studies have shown that sEH inhibitors protect the BBB from brain injury. Therefore, we investigated whether deletion of hepatic Ephx2 protected the BBB following controlled cortical injury (CCI).” 

In the United States alone, annual statistics show that 1.5 million people a year are diagnosed with TBI;  230,000 are hospitalized; and 52,000 die. Heavyweight champion Muhammad Ali estimated that he received 290,000 blows to the head during his 21-year professional boxing career. But more commonly, TBI results from falls, statistics show. The National Institutes of Health defines TBI as being “caused by forceful bump, blow or jolt to the head or body, or from an object that pieces the skull and enters the brain.”

“TBI leads to a breakdown of the blood brain barrier,” said co-author Hammock, a member of the National Academy of Sciences and the National Academy of Inventors and whose pioneering work on sEH inhibitors spans 50 years. “We see from cases like Muhammad Ali that repeated TBI can lead to chronic central nervous system injury, dementia and other issues.”

“In the study from the Zhu laboratory, one of the exciting basic discoveries is that mammals have a natural mechanism to partially address traumatic brain injury,” said Hammock, who holds a joint appointment with the Department of Entomology and Nematology and the UC Davis Comprehensive Cancer Center. “By a mechanism under investigation, the injured brain communicates to the liver to down-regulate the production of an enzyme called the soluble epoxide hydrolase (sEH) that degrades natural inflammation resolving mediators.  Thus, the concentration of these injury-resolving mediators also produced in the liver go up reducing deleterious inflammation throughout the injured animal.  This soluble epoxide hydrolase inhibitor used as a tool in these studies is building on this natural mechanism to minimize the harmful effects of TBI.”

"Importantly, the soluble epoxide hydrolase inhibitor that the authors used here is also currently in human clinical safety trials for treating pain and inflammation,” said psychiatrist and neuroscientist Dr. Andrew Pieper, the Rebecca A. Barchas Professor in Translational Psychiatry, Case Western Reserve University, Cleveland. “The results shown here indicate that this agent, or related materials altering this same pathway, might mitigate the acute and long-term complications of TBI, or of neuroinflammatory conditions of the brain in general. Pieper, who holds both a Ph.D. and a M.D.. is the Morley-Mather Chair in Neuropsychiatry, University Hospitals of Cleveland Medical Center;  director of the Brain Health Medicines Center, Harrington Discovery Institute; and psychiatrist at Louis Stokes Cleveland VA Medical Center, Cleveland.

Neuroscience researcher Daniela Kaufer, associate dean of biological sciences at UC Berkeley and a professor with the Department of Integrative Biology and Helen Wills Neuroscience Institute, praised the research possibilities. “The brain has a barrier which helps protect it from harmful materials in the blood,” said Kaufer, who was not involved in the research. “TBI reduces this barrier and its reduction is associated with aging.  Possibly the pathway described in this PNAS paper could be manipulated to protect the blood brain barrier and reduce the apparent aging of the brain caused by repeated TBI.” 

“The reality is that we know moderate and severe TBI leads to significant disability in a high percentage of patients,” said neuroscience researcher Gene Gurkoff, an associate professor in the  Department of Neurological Surgery, UC Davis Health, who specializes in traumatic brain injury and epilepsy. 

“My understanding of how we classify milds at UC Davis right now is that these are patients that behaviorally are mild injuries, but that they have something on a CT or MRI scan that indicates that the injury is more than a concussion, said Gurkoff, who was not involved in the research. “These patients are more likely to have long-term effects than concussion alone, but a lot less likely than moderate-severe. They also don't usually end up in the ICU. Then there are the concussions. Head injuries but no evidence of a radiological finding.” 

“Add on top of that, repeat mild or repeat concussion,” Gurkoff said. “While some investigators will suggest that we have a good handle on repeat TBI--I still think it is the Wild West. It is clear that in a subset of humans, repeat TBI, even concussive, is catastrophic. Others seem to be fine. We also haven't dissected whether repeat TBI on its own is causal --or because many of the patients are in high risk/high stress situations--and it is the combination of TBI/repeat TBI with something else.” 

“What gets me excited about certain compounds--Bruce's would be an example--is that if you have a low-risk compound, is it feasible that you give it to patients who might not develop long-term consequences?” Gurkoff asked. “For example, let's say a patient comes in and based on his injury and history, we might estimate there is a 10 percent chance he has a problem. You aren't going to schedule these patients for surgery--on the extreme--because the risk is too high given they most likely will recover. Having a low-risk compound that can be given to soldiers, athletes, etc, with mild or repeat mild--or concussion/repeat concussion--would be fantastic!”    

The research drew financial support from the National Natural Science Foundation of China, Scientific and Technological Innovation, and partial support from Hammock's grants from the National Institute of Environmental Health Sciences' RIVER Award (Revolutionizing Innovative, Visionary Environmental Health Research) and the National Institute of Neurological Disorders and Stroke. 

Hammock, who co-founded the Davis-based EicOsis LLC in 2011 to develop a drug candidate to treat chronic inflammation, sees similarities between the sEH inhibitor cited in the newly published research and the drug candidate in EicOsis that is moving through human safety clinical trials. “In fact,” Hammock said, “the same compound was selected by the National Institute of Aging for a long-term aging study in mice, in part because TBI and loss of the blood brain barrier function may lead to apparent aging of the brain.” 

“This pioneering study provides clear evidence of the importance of liver-derived epoxy fatty acids (EpFAs) and reactive astrocytes from the immune system in protecting the brain from significant damage and post-traumatic dysfunction following percussive injury,” said William Schmidt, EicOsis vice president of clinical development. “As of now, there are no proven drug therapies that provide protective effects to the brain following single or repeated blows to the head from falls, auto accidents, or sports injuries.” 

“The data from this study,” Schmidt said, “provides a pathway for developing inhibitors of sEH that, in turn, will enhance the availability of EpFAs circulating in blood to protect and restore the blood-brain barrier following TBI.  I am hopeful that further preclinical studies will confirm these data and lead to a new type of drug therapy based on inhibitors of the sEH enzyme.” 

“Clinical studies for TBI may still be a year or so away,” Schmidt added, “but EicOsis has an sEH inhibitor in early clinical development that may be suitable in the future for evaluation in patients with TBI.” 

Hammock and colleague Sarjeet Gill co-discovered sEH in 1969 when they were researching insect developmental biology and green insecticides in the UC Berkeley lab of John Casida (1929-2018).

The enzyme is a key regulatory enzyme involved in the metabolism of fatty acids. It regulates a new class of natural chemical mediators, which in turn regulates inflammation, blood pressure and pain.  The epoxy fatty acids control blood pressure, fibrosis, immunity, tissue growth, depression, pain, and inflammation, to name a few processes, Hammock said.

Resources:
PNAS paper: https://doi.org/10.1073/pnas.2301360120 
Traumatic Brain Injury, National Institutes of Health 
Traumatic Brain Injury, Mayo Clinic

Contacts: 
Bruce Hammock, PhD: bdhammock@ucdavis.edu 
Irene Cortés-Puch, M.D., EicOsis: icortespuch@eicosis.com