Department Of Emergency Medicine

Neurotrauma and Brain Barriers Research Laboratory

The Neurotrauma and Brain Barriers Research Laboratory was established in 2008 at the Department of Emergency Medicine and is directed by Dr. Adam Chodobski. Our laboratory is located on the Rhode Island Hospital Campus in Coro West, Suite 112. Our research focuses on dysfunction of the blood-brain barrier resulting from neurotrauma, post-traumatic brain edema, and neuroinflammation.

• Adam Chodobski, Ph.D.

Dr. Chodobski is an Associate Professor in the Department of Emergency Medicine and is a trainer in the Molecular Pharmacology and Physiology Graduate Program at Brown University. Native of Poland, he received his Master's Degree in Biomedical Engineering from the Technical University in Warsaw and a Ph.D. degree in Neuroscience from Medical School of Warsaw. He spent two years as a post-doctoral fellow at the Howard Florey Institute of Experimental Physiology and Medicine in Melbourne, Australia. He was also a recipient of the Wellcome Trust grant to conduct research in the Department of Physiology at St Thomas's Hospital in London, UK. Dr. Chodobski joined the faculty at Alpert Medical School of Brown University in 1995. He is a member of several professional societies and served as a reviewer at various study sections at the NIH. He has edited a book on the blood-cerebrospinal fluid barrier. His research is supported by NIH. In 1999 Dr. Chodobski and his wife Dr. Joanna Szmydynger-Chodobska established a new Gordon Research Conference Series on "Barriers of the CNS." This conference has become one of two major international conferences on brain barriers, attracting many scientists in the field from and outside the US.



• Joanna Szmydynger-Chodobska, Ph.D.

Dr. Szmydynger-Chodobska is an Assistant Professor in the Department of Emergency Medicine at Brown University. Like her husband Dr. Adam Chodobski, she is native of Poland. She received her Master's Degree in Biology from Warsaw University and a Ph.D. degree in Neuroscience from Medical School of Warsaw. She pursued her pre-doctoral training at the Howard Florey Institute of Experimental Physiology and Medicine in Melbourne, Australia, where she accompanied her husband, working on water and electrolyte balance in the brain. Dr. Chodobska joined the faculty at Alpert Medical School of Brown University in 1995. She is a member of several professional societies and published articles in various scientific journals. In 1999 Dr. Szmydynger-Chodobska together with her husband Dr. Adam Chodobski established and co-chaired a new Gordon Research Conference Series on "Barriers of the CNS."



• Brian Zink, M.D.

Dr. Brian Zink is Professor and Chair of the Department of Emergency Medicine at Brown University, and Chief of Emergency Medicine at Rhode Island and The Miriam Hospitals. He received his M.D. from the University of Rochester, and did his emergency medicine residency at the University of Cincinnati program, where he was a Chief Resident in 1987–88. Previously, Dr. Zink has served as Assistant Dean for Medical Student Career Development, Associate Dean for Student Programs and Director of Student Biomedical Research Programs at the University of Michigan Medical School. He is a member of numerous professional societies and advisory boards. He has expertise both in clinical and experimental traumatic brain injury with particular interest in the role of alcohol in TBI. He collaborates with Drs. Chodobski on translational aspects of research on TBI.

• Otis Warren, MD.

Otis Warren MD is an Assistant Professor of Clinical Medicine at Brown University in the department of emergency medicine. He did his residency at Alameda County Medical Center in Oakland, CA and graduated from the University of Pennsylvania School of Medicine in 2005. His research interests are related to the clinical evaluation of alcohol-intoxicated patients, and the relation to traumatic brain injury. His involvement with the Chodobski lab is in clinical research on inflammatory mediators of traumatic brain injury.

• Jean-Francois Ghersi-Egea, Pharm.D., Ph.D.

Dr. Ghersi-Egea is the Head of the Neurooncology and Neuroinflammation Program and the Blood-Brain Interface Group at INSERM, Lyon University, France. His interest is in pathophysiology and pharmacology of the blood-brain and blood-cerebrospinal fluid barriers. Dr. Ghersi-Egea collaborates with Drs. Chodobski on various projects concerning the role of the blood-cerebrospinal fluid barrier in traumatic brain injury. These studies focus on post-traumatic production of proinflammatory mediators and invasion of inflammatory cells.

• Nathalie Strazielle, Pharm.D., Ph.D.

Dr. Strazielle is an independent investigator and the Head of Brain-I R&D in Neuropharmacology at INSERM, Lyon University, France. She is an expert in the in vitro models of brain barriers. She studies the metabolism and transport of drugs and endogenous factors across the blood-cerebrospinal fluid barrier. Her company offers research and development services to both the academia and industry.

• Danica Stanimirovic, M.D., Ph.D.

Dr. Stanimirovic is the Director of Neurobiology Program at the Institute for Biological Sciences, National Research Council of Canada. She is an expert in proteomics of the blood-brain barrier. Dr. Stanimirovic collaborates with Drs. Chodobski on proteomic analysis of vasopressin-dependent changes in BBB function.

• Alpert Medical School of Brown University


• Research at Brown

Areas of Research

• Dysfunction of the Blood-Brain Barrier and Edema Formation after Neurotrauma

Dysfunction of the Blood-Brain Barrier and Edema Formation after Neurotrauma Traumatic brain injury (TBI) is the leading cause of death and long-term disability in developed countries, particularly affecting the young population and elderly. One of the major clinical problems associated with TBI, as well as other types of brain injury, such as subarachnoid or intracerebral hemorrhage and ischemic stroke, is the formation of cerebral edema. Although the cellular and molecular events leading to edema may slightly differ in various forms of brain injury, the end result is similar – a rapid swelling of neural tissue, which, when uncontrolled, may result in death. Despite many years of intense research, no effective therapies have been devised to combat this condition. One of the key mechanisms underlying the formation of edema occurring after brain injury is disruption of the blood brain barrier (BBB). The BBB constitutes both the anatomical and functional barrier, playing an essential role in maintaining an optimal environment for neurons and glia. It tightly regulates the composition of brain fluids by controlling selective access of blood-borne ions, nutrients, and polypeptides to brain parenchyma. The BBB is also involved in removal of potentially noxious metabolites from brain parenchyma and prevents the entry of neurotoxic plasma constituents and xenobiotics to the central nervous system (CNS). The major components of the BBB are tight junctions located between adjacent endothelial cells of brain microvessels. However, the endothelial cells alone are not sufficient to maintain the BBB integrity. It has been well documented that astrocytes, whose foot processes are intimately associated with brain endothelium, critically contribute to the tightness of the BBB. Astrocytes can also release chemical factors that regulate other properties of the BBB, such as transport activities and endothelial interactions with circulating immune cells. Because of this close anatomical and functional relationship between the cerebrovascular endothelium and astrocytes, a new term, the gliovascular unit, has been proposed. After injury, the integrity of BBB is compromised, which results in increased permeability to the low- and high-molecular weight molecules and the formation of vasogenic edema. Multiple factors, including reactive oxygen species, proinflammatory cytokines, vascular endothelial growth factor, and matrix metalloproteinases, have been implicated in the leakage of the BBB observed after injury. In our laboratory, we are interested in how arginine vasopressin (AVP) contributes to the formation of post-traumatic edema. Over the years experimental evidence has accumulated supporting an important role for AVP in promoting disruption of the BBB, exacerbating cerebral edema, and increasing the loss of neural tissue in various forms/models of brain injury, such as cerebral ischemia, intracerebral hemorrhage, and cryogenic or traumatic injury. Animal studies have demonstrated that AVP contributes to 40–60% of increased BBB permeability and 30–40% of edema, and to 40–70% of the size of post-ischemic infarct or post-traumatic lesion. Consistent with these findings, we have shown that, after injury, the synthesis of AVP and the expression of AVP receptors in the brain are significantly upregulated. The cellular and molecular mechanisms underlying the pathophysiological actions of AVP on an injured brain remain largely unknown. Specifically, it is not known (1) How AVP increases the permeability of the BBB and exacerbates cerebral edema; (2) Which signal transduction pathways or effector proteins mediate these AVP actions; and (3) Whether AVP only exacerbates the formation of vasogenic edema or also contributes to the formation of cytotoxic edema. To answer these questions, we use the controlled cortical impact model of brain injury in rodents. In these experiments, we employ a genetic model of AVP deficiency, the Brattleboro rat. In Brattleboro rats, the AVP gene is mutated, which prevents the production of biologically active hormone. We also conduct experiments on cultures of brain endothelium and astrocytes to obtain a comprehensive insight into the cellular and molecular mechanisms underlying the AVP-dependent formation of brain edema.



• Traumatic Brain Injury and Neuroinflammation

Traumatic Brain Injury and Neuroinflammation Research involving the animal models of brain injury as well as clinical studies of patients with TBI have demonstrated that neurotrauma results in a rapid and substantial increase in CNS synthesis of proinflammatory cytokines, such as interleukin-1β and tumor necrosis factor-α. Shortly after the injury, there is a surge in production of proinflammatory cytokines in the injured brain parenchyma and their expression continues to be upregulated for several days after trauma. Proinflammatory cytokines not only promote an acute and delayed neuronal death, but can also interfere with survival signals generated by growth factors. In addition, proinflammatory cytokines exert various adverse effects on the BBB, including disruption of tight junctions and increase in the BBB permeability, the induction of expression of cell adhesion molecules, and production of chemokines. Although the role of proinflammatory cytokines in neuronal repair and long-term recovery is not completely understood, an early anti-inflammatory intervention has demonstrated beneficial effects in TBI. Dysfunction of the BBB observed after injury is central to the progression of post-traumatic neuroinflammation. Brain endothelium itself can be an important source of proinflammatory mediators, such as neutrophil and monocyte chemoattractants. Increased production of chemokines and augmented expression of cell adhesion molecules on the surface of cerebrovascular endothelium promote invasion of inflammatory cells with detrimental consequences to the integrity of neural tissue. Our laboratory has demonstrated that AVP contributes to dysfunction of the BBB by amplifying the synthesis of proinflammatory mediators and, consequently, promoting the invasion of inflammatory cells. However, the nature of these proinflammatory mediators and the signaling cascades involved are yet to be completely elucidated. We have also shown that AVP increases the loss of neural tissue occurring after injury, but it is currently unclear whether this phenomenon is related to AVP-mediated exacerbation of edema and inflammatory response or is associated with other AVP-dependent pathophysiological mechanisms. Our current investigations focus on answering these questions. If you would like to learn more about our research or become involved in our projects, please call at -401-444-4285 or contact us via e-mail at adam_chodobski@brown.edu or joanna_szmydynger-chodobska@brown.edu

Chodobski A, Chung I, Kozniewska E, Ivanenko T, Chang W, Harrington JF, Duncan JA, Szmydynger-Chodobska J. (2003):
 Early neutrophilic expression of vascular endothelial growth factor after traumatic brain injury.
Neuroscience 122: 853–867.

Szmydynger-Chodobska J, Chung I, Kozniewska E, Tran B, Harrington JF, Duncan JA, Chodobski A. (2004):
 Increased expression of vasopressin V1a receptors after traumatic brain injury. J. Neurotrauma 21: 1090–1102.

Redzic ZB, Preston JE, Duncan JA, Chodobski A, and Szmydynger-Chodobska J. (2005):
 The choroid plexus-CSF system: from development to aging.
Curr. Top. Dev. Biol. 71: 1–52.

Chodobski A. (2006):
  Possible new mechanism underlying hypertonic saline therapy for cerebral edema.
J. Appl.Physiol. 100: 1437–1438.

Szmydynger-Chodobska J, Strazielle N, Zink BJ, Ghersi-Egea JF, Chodobski A. (2009):
  The role of the choroid plexus in neutrophil invasion following traumatic brain injury.
J Cereb. Blood Flow Metab. 29: 1503–1516.

Szmydynger-Chodobska J., Fox L.M., Lynch K.M., Zink B.J., and Chodobski A. (2010): Vasopressin Amplifies the Production of Proinflammatory Mediators in Traumatic Brain Injury. J Neurotrauma 27:1449–1461.

Szmydynger-Chodobska J., Zink B.J., and Chodobski A. (2010): Multiple sites of vasopressin synthesis in the injured brain. J. Cerebral Blood Flow and Metabolism,: 1–5.