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.