Blood-Brain Barrier Leakage during Early Epileptogenesis Is Associated with Rapid Remodeling of the Neurovascular Unit

Abstract Increased permeability of the blood-brain barrier (BBB) following cerebral injury results in regional extravasation of plasma proteins and can critically contribute to the pathogenesis of epilepsy. Here, we comprehensively explored the spatiotemporal evolution of a main extravasation component, albumin, and illuminate associated responses of the neurovascular unit (NVU) contributing to early epileptogenic neuropathology. We applied translational in vivo MR imaging and complementary immunohistochemical analyses in the widely used rat pilocarpine-post status epilepticus (SE) model. The observed rapid BBB leakage affected major epileptogenesis-associated brain regions, peaked between 1 and 2 days post SE, and rapidly declined thereafter, accompanied by cerebral edema generally following the same time course. At peak of BBB leakage,serum albumin colocalized with NVU constituents, like vascular components, neurons and brain immune cells. Surprisingly, astroglial markers did not colocalize with albumin and aquaporin-4 (AQP4) was clearly reduced in areas of leaky BBB, indicating a severe disturbance of astrocyte-mediated endothelial-neuronal coupling. In addition, a distinct adaptive reorganization process of the NVU vasculature apparently takes place at sites of albumin presence, substantiated by reduced immunoreactivity of endothelial and changes in vascular basement membrane markers. Taken together, degenerative events at the level of the NVU, affecting vessels, astrocytes and neurons, seem to outweigh reconstructive processes. Considering the rapidly occurring BBB leakage and subsequent impairment of the NVU, our data support the necessity of a prompt BBB-restoring treatment as one component of rational therapeutic intervention to prevent epileptogenesis and the development of other detrimental sequelae of SE. Significance Statement Blood-brain barrier (BBB) leakage is critically involved in brain insult-mediated epilepsy development. Here, we demonstrate rapid but transient BBB damage within hours after experimental status epilepticus (SE), an epileptogenic insult, and subsequent degenerative events at the level of the so called neurovascular unit (NVU), which reflects the anatomic and functional interplay between brain vasculature, glial cells and neurons. Analyses at cellular level revealed degeneration of various NVU components, which seem to outweigh reconstructive processes, thus providing potential targets for protective pharmacotherapy. The findings emphasize the requirement and expedience of rapid BBB-stabilizing treatment as a primary element of epilepsy-preventive therapeutic interventions.