RT Journal Article
SR Electronic
T1 Blood–Brain Barrier Leakage during Early Epileptogenesis Is Associated with Rapid Remodeling of the Neurovascular Unit
JF eneuro
JO eNeuro
FD Society for Neuroscience
SP ENEURO.0123-18.2018
DO 10.1523/ENEURO.0123-18.2018
VO 5
IS 3
A1 Marion Bankstahl
A1 Heike Breuer
A1 Ina Leiter
A1 Martin Märkel
A1 Pablo Bascuñana
A1 Dominik Michalski
A1 Frank M. Bengel
A1 Wolfgang Löscher
A1 Martin Meier
A1 Jens P. Bankstahl
A1 Wolfgang Härtig
YR 2018
UL http://www.eneuro.org/content/5/3/ENEURO.0123-18.2018.abstract
AB 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 explore 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 d 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, such as 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.