| Autor: |
Bankstahl M; Department of Pharmacology, Toxicology and Pharmacy, University of Veterinary Medicine Hannover and Center for Systems Neuroscience, Bünteweg 17, Hannover, 30559, Germany., Breuer H; Department of Pharmacology, Toxicology and Pharmacy, University of Veterinary Medicine Hannover and Center for Systems Neuroscience, Bünteweg 17, Hannover, 30559, Germany.; Department of Nuclear Medicine, Hannover Medical School, Hannover, 30625, Germany., Leiter I; Department of Pharmacology, Toxicology and Pharmacy, University of Veterinary Medicine Hannover and Center for Systems Neuroscience, Bünteweg 17, Hannover, 30559, Germany.; Department of Nuclear Medicine, Hannover Medical School, Hannover, 30625, Germany., Märkel M; Paul Flechsig Institute for Brain Research, University of Leipzig, Liebigstr. 19, Leipzig, 04103, Germany., Bascuñana P; Department of Nuclear Medicine, Hannover Medical School, Hannover, 30625, Germany., Michalski D; Department of Neurology, University of Leipzig, Liebigstr. 20, Leipzig, 04103, Germany., Bengel FM; Department of Nuclear Medicine, Hannover Medical School, Hannover, 30625, Germany., Löscher W; Department of Pharmacology, Toxicology and Pharmacy, University of Veterinary Medicine Hannover and Center for Systems Neuroscience, Bünteweg 17, Hannover, 30559, Germany., Meier M; Preclinical Imaging Labs, Central Laboratory Animal Facility & Institute for Laboratory Animal Science, Hannover Medical School, Hannover, 30625, Germany., Bankstahl JP; Department of Nuclear Medicine, Hannover Medical School, Hannover, 30625, Germany., Härtig W; Paul Flechsig Institute for Brain Research, University of Leipzig, Liebigstr. 19, Leipzig, 04103, Germany. |
| Abstrakt: |
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. |
