Blood–brain barrier disruption results in delayed functional and structural alterations in the rat neocortex

Disruption of the blood-brain barrier (BBB) is a characteristic finding in common neurological disorders. Human data suggest BBB disruption may underlie cerebral dysfunction. Animal experiments show the development of epileptiform activity following BBB breakdown. In the present study we investigated the neurophysiological, structural and functional consequences of BBB disruption. Adult rats underwent focal BBB disruption in the rat sensory-motor cortex using the bile salt sodium deoxycholate (DOC). Magnetic resonance imaging in-vivo showed an early BBB disruption with delayed reduction in cortical volume. This was associated with a reduced number of neurons and an increased number of astrocytes. In-vitro experiments showed that the threshold for spreading depression and the propagation velocity of the evoked epileptic potentials were increased 1 month after treatment. Furthermore, animals' motor functions deteriorated during the first few weeks following BBB disruption. Treatment with serum albumin resulted in a similar cell loss confirming that the effect of DOC was due to opening of the BBB. Our findings suggest that delayed neurodegeneration and functional impairment occur following the development of the epileptic focus in the BBB-permeable cerebral cortex.

[1]  U. Heinemann,et al.  Optical Imaging Reveals Characteristic Seizure Onsets, Spread Patterns, and Propagation Velocities in Hippocampal–Entorhinal Cortex Slices of Juvenile Rats , 2000, Neurobiology of Disease.

[2]  T. Gabrielsen,et al.  Seizure induced disruption of blood-brain barrier demonstrated by CT. , 1989, Journal of computer assisted tomography.

[3]  W T Blume,et al.  Amygdaloid sclerosis in temporal lobe epilepsy , 1993, Annals of neurology.

[4]  B W Connors,et al.  Layer‐Specific Pathways for the Horizontal Propagation of Epileptiform Discharges in Neocortex , 1998, Epilepsia.

[5]  R. Zappulla,et al.  Electroencephalographic consequences of sodium dehydrocholate-induced blood-brain barrier disruption: Part 2. Generation and propagation of spike activity after the topical application of sodium dehydrocholate. , 1985, Neurosurgery.

[6]  K. Hynynen,et al.  Targeted delivery of antibodies through the blood-brain barrier by MRI-guided focused ultrasound. , 2006, Biochemical and biophysical research communications.

[7]  D. Prince,et al.  The lateral spread of ictal discharges in neocortical brain slices , 1990, Epilepsy Research.

[8]  T. Erkinjuntti,et al.  Serum and cerebrospinal fluid proteins and the blood-brain barrier in Alzheimer's disease and multi-infarct dementia. , 1987, European neurology.

[9]  Jens P Dreier,et al.  Lasting Blood-Brain Barrier Disruption Induces Epileptic Focus in the Rat Somatosensory Cortex , 2004, The Journal of Neuroscience.

[10]  R. Simon,et al.  Epilepsy and Apoptosis Pathways , 2005, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[11]  N. Abbott,et al.  Astrocyte–endothelial interactions and blood–brain barrier permeability * , 2002 .

[12]  B. Connors,et al.  Periodicity and directionality in the propagation of epileptiform discharges across neocortex. , 1988, Journal of neurophysiology.

[13]  W. Hauser,et al.  A population-based study of seizures after traumatic brain injuries. , 1998, The New England journal of medicine.

[14]  D. Kaufer,et al.  Frequent Blood–Brain Barrier Disruption in the Human Cerebral Cortex , 2001, Cellular and Molecular Neurobiology.

[15]  D. Prince,et al.  Epileptogenesis in chronically injured cortex: in vitro studies. , 1993, Journal of neurophysiology.

[16]  R. Zappulla,et al.  Electroencephalographic consequences of sodium dehydrocholate-induced blood-brain barrier disruption: Part 1. Acute and chronic effects of intracarotid sodium dehydrocholate. , 1985, Neurosurgery.

[17]  M. Holtkamp,et al.  Transient loss of inhibition precedes spontaneous seizures after experimental status epilepticus , 2005, Neurobiology of Disease.

[18]  M. Hildebrandt,et al.  Neuropathological spectrum of cortical dysplasia in children with severe focal epilepsies , 2005, Acta Neuropathologica.

[19]  A. Logan,et al.  Chronic fatigue syndrome: neurological findings may be related to blood--brain barrier permeability. , 2001, Medical hypotheses.

[20]  M. Gutnick,et al.  Long-term changes in neocortical activity after chemical kindling with systemic pentylenetetrazole: an in vitro study. , 1994, Journal of neurophysiology.

[21]  D A Turner,et al.  Similar propagation of SD and hypoxic SD-like depolarization in rat hippocampus recorded optically and electrically. , 1998, Journal of neurophysiology.

[22]  I. Bechmann,et al.  Reactive astrocytes upregulate fas (CD95) and fas ligand (CD95L) expression but do not undergo programmed cell death during the course of anterograde degeneration , 2000, Glia.

[23]  E. Neuwelt Mechanisms of Disease: The Blood-Brain Barrier , 2004, Neurosurgery.

[24]  U. Heinemann,et al.  Persistent BBB disruption may underlie alpha interferon-induced seizures , 2005, Journal of Neurology.

[25]  H. Konno,et al.  Sequelae of the osmotic blood-brain barrier opening in rats. , 1988, Journal of neurosurgery.

[26]  K. Teramura,et al.  Neurotoxicity of serum components, comparison between CA1 and striatum. , 1997, Acta neurochirurgica. Supplement.

[27]  M. Gomori,et al.  In vivo assessment of the window of barrier opening after osmotic blood-brain barrier disruption in humans. , 2000, Journal of neurosurgery.

[28]  E. Shohami,et al.  Long-term effect of HU-211, a novel non-competitive NMDA antagonist, on motor and memory functions after closed head injury in the rat , 1995, Brain Research.

[29]  Christian E Elger,et al.  Chronic epilepsy and cognition , 2004, The Lancet Neurology.

[30]  R. Raghupathi,et al.  Cell Death Mechanisms Following Traumatic Brain Injury , 2004, Brain pathology.

[31]  A. Friedman,et al.  Pyridostigmine enhances glutamatergic transmission in hippocampal CA1 neurons , 2003, Experimental Neurology.

[32]  W. Pardridge Molecular biology of the blood-brain barrier. , 2005, Molecular biotechnology.

[33]  R. Pascual-Marqui,et al.  Focal Cortical Dysfunction and Blood–Brain Barrier Disruption in Patients With Postconcussion Syndrome , 2005, Journal of clinical neurophysiology : official publication of the American Electroencephalographic Society.

[34]  Roberto Spreafico,et al.  Damage, Reorganization, and Abnormal Neocortical Hyperexcitability in the Pilocarpine Model of Temporal Lobe Epilepsy , 2002, Epilepsia.

[35]  Y. Ben-Ari,et al.  Glial reaction after seizure induced hippocampal lesion: immunohistochemical characterization of proliferating glial cells , 1994, Journal of neurocytology.

[36]  U. Dirnagl,et al.  Pathophysiology of Stroke: Lessons from Animal Models , 2004, Metabolic Brain Disease.

[37]  Cenk Ayata,et al.  Ischaemic brain oedema , 2002, Journal of Clinical Neuroscience.

[38]  Hermona Soreq,et al.  Pyridostigmine brain penetration under stress enhances neuronal excitability and induces early immediate transcriptional response , 1996, Nature Medicine.

[39]  D. Olton,et al.  Repeated exposure to diisopropylfluorophosphate (DFP) produces increased sensitivity to cholinergic antagonists in discrimination retention and reversal , 2005, Psychopharmacology.

[40]  M. Nedergaard,et al.  The blood–brain barrier: an overview Structure, regulation, and clinical implications , 2004, Neurobiology of Disease.

[41]  M. Gutnick,et al.  Non-uniform propagation of epileptiform discharge in brain slices of rat neocortex , 1993, Neuroscience.

[42]  J. Greenwood,et al.  The Effect of Bile Salts on the Permeability and Ultrastructure of the Perfused, Energy-Depleted, Rat Blood-Brain Barrier , 1991, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[43]  Ulrich Dirnagl,et al.  Increased Extracellular K+ Concentration Reduces the Efficacy of N-methyl-d-aspartate Receptor Antagonists to Block Spreading Depression-Like Depolarizations and Spreading Ischemia , 2005, Stroke.

[44]  D. Kaufer,et al.  Blood-Brain Barrier Modulations and Low- Level Exposure to Xenobiotics , 2000 .

[45]  J. Bureš,et al.  Reduced incidence of cortical spreading depression in the course of pentylenetetrazol kindling in rats , 1993, Brain Research.

[46]  J. Lafuente,et al.  Traumatic brain injuries: structural changes , 1991, Journal of the Neurological Sciences.

[47]  E. Cavalheiro,et al.  Blockade of spreading depression in chronic epileptic rats: reversion by diazepam , 1997, Epilepsy Research.

[48]  M. Gutnick,et al.  Hyperexcitability in a model of cortical maldevelopment. , 1996, Cerebral cortex.

[49]  R. Dingledine,et al.  Neuronal and glial pathological changes during epileptogenesis in the mouse pilocarpine model , 2003, Experimental Neurology.

[50]  G. Somjen Mechanisms of spreading depression and hypoxic spreading depression-like depolarization. , 2001, Physiological reviews.

[51]  B. Connors,et al.  Electrophysiological properties of neocortical neurons in vitro. , 1982, Journal of neurophysiology.

[52]  R. Kalaria,et al.  Blood‐Brain Barrier Abnormalities in Alzheimer's Disease a , 1991, Annals of the New York Academy of Sciences.

[53]  T. Lehmann,et al.  Effects of barium, furosemide, ouabaine and 4,4′-diisothiocyanatostilbene-2,2′-disulfonic acid (DIDS) on ionophoretically-induced changes in extracellular potassium concentration in hippocampal slices from rats and from patients with epilepsy , 2002, Brain Research.

[54]  B. Connors,et al.  Mechanisms of neocortical epileptogenesis in vitro. , 1982, Journal of neurophysiology.

[55]  S. Schuchmann,et al.  Cell death and metabolic activity during epileptiform discharges and status epilepticus in the hippocampus. , 2002, Progress in brain research.

[56]  Cornford Em Epilepsy and the blood brain barrier: endothelial cell responses to seizures. , 1999 .