Lasting Blood-Brain Barrier Disruption Induces Epileptic Focus in the Rat Somatosensory Cortex
Perturbations in the integrity of the blood-brain barrier have been reported in both humans and animals under numerous pathological conditions. Although the blood-brain barrier prevents the penetration of many blood constituents into the brain extracellular space, the effect of such perturbations on...
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description | Perturbations in the integrity of the blood-brain barrier have been reported in both humans and animals under numerous pathological conditions. Although the blood-brain barrier prevents the penetration of many blood constituents into the brain extracellular space, the effect of such perturbations on the brain function and their roles in the pathogenesis of cortical diseases are unknown. In this study we established a model for focal disruption of the blood-brain barrier in the rat cortex by direct application of bile salts. Exposure of the cerebral cortex in vivo to bile salts resulted in long-lasting extravasation of serum albumin to the brain extracellular space and was associated with a prominent activation of astrocytes with no inflammatory response or marked cell loss. Using electrophysiological recordings in brain slices we found that a focus of epileptiform discharges developed within 4-7 d after treatment and could be recorded up to 49 d postoperatively in >60% of slices from treated animals but only rarely (10%) in sham-operated controls. Epileptiform activity involved both glutamatergic and GABAergic neurotransmission. Epileptiform activity was also induced by direct cortical application of native serum, denatured serum, or albumin-containing solution. In contrast, perfusion with serum-adapted electrolyte solution did not induce abnormal activity, thereby suggesting that the exposure of the serum-devoid brain environment to serum proteins underlies epileptogenesis in the blood-brain barrier-disrupted cortex. Although many neuropathologies entail a compromised blood-brain barrier, this is the first direct evidence that it may have a role in the pathogenesis of focal cortical epilepsy, a common neurological disease. |
doi_str_mv | 10.1523/JNEUROSCI.1751-04.2004 |
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Although the blood-brain barrier prevents the penetration of many blood constituents into the brain extracellular space, the effect of such perturbations on the brain function and their roles in the pathogenesis of cortical diseases are unknown. In this study we established a model for focal disruption of the blood-brain barrier in the rat cortex by direct application of bile salts. Exposure of the cerebral cortex in vivo to bile salts resulted in long-lasting extravasation of serum albumin to the brain extracellular space and was associated with a prominent activation of astrocytes with no inflammatory response or marked cell loss. Using electrophysiological recordings in brain slices we found that a focus of epileptiform discharges developed within 4-7 d after treatment and could be recorded up to 49 d postoperatively in >60% of slices from treated animals but only rarely (10%) in sham-operated controls. Epileptiform activity involved both glutamatergic and GABAergic neurotransmission. Epileptiform activity was also induced by direct cortical application of native serum, denatured serum, or albumin-containing solution. In contrast, perfusion with serum-adapted electrolyte solution did not induce abnormal activity, thereby suggesting that the exposure of the serum-devoid brain environment to serum proteins underlies epileptogenesis in the blood-brain barrier-disrupted cortex. Although many neuropathologies entail a compromised blood-brain barrier, this is the first direct evidence that it may have a role in the pathogenesis of focal cortical epilepsy, a common neurological disease.</description><identifier>ISSN: 0270-6474</identifier><identifier>EISSN: 1529-2401</identifier><identifier>DOI: 10.1523/JNEUROSCI.1751-04.2004</identifier><identifier>PMID: 15356194</identifier><language>eng</language><publisher>United States: Soc Neuroscience</publisher><subject>2-Amino-5-phosphonovalerate - pharmacology ; 6-Cyano-7-nitroquinoxaline-2,3-dione - pharmacology ; Animals ; Bicuculline - pharmacology ; Bile Acids and Salts - toxicity ; Blood-Brain Barrier - drug effects ; Blood-Brain Barrier - physiology ; Coloring Agents - pharmacokinetics ; Dehydrocholic Acid - toxicity ; Deoxycholic Acid - toxicity ; Electrophysiology ; Epilepsies, Partial - chemically induced ; Epilepsies, Partial - physiopathology ; Evans Blue - pharmacokinetics ; Excitatory Amino Acid Antagonists - pharmacology ; gamma-Aminobutyric Acid - physiology ; Glutamic Acid - physiology ; Male ; Neurobiology of Disease ; Permeability ; Rats ; Rats, Wistar ; Receptors, AMPA - antagonists & inhibitors ; Receptors, GABA - drug effects ; Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors ; Serum ; Serum Albumin - toxicity ; Somatosensory Cortex - physiopathology</subject><ispartof>The Journal of neuroscience, 2004-09, Vol.24 (36), p.7829-7836</ispartof><rights>Copyright © 2004 Society for Neuroscience 0270-6474/04/247829-08.00/0 2004</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c592t-be3de7db9d1b82b4849d6e65c6ccbc7d0079ce1ee735311cccc6811332d6c3df3</citedby><cites>FETCH-LOGICAL-c592t-be3de7db9d1b82b4849d6e65c6ccbc7d0079ce1ee735311cccc6811332d6c3df3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6729929/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6729929/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,727,780,784,885,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/15356194$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Seiffert, Ernst</creatorcontrib><creatorcontrib>Dreier, Jens P</creatorcontrib><creatorcontrib>Ivens, Sebastian</creatorcontrib><creatorcontrib>Bechmann, Ingo</creatorcontrib><creatorcontrib>Tomkins, Oren</creatorcontrib><creatorcontrib>Heinemann, Uwe</creatorcontrib><creatorcontrib>Friedman, Alon</creatorcontrib><title>Lasting Blood-Brain Barrier Disruption Induces Epileptic Focus in the Rat Somatosensory Cortex</title><title>The Journal of neuroscience</title><addtitle>J Neurosci</addtitle><description>Perturbations in the integrity of the blood-brain barrier have been reported in both humans and animals under numerous pathological conditions. 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Epileptiform activity involved both glutamatergic and GABAergic neurotransmission. Epileptiform activity was also induced by direct cortical application of native serum, denatured serum, or albumin-containing solution. In contrast, perfusion with serum-adapted electrolyte solution did not induce abnormal activity, thereby suggesting that the exposure of the serum-devoid brain environment to serum proteins underlies epileptogenesis in the blood-brain barrier-disrupted cortex. 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subjects | 2-Amino-5-phosphonovalerate - pharmacology 6-Cyano-7-nitroquinoxaline-2,3-dione - pharmacology Animals Bicuculline - pharmacology Bile Acids and Salts - toxicity Blood-Brain Barrier - drug effects Blood-Brain Barrier - physiology Coloring Agents - pharmacokinetics Dehydrocholic Acid - toxicity Deoxycholic Acid - toxicity Electrophysiology Epilepsies, Partial - chemically induced Epilepsies, Partial - physiopathology Evans Blue - pharmacokinetics Excitatory Amino Acid Antagonists - pharmacology gamma-Aminobutyric Acid - physiology Glutamic Acid - physiology Male Neurobiology of Disease Permeability Rats Rats, Wistar Receptors, AMPA - antagonists & inhibitors Receptors, GABA - drug effects Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors Serum Serum Albumin - toxicity Somatosensory Cortex - physiopathology |
title | Lasting Blood-Brain Barrier Disruption Induces Epileptic Focus in the Rat Somatosensory Cortex |
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