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Microvascular stabi...
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Greene, ChrisTrinity Coll Dublin, Smurfit Inst Genet, Dublin 2, Ireland.
(author)
Microvascular stabilization via blood-brain barrier regulation prevents seizure activity
- Article/chapterEnglish2022
Publisher, publication year, extent ...
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2022-04-14
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Springer Nature,2022
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electronicrdacarrier
Numbers
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LIBRIS-ID:oai:DiVA.org:uu-473556
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https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-473556URI
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https://doi.org/10.1038/s41467-022-29657-yDOI
Supplementary language notes
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Language:English
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Summary in:English
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Subject category:ref swepub-contenttype
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Subject category:art swepub-publicationtype
Notes
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Blood-brain barrier (BBB) dysfunction is associated with worse epilepsy outcomes however the underlying molecular mechanisms of BBB dysfunction remain to be elucidated. Tight junction proteins are important regulators of BBB integrity and in particular, the tight junction protein claudin-5 is the most enriched in brain endothelial cells and regulates size-selectivity at the BBB. Additionally, disruption of claudin-5 expression has been implicated in numerous disorders including schizophrenia, depression and traumatic brain injury, yet its role in epilepsy has not been fully deciphered. Here we report that claudin-5 protein levels are significantly diminished in surgically resected brain tissue from patients with treatment-resistant epilepsy. Concomitantly, dynamic contrast-enhanced MRI in these patients showed widespread BBB disruption. We show that targeted disruption of claudin-5 in the hippocampus or genetic heterozygosity of claudin-5 in mice exacerbates kainic acid-induced seizures and BBB disruption. Additionally, inducible knockdown of claudin-5 in mice leads to spontaneous recurrent seizures, severe neuroinflammation, and mortality. Finally, we identify that RepSox, a regulator of claudin-5 expression, can prevent seizure activity in experimental epilepsy. Altogether, we propose that BBB stabilizing drugs could represent a new generation of agents to prevent seizure activity in epilepsy patients.
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Hanley, NicoleTrinity Coll Dublin, Smurfit Inst Genet, Dublin 2, Ireland.
(author)
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Reschke, Cristina R.Univ Med & Hlth Sci, Sci Fdn Ireland Res Ctr Chron & Rare Neurol Dis, Royal Coll Surg Ireland, FutureNeuro, Dublin, Ireland.;RCSI Univ Med & Hlth Sci, Sch Pharm & Biomol Sci, Dublin 2, Ireland.
(author)
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Reddy, AvrilTrinity Coll Dublin, Smurfit Inst Genet, Dublin 2, Ireland.
(author)
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Andaloussi Mäe, MaarjaUppsala universitet,Vaskulärbiologi(Swepub:uu)maaan970
(author)
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Connolly, RuairiUniv Med & Hlth Sci, Sci Fdn Ireland Res Ctr Chron & Rare Neurol Dis, Royal Coll Surg Ireland, FutureNeuro, Dublin, Ireland.;St James Hosp, Dept Neurol, Hlth Care Ctr, Hosp 5, Dublin 8, Ireland.;Trinity Coll Dublin, Biomed Sci Inst, Acad Unit Neurol, Room 5-41, Dublin 2, Ireland.
(author)
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Behan, ClaireUniv Med & Hlth Sci, Sci Fdn Ireland Res Ctr Chron & Rare Neurol Dis, Royal Coll Surg Ireland, FutureNeuro, Dublin, Ireland.;St James Hosp, Dept Neurol, Hlth Care Ctr, Hosp 5, Dublin 8, Ireland.;Trinity Coll Dublin, Biomed Sci Inst, Acad Unit Neurol, Room 5-41, Dublin 2, Ireland.
(author)
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O'Keeffe, EoinTrinity Coll Dublin, Smurfit Inst Genet, Dublin 2, Ireland.
(author)
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Bolger, IsobelTrinity Coll Dublin, Smurfit Inst Genet, Dublin 2, Ireland.
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Hudson, NatalieTrinity Coll Dublin, Smurfit Inst Genet, Dublin 2, Ireland.
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Delaney, ConorTrinity Coll Dublin, Smurfit Inst Genet, Dublin 2, Ireland.
(author)
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Farrell, Michael A.Beaumont Hosp, Dept Neuropathol, Dublin, Ireland.
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O'Brien, Donncha F.Beaumont Hosp, Dept Neurosurg, Dublin, Ireland.
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Cryan, JaneBeaumont Hosp, Dept Neuropathol, Dublin, Ireland.
(author)
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Brett, Francesca M.Beaumont Hosp, Dept Neuropathol, Dublin, Ireland.
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Beausang, AlanBeaumont Hosp, Dept Neuropathol, Dublin, Ireland.
(author)
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Betsholtz, ChristerUppsala universitet,Vaskulärbiologi(Swepub:uu)chbet517
(author)
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Henshall, David C.Univ Med & Hlth Sci, Sci Fdn Ireland Res Ctr Chron & Rare Neurol Dis, Royal Coll Surg Ireland, FutureNeuro, Dublin, Ireland.;RCSI Univ Med & Hlth Sci, Dept Physiol & Med Phys, Dublin 2, Ireland.
(author)
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Doherty, Colin P.Univ Med & Hlth Sci, Sci Fdn Ireland Res Ctr Chron & Rare Neurol Dis, Royal Coll Surg Ireland, FutureNeuro, Dublin, Ireland.;St James Hosp, Dept Neurol, Hlth Care Ctr, Hosp 5, Dublin 8, Ireland.;Trinity Coll Dublin, Biomed Sci Inst, Acad Unit Neurol, Room 5-41, Dublin 2, Ireland.
(author)
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Campbell, MatthewTrinity Coll Dublin, Smurfit Inst Genet, Dublin 2, Ireland.;Univ Med & Hlth Sci, Sci Fdn Ireland Res Ctr Chron & Rare Neurol Dis, Royal Coll Surg Ireland, FutureNeuro, Dublin, Ireland.
(author)
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Trinity Coll Dublin, Smurfit Inst Genet, Dublin 2, Ireland.Univ Med & Hlth Sci, Sci Fdn Ireland Res Ctr Chron & Rare Neurol Dis, Royal Coll Surg Ireland, FutureNeuro, Dublin, Ireland.;RCSI Univ Med & Hlth Sci, Sch Pharm & Biomol Sci, Dublin 2, Ireland.
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In:Nature Communications: Springer Nature132041-1723
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Greene, Chris
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Hanley, Nicole
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Reschke, Cristin ...
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Reddy, Avril
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Andaloussi Mäe, ...
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Connolly, Ruairi
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Behan, Claire
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O'Keeffe, Eoin
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Bolger, Isobel
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Hudson, Natalie
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Delaney, Conor
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Farrell, Michael ...
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O'Brien, Donncha ...
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Cryan, Jane
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Brett, Francesca ...
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Beausang, Alan
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Betsholtz, Chris ...
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Henshall, David ...
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Doherty, Colin P ...
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Campbell, Matthe ...
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