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Microvascular stabilization via blood-brain barrier regulation prevents seizure activity

Greene, Chris (author)
Trinity Coll Dublin, Smurfit Inst Genet, Dublin 2, Ireland.
Hanley, Nicole (author)
Trinity Coll Dublin, Smurfit Inst Genet, Dublin 2, Ireland.
Reschke, Cristina R. (author)
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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Reddy, Avril (author)
Trinity Coll Dublin, Smurfit Inst Genet, Dublin 2, Ireland.
Andaloussi Mäe, Maarja (author)
Uppsala universitet,Vaskulärbiologi
Connolly, Ruairi (author)
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.
Behan, Claire (author)
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.
O'Keeffe, Eoin (author)
Trinity Coll Dublin, Smurfit Inst Genet, Dublin 2, Ireland.
Bolger, Isobel (author)
Trinity Coll Dublin, Smurfit Inst Genet, Dublin 2, Ireland.
Hudson, Natalie (author)
Trinity Coll Dublin, Smurfit Inst Genet, Dublin 2, Ireland.
Delaney, Conor (author)
Trinity Coll Dublin, Smurfit Inst Genet, Dublin 2, Ireland.
Farrell, Michael A. (author)
Beaumont Hosp, Dept Neuropathol, Dublin, Ireland.
O'Brien, Donncha F. (author)
Beaumont Hosp, Dept Neurosurg, Dublin, Ireland.
Cryan, Jane (author)
Beaumont Hosp, Dept Neuropathol, Dublin, Ireland.
Brett, Francesca M. (author)
Beaumont Hosp, Dept Neuropathol, Dublin, Ireland.
Beausang, Alan (author)
Beaumont Hosp, Dept Neuropathol, Dublin, Ireland.
Betsholtz, Christer (author)
Uppsala universitet,Vaskulärbiologi
Henshall, David C. (author)
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.
Doherty, Colin P. (author)
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.
Campbell, Matthew (author)
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.
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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. (creator_code:org_t)
2022-04-14
2022
English.
In: Nature Communications. - : Springer Nature. - 2041-1723. ; 13
Related links:
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  • Journal article (peer-reviewed)
Abstract Subject headings
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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.

Subject headings

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Neurologi (hsv//swe)
MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Neurology (hsv//eng)

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art (subject category)

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