Microvascular stabilization via blood-brain barrier regulation prevents seizure activity.pdf (4.55 MB)
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Microvascular stabilization via blood-brain barrier regulation prevents seizure activity

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posted on 07.06.2022, 16:47 authored by Chris Greene, Nicole Hanley, Cristina Ruedell ReschkeCristina Ruedell Reschke, Avril Reddy, Maarja A Mäe, Ruairi Connolly, Claire Behan, Eoin O’Keeffe, Isobel Bolger, Natalie Hudson, Conor Delaney, Michael A Farrell, Donncha O'BrienDonncha O'Brien, Jane CryanJane Cryan, Francesca BrettFrancesca Brett, Alan Beausang, Christer Betsholtz, David HenshallDavid Henshall, Colin P Doherty, Matthew Campbell
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.

Funding

Science Foundation Ireland (SFI), (12/YI/B2614 and 11/PI/1080)

Irish Research Council (IRC)

SFI under grant number 16/RC/3948 and co-funded by European Regional Development fund by FutureNeuro industry partners

European Research Council (ERC) grant, “Retina‐Rhythm” (864522)

History

Comments

The original article is available at https://www.nature.com/

Published Citation

Greene C. et al. Microvascular stabilization via blood-brain barrier regulation prevents seizure activity. Nat Commun. 2022;13(1):2003

Publication Date

14 April 2022

PubMed ID

35422069

Department/Unit

  • Beaumont Hospital
  • FutureNeuro Centre
  • Physiology and Medical Physics
  • School of Pharmacy and Biomolecular Sciences

Research Area

  • Neurological and Psychiatric Disorders

Publisher

Nature Pub. Group

Version

  • Published Version (Version of Record)