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Author Notes:

Correspondence: Donald G. Stein, Ph.D., Department of Emergency Medicine, Brain Research Laboratory, 1365B Clifton Road NE, Emory University, Atlanta, GA 30322, USA; Phone: 1-404-712-2540; Fax: 1-404-727-2388; Email: donald.stein@emory.edu

Disclosures: DGS is entitled to royalty payment from BHR Pharmaceuticals related to research on progesterone and brain injury; His future financial interests may be affected by the outcome of this research.

The terms of this arrangement have been reviewed and approved by Emory University, which receives the largest share of any benefits in accordance with its conflict of interest policies.

The abstract was accepted for poster presentation in the AHA/ASA annual “International Stroke Conference” February 2010, San Antonio, TX.

Subjects:

Research Funding:

This work was supported by NIH/NINDS grants 1RO1 NS048451-04 and 5R01HD61971-02 to DGS, an Emory URC award to IS, AHA SDG grant 0830481N to FH, research funding from the Department of Pediatric Cardiovascular Surgery at the Children’s Hospital of Atlanta, and a gift in support of research from BHR Pharmaceuticals.

Keywords:

  • permanent middle cerebral artery occlusion
  • progesterone
  • allopregnanolone
  • blood-brain barrier
  • cytokines
  • inflammatory response
  • ischemia
  • metalloproteinases
  • tight junction proteins
  • tumor necrosis factor-alpha

Progesterone and allopregnanolone attenuate blood-brain barrier dysfunction following permanent focal ischemia by regulating the expression of matrix metalloproteinases

Tools:

Journal Title:

Experimental Neurology

Volume:

Volume 226, Number 1

Publisher:

, Pages 183-190

Type of Work:

Article | Post-print: After Peer Review

Abstract:

Blood-brain barrier (BBB) breakdown after stroke is linked to the up-regulation of metalloproteinases (MMPs) and inflammation. This study examines the effects of progesterone (PROG) and its neuroactive metabolite allopregnanolone (ALLO) on BBB integrity following permanent middle cerebral artery occlusion (pMCAO). Rats underwent pMCAO by electro-coagulation and received intraperitoneal injections of PROG (8 mg/kg), ALLO (8 mg/kg) or vehicle at 1 h post-occlusion and then subcutaneous injections (8 mg/kg) at 6, 24, and 48 h. MMP activation and expression were analyzed by Western blot, immunohistochemistry and gelatin zymography 72 h post-pMCAO. Occludin1, claudin5, tumor necrosis factor-alpha (TNF-α) and Interleukin-6 (IL-6) were analyzed at 72 h post-pMCAO with Western blots. BBB permeability was measured by Evans blue extravasation and infarct size was evaluated by cresyl violet at 72 h after pMCAO. Ischemic injury significantly (p<0.05) increased the expression of MMP-9, MMP-2, TNF-α and IL-6, and reduced the level of occludin1 and claudin5. These changes were followed by increased infarct size (% contralateral hemisphere) and Evans blue extravasation into the brain indicating compromise of the BBB. PROG and ALLO attenuated BBB disruption and infarct size following pMCAO by reducing MMPs and the inflammatory response and by preventing the degradation of occludin1 and claudin5. We conclude that PROG and ALLO can help to protect BBB disruption following pMCAO.

Copyright information:

© 2010 Elsevier Inc. All rights reserved.

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommerical-NoDerivs 3.0 Unported License (http://creativecommons.org/licenses/by-nc-nd/3.0/).

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