Cited by 159Barrier Structure and Function StudiesAcute Ischemic Stroke ManagementTraumatic Brain Injury and Neurovascular Disturbances

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

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Ishrat, Tauheed, Sayeed, Iqbal, Atif, Fahim, Hua, Fang, Stein, Donald G.·2010·Experimental Neurology

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 levels 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.

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Crossref · 10.1016/j.expneurol.2010.08.023

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  • Progesterone and allopregnanolone can reduce neuroinflammation and improve barrier function by downregulating expression of metalloproteinases in a mouse model of ischemic stroke.

    “Progesterone and allopregnanolone can reduce neuroinflammation and improve barrier function by downregulating expression of metalloproteinases as shown in a mouse model of ischemic stroke (282).”

    From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [282]

    The Conclusions state that progesterone and allopregnanolone inhibit inflammation, down-regulate MMP induction, and preserve blood–brain barrier integrity after ischemic stroke. The Discussion (BBB compromise, inflammation and edema) reports reduced MMP-9 and MMP-2 expression but describes the mechanism as possible. Crucially, the study used rats, not mice, as the Discussion (Neurosteroid treatments improve stroke outcomes) specifies. (LLM, conf=0.91)

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Authors
Ishrat, T., Sayeed, I., Atif, F., Hua, F., & Stein, D. G.
Affiliations
Emory University (US)
Corresponding author
Stein, Donald G.
Venue
Experimental Neurology
Publisher
Elsevier BV
Published
2010-11
Volume
226
Issue
1
Pages
183-190
ISSN
0014-4886 (ISSN-L)
OpenAlex
W1977180011
Cited by
159
References
70
Citations by year
2026: 6 · 2025: 6 · 2024: 2 · 2023: 4 · 2022: 11 · 2021: 7 · 2020: 11 · 2019: 5 · 2018: 15 · 2017: 7 · 2016: 7 · 2015: 18 · 2014: 14 · 2013: 19 · 2012: 13
FWCI
8.73
Type
journal article
Language
en
Open access
Locations
  • Experimental Neurology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health
  • National Institute of Neurological Disorders and Stroke (R01NS048451)
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD061971, 5R01HD61971-02)
Topics
  • Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
  • Health Sciences › Medicine › Epidemiology › Acute Ischemic Stroke Management
  • Health Sciences › Medicine › Neurology › Traumatic Brain Injury and Neurovascular Disturbances
Keywords
progesterone, allopregnanolone, blood-brain barrier dysfunction, permanent middle cerebral artery occlusion, focal cerebral ischemia, matrix metalloproteinases, MMP-9, MMP-2, claudin-5, neuroinflammation, TNF-α, interleukin-6, blood-brain barrier permeability, infarct size, neuroprotection
MeSH terms
Animals, Blood-Brain Barrier, Brain Edema, Brain Ischemia, Immunohistochemistry, Ligation, Male, Membrane Proteins, Permeability, Pregnanolone, Progesterone, Tumor Necrosis Factor-alpha, Blotting, Western, Interleukin-6, Rats, Sprague-Dawley, Infarction, Middle Cerebral Artery, Stroke, Middle Cerebral Artery, Matrix Metalloproteinase 2, Matrix Metalloproteinase 9, Matrix Metalloproteinases, Rats, Claudin-5, Occludin

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