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Progesterone and allopregnanolone attenuate blood–brain barrier dysfunction following permanent focal ischemia by regulating the expression of matrix metalloproteinases
Open accessAbstract
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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“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]
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Metadata
- 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)
- PMC
- PMC2963070
- 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
- green
- www.ncbi.nlm.nih.gov
- 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 › Clinical Neurology › Acute Ischemic Stroke Management
- Health Sciences › Medicine › Clinical 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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