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 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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Progesterone in experimental permanent stroke: a dose-response and therapeutic time-window study
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Self-citationTajalli-Nezhad, S., Karimian, M., Beyer, C., Atlasi, M. A., & Tameh, A. A. (2018) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-018-2953-2 · Cited by 83 · see citing works
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“Inhibition of MMP-2/-9 expression by progesterone and its neuroactive metabolite allopregnanolone attenuated BBB disruption and infarct size in a rat model of permanent middle cerebral artery occlusion [50].”
BackgroundProgesterone is neuroprotective following cerebral ischaemia in reproductively ageing female mice
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Neuroactive steroids, their metabolites, and neuroinflammation
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Won, S., Lee, J., & Stein, D. G. (2015) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2015.06.007 · Cited by 76 · see citing works
Self-citationKim, J., Kim, T.-Y., Cho, K.-S., Kim, H., & Koh, J. (2013) · Neurobiology of Disease · doi:10.1016/j.nbd.2013.07.011 · Cited by 74 · see citing works
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Hua, F., Reiss, J. I., Tang, H., Wang, J., Fowler, X., Sayeed, I., & Stein, D. G. (2012) · Hormones and Behavior · doi:10.1016/j.yhbeh.2012.02.017 · Cited by 66 · see citing works
Self-citationIshrat, T., Pillai, B. A., Soliman, S. M., Fouda, A. Y., Kozak, A., Johnson, M. H., Ergul, A., & Fagan, S. C. (2014) · Molecular Neurobiology · doi:10.1007/s12035-014-8830-6 · Cited by 67 · see citing works
Self-citationStress primes microglial polarization after global ischemia: Therapeutic potential of progesterone
Espinosa‐García, C., Sayeed, I., Yousuf, S., Atif, F., Sergeeva, E. G., Neigh, G. N., & Stein, D. G. (2017) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2017.06.012 · Cited by 65 · see citing works
Self-citationCurrent Therapeutic Strategies to Mitigate the eNOS Dysfunction in Ischaemic Stroke
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Static and Dynamic Factors Promoting Resilience following Traumatic Brain Injury: A Brief Review
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Yousuf, S., Atif, F., Sayeed, I., Wang, J., & Stein, D. G. (2012) · Neuroscience · doi:10.1016/j.neuroscience.2012.10.017 · Cited by 62 · see citing works
Self-citationProgesterone in transient ischemic stroke: a dose–response study
Yousuf, S., Atif, F., Sayeed, I., Tang, H.-L., & Stein, D. G. (2014) · Psychopharmacology · doi:10.1007/s00213-014-3556-8 · Cited by 59 · see citing works
Self-citationEspinosa‐García, C., Atif, F., Yousuf, S., Sayeed, I., Neigh, G. N., & Stein, D. G. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21113740 · Cited by 59 · see citing works
Self-citationSex steroid hormone-mediated functional regulation of microglia-like BV-2 cells during hypoxia
Habib, P., Dreymueller, D., Ludwig, A., Beyer, C., & Dang, J. (2013) · The Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/j.jsbmb.2013.06.003 · Cited by 67 · see citing works
Sex-related differences in effects of progesterone following neonatal hypoxic brain injury
Peterson, B. L., Won, S., Geddes, R. I., Sayeed, I., & Stein, D. G. (2015) · Behavioural Brain Research · doi:10.1016/j.bbr.2015.03.005 · Cited by 58 · see citing works
Self-citationYousuf, S., Sayeed, I., Atif, F., Tang, H., Wang, J., & Stein, D. G. (2013) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1038/jcbfm.2013.198 · Cited by 56 · see citing works
Self-citationIs progesterone a worthy candidate as a novel therapy for traumatic brain injury?
Stein, D. G. (2011) · Dialogues in Clinical Neuroscience · doi:10.31887/dcns.2011.13.2/dstein · Cited by 54 · see citing works
Self-citationMethod parameters’ impact on mortality and variability in rat stroke experiments: a meta-analysis
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The Effect of Progesterone Dose on Gene Expression after Traumatic Brain Injury
Anderson, G., Farin, F., Bammler, T., Beyer, R., Swan, A., Wilkerson, H.-W., Kantor, E., & Hoane, M. (2011) · Journal of Neurotrauma · doi:10.1089/neu.2011.1911 · Cited by 55 · see citing works
Astrocytes as a target for neuroprotection: Modulation by progesterone and dehydroepiandrosterone
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Steroids in Stroke with Special Reference to Progesterone
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Progesterone and allopregnanolone exacerbate hypoxic-ischemic brain injury in immature rats
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Neuroprotection in Preterm Infants
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Selective Gelatinase Inhibitor Neuroprotective Agents Cross the Blood-Brain Barrier
Gooyit, M., Suckow, M. A., Schroeder, V. A., Wolter, W. R., Mobashery, S., & Chang, M. (2012) · ACS Chemical Neuroscience · doi:10.1021/cn300062w · Cited by 37 · see citing works
Remus, E. W., Sayeed, I., Won, S., Lyle, A. N., & Stein, D. G. (2015) · Experimental Neurology · doi:10.1016/j.expneurol.2015.07.010 · Cited by 35 · see citing works
Self-citationZhu, X., Fréchou, M., Schumacher, M., & Guennoun, R. (2018) · The Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/j.jsbmb.2018.07.014 · Cited by 35 · see citing works
Progress in progestin-based therapies for neurological disorders
Sitruk-Ware, R. L., Bonsack, B., Brinton, R. D., Schumacher, M., Kumar, N., Lee, J.-Y., Castelli, V., Corey, S., Coats, A. B., Sadanandan, N., et al. (2020) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2020.12.007 · Cited by 35 · see citing works
Novel actions of progesterone: what we know today and what will be the scenario in the future?
Kaore, S. N., Langade, D., Yadav, V. K., Sharma, P., Thawani, V., & Sharma, R. (2012) · Journal of Pharmacy and Pharmacology · doi:10.1111/j.2042-7158.2012.01464.x · Cited by 34 · see citing works
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Allopregnanolone promotes proliferation and differential gene expression in human glioblastoma cells
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The Hypothalamic-Pituitary-Ovarian Axis, Ovarian Disorders, and Brain Aging
Valera, H., Chen, A., & Grive, K. J. (2025) · Endocrinology · doi:10.1210/endocr/bqaf137 · Cited by 32 · see citing works
Allen, R. S., Sayeed, I., Oumarbaeva, Y., Morrison, K. C., Choi, P., Pardue, M. T., & Stein, D. G. (2016) · Restorative Neurology and Neuroscience · doi:10.3233/rnn-160672 · Cited by 32 · see citing works
Self-citationNeurosteroids: A novel promise for the treatment of stroke and post‐stroke complications
Xu, J., Zhou, Y., Yan, C., Wang, X., Lou, J., Luo, Y., Gao, S., Wang, J., Wu, L., Gao, X., et al. (2021) · Journal of Neurochemistry · doi:10.1111/jnc.15503 · Cited by 31 · see citing works
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Self-citationGiatti, S., Diviccaro, S., Falvo, E., García‐Segura, L. M., & Melcangi, R. C. (2020) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2020.100836 · Cited by 32 · see citing works
Progesterone Treatment in Two Rat Models of Ocular Ischemia
Allen, R. S., Olsen, T. W., Sayeed, I., Cale, H. A., Morrison, K. C., Oumarbaeva, Y., Lucaciu, I., Boatright, J. H., Pardue, M. T., & Stein, D. G. (2015) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.14-16070 · Cited by 30 · see citing works
Self-citationLow maternal progesterone may contribute to both obstetrical complications and autism
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Gender difference in the effect of progesterone on neonatal hypoxic/ischemic brain injury in mouse
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Progesterone: Synthesis, Metabolism, Mechanism of Action, and Effects in the Nervous System
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Wali, B., Ishrat, T., Stein, D. G., & Sayeed, I. (2016) · Behavioural Brain Research · doi:10.1016/j.bbr.2016.02.024 · Cited by 27 · see citing works
Self-citationThe Blood–Brain Barrier: Much More Than a Selective Access to the Brain
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Brain edema in acute liver failure: Role of neurosteroids
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Progesterone and Vitamin D Hormone as a Biologic Treatment of Traumatic Brain Injury in the Aged
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Self-citationNeurosteroids and the Nervous System
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Self-citationBlood brain barrier inflammation and potential therapeutic role of phytochemicals
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A Narrative Review on Axonal Neuroprotection in Multiple Sclerosis
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Pretreatment with Danhong injection protects the brain against ischemia-reperfusion injury
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Age-related ultrastructural neurovascular changes in the female mouse cortex and hippocampus
Frías-Anaya, E., Gromnicova, R., Kraev, I., Rogachevsky, V. V., Male, D. K., Crea, F., Hawkes, C. A., & Romero, I. A. (2020) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2020.12.008 · Cited by 19 · see citing works
- 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 › 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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