The DOI matches its Crossref record; 63 of the 63 references it cites were found in a registry or an index.
Losartan prevents acquired epilepsy via TGF‐β signaling suppression
Open accessAbstract
Objective: Acquired epilepsy is frequently associated with structural lesions after trauma, stroke, and infections. Although seizures are often difficult to treat, there is no clinically applicable strategy to prevent the development of epilepsy in patients at risk. We have recently shown that vascular injury is associated with activation of albumin‐mediated transforming growth factor β (TGF‐β) signaling, and followed by local inflammatory response and epileptiform activity ex vivo. Here we investigated albumin‐mediated TGF‐β signaling and tested the efficacy of blocking the TGF‐β pathway in preventing epilepsy. Methods: We addressed the role of TGF‐β signaling in epileptogenesis in 2 different rat models of vascular injury, combining in vitro and in vivo biochemical assays, gene expression, and magnetic resonance and direct optical imaging for blood–brain barrier permeability and vascular reactivity. Long‐term electrocorticographic recordings were acquired in freely behaving animals. Results: We demonstrate that serum‐derived albumin preferentially induces activation of the activin receptor‐like kinase 5 pathway of TGF‐β receptor I in astrocytes. We further show that the angiotensin II type 1 receptor antagonist, losartan, previously identified as a blocker of peripheral TGF‐β signaling, effectively blocks albumin‐induced TGF‐β activation in the brain. Most importantly, losartan prevents the development of delayed recurrent spontaneous seizures, an effect that persists weeks after drug withdrawal. Interpretation: TGF‐β signaling, activated in astrocytes by serum‐derived albumin, is involved in epileptogenesis. We propose losartan, a drug approved by the US Food and Drug Administration, as an efficient antiepileptogenic therapy for epilepsy associated with vascular injury. Ann Neurol 2014;75:864–875
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Furthermore, in vivo pharmacological blockade of TGFβRI/II using SB431542 and losartan19,20 decreases Smad2/3 signaling in the peri-infarct tissue (Supplementary Fig. 5) during the period of GDF activity after stroke.”
From GDF10 is a signal for axonal sprouting and functional recovery after stroke (2015) · cites this paper as [19]
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Learning representations by back-propagating errors
Rumelhart, D. E., Hinton, G. E., & Williams, R. J. (1986) · Nature · doi:10.1038/323533a0 · Cited by 31,892
Mechanisms of TGF-β Signaling from Cell Membrane to the Nucleus
Shi, Y., & Massagué, J. (2003) · Cell · doi:10.1016/s0092-8674(03)00432-x · Cited by 5,860
Astrocyte-endothelial interactions at the blood-brain barrier
Abbott, N. J., Rönnbäck, L., & Hansson, E. (2006) · Nature Reviews Neuroscience · doi:10.1038/nrn1824 · Cited by 5,595
Structure and function of the blood–brain barrier
Abbott, N. J., Patabendige, A. A. K., Dolman, D. E. M., Yusof, S. R., & Begley, D. J. (2010) · Neurobiology of Disease · doi:10.1016/j.nbd.2009.07.030 · Cited by 5,185
TGF-β signalling from cell membrane to nucleus through SMAD proteins
Heldin, C., Miyazono, K., & ten Dijke, P. (1997) · Nature · doi:10.1038/37284 · Cited by 3,697
Massagué, J. (2012) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3434 · Cited by 3,239
Massagué, J. (2000) · Nature Reviews Molecular Cell Biology · doi:10.1038/35043051 · Cited by 1,925
The role of inflammation in epilepsy
Vezzani, A., French, J., Bartfai, T., & Baram, T. Z. (2011) · Nature Reviews Neurology · doi:10.1038/nrneurol.2010.178 · Cited by 1,876
Comprehensive Algorithm for Quantitative Real-Time Polymerase Chain Reaction
Zhao, S., & Fernald, R. D. (2005) · Journal of Computational Biology · doi:10.1089/cmb.2005.12.1047 · Cited by 1,314
Restart procedures for the conjugate gradient method
Powell, M. J. D. (1977) · Mathematical programming · doi:10.1007/bf01593790 · Cited by 1,252
Blood–brain barrier breakdown as a therapeutic target in traumatic brain injury
Shlosberg, D., Benifla, M., Kaufer, D., & Friedman, A. (2010) · Nature Reviews Neurology · doi:10.1038/nrneurol.2010.74 · Cited by 897
Self-citationSynergistic Signaling in Fetal Brain by STAT3-Smad1 Complex Bridged by p300
Nakashima, K., Yanagisawa, M., Arakawa, H., Kimura, N., Hisatsune, T., Kawabata, M., Miyazono, K., & Taga, T. (1999) · Science · doi:10.1126/science.284.5413.479 · Cited by 868
A Direct Method of Nonparametric Measurement Selection
Whitney, A. W. (1971) · IEEE Transactions on Computers · doi:10.1109/t-c.1971.223410 · Cited by 852
Blood-brain barrier leakage may lead to progression of temporal lobe epilepsy
van Vliet, E. A., da Costa Araujo, S., Redeker, S., van Schaik, R., Aronica, E., & Gorter, J. A. (2007) · Brain · doi:10.1093/brain/awl318 · Cited by 775
Astrocyte-derived VEGF-A drives blood-brain barrier disruption in CNS inflammatory disease
Argaw, A. T., Asp, L., Zhang, J., Navrazhina, K., Pham, T., Mariani, J. N., Mahase, S., Dutta, D. J., Seto, J., Kramer, E. G., et al. (2012) · Journal of Clinical Investigation · doi:10.1172/jci60842 · Cited by 733
New avenues for anti-epileptic drug discovery and development
Löscher, W., Klitgaard, H., Twyman, R. E., & Schmidt, D. (2013) · Nature Reviews Drug Discovery · doi:10.1038/nrd4126 · Cited by 696
Cohn, R. D., van Erp, C., Habashi, J. P., Soleimani, A. A., Klein, E. C., Lisi, M. T., Gamradt, M., Rhys, C. M. A., Holm, T. M., Loeys, B., et al. (2007) · Nature Medicine · doi:10.1038/nm1536 · Cited by 672
TGF- receptor-mediated albumin uptake into astrocytes is involved in neocortical epileptogenesis
Ivens, S., Kaufer, D., Flores, L. P., Bechmann, I., Zumsteg, D., Tomkins, O., Seiffert, E., Heinemann, U., & Friedman, A. (2007) · Brain · doi:10.1093/brain/awl317 · Cited by 567
Self-citationLasting Blood-Brain Barrier Disruption Induces Epileptic Focus in the Rat Somatosensory Cortex
Seiffert, E., Dreier, J. P., Ivens, S., Bechmann, I., Tomkins‐Netzer, O., Heinemann, U., & Friedman, A. (2004) · Journal of Neuroscience · doi:10.1523/jneurosci.1751-04.2004 · Cited by 518
Self-citationHerman, S. T. (2002) · Neurology · doi:10.1212/wnl.59.9_suppl_5.s21 · Cited by 433
The Blood–Brain Barrier and Epilepsy
Oby, E. R., & Janigro, D. (2006) · Epilepsia · doi:10.1111/j.1528-1167.2006.00817.x · Cited by 399
Transcriptome Profiling Reveals TGF- Signaling Involvement in Epileptogenesis
Cacheaux, L. P., Ivens, S., David, Y. B., Lakhter, A. J., Bar‐Klein, G., Shapira, M., Heinemann, U., Friedman, A., & Kaufer, D. (2009) · Journal of Neuroscience · doi:10.1523/jneurosci.0430-09.2009 · Cited by 392
Self-citationLim, D., Lutucuta, S., Bachireddy, P., Youker, K. A., Evans, A. J., Entman, M. L., Roberts, R., & Marian, A. J. (2001) · Circulation · doi:10.1161/01.cir.103.6.789 · Cited by 387
Overview and introduction: The blood–brain barrier in health and disease
Abbott, N. J., & Friedman, A. (2012) · Epilepsia · doi:10.1111/j.1528-1167.2012.03696.x · Cited by 378
Self-citationFerrari, G. M., Ferrari, G., Cook, B., Terushkin, V., Pintucci, G., & Mignatti, P. (2008) · Nature Precedings · doi:10.1002/jcp.21706 · Cited by 348
David, Y., Cacheaux, L. P., Ivens, S., Lapilover, E., Heinemann, U., Kaufer, D., & Friedman, A. (2009) · Journal of Neuroscience · doi:10.1523/jneurosci.2323-09.2009 · Cited by 337
Self-citationMechanisms of Disease: The Blood-Brain Barrier
Neuwelt, E. A. (2004) · Neurosurgery · doi:10.1227/01.neu.0000097715.11966.8e · Cited by 317
Friedman, A., Kaufer, D., & Heinemann, U. (2009) · Epilepsy Research · doi:10.1016/j.eplepsyres.2009.03.005 · Cited by 270
Self-citationSeizure-induced brain-borne inflammation sustains seizure recurrence and blood-brain barrier damage
Librizzi, L., Noè, F., Vezzani, A., de Curtis, M., & Ravizza, T. (2012) · Annals of Neurology · doi:10.1002/ana.23567 · Cited by 253
A portrait of Transforming Growth Factor β superfamily signalling: Background matters
Horbelt, D., Denkis, A., & Knaus, P. I. (2011) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2011.12.013 · Cited by 207
Becker, A. J., Pitsch, J., Гарриевич, С. Д., Opitz, T., Staniek, M., Chen, C., Campbell, K. P., Schoch, S., Yaari, Y., & Beck, H. (2008) · Journal of Neuroscience · doi:10.1523/jneurosci.1421-08.2008 · Cited by 205
Angiotensin II sustains brain inflammation in mice via TGF-β
Lanz, T. V., Ding, Z., Ho, P. P.-K., Luo, J., Agrawal, A., Srinagesh, H. K., Axtell, R. C., Zhang, H., Platten, M., Wyss‐Coray, T., et al. (2010) · Journal of Clinical Investigation · doi:10.1172/jci41709 · Cited by 200
Tomkins‐Netzer, O., Friedman, O., Ivens, S., Reiffurth, C., Major, S., Dreier, J. P., Heinemann, U., & Friedman, A. (2006) · Neurobiology of Disease · doi:10.1016/j.nbd.2006.10.006 · Cited by 175
Self-citationLosartan decreases plasma levels of TGF-β1 in transplant patients with chronic allograft nephropathy
Campistol, J. M., Inigo, P. J., Jiménez, W., Lario, S., Clesca, P., Oppenheimer, F., & Rivera, F. (1999) · Kidney International · doi:10.1046/j.1523-1755.1999.00597.x · Cited by 160
Matsuyama, S., Iwadate, M., Kondo, M., Saitoh, M., Hanyu, A., Shimizu, K., Aburatani, H., Mishima, H. K., Imamura, T., Miyazono, K., et al. (2003) · PubMed · Cited by 142
Lavoie, P., Robitaille, G., Agharazii, M., Ledbetter, S., Lebel, M., & Larivière, R. (2005) · Journal of Hypertension · doi:10.1097/01.hjh.0000182521.44440.c5 · Cited by 141
Friedman, A. (2011) · Epilepsia · doi:10.1111/j.1528-1167.2011.03227.x · Cited by 125
Self-citationKaur, K., Sharma, A. K., & Singal, P. K. (2006) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.01327.2005 · Cited by 122
Fukuda, S., Abematsu, M., Mori, H., Yanagisawa, M., Kagawa, T., Nakashima, K., Yoshimura, A., & Taga, T. (2007) · Molecular and Cellular Biology · doi:10.1128/mcb.02435-06 · Cited by 122
TGF-β1 activates two distinct type I receptors in neurons
König, H., Kögel, D., Rami, A., & Prehn, J. H. M. (2005) · The Journal of Cell Biology · doi:10.1083/jcb.200407027 · Cited by 118
Janigro, D. (2012) · Epilepsia · doi:10.1111/j.1528-1167.2012.03472.x · Cited by 117
Clathrin-mediated endocytosis of FITC-albumin in alveolar type II epithelial cell line RLE-6TN
Yumoto, R., Nishikawa, H., Okamoto, M., Katayama, H., Nagai, J., & Takano, M. (2005) · American Journal of Physiology-Lung Cellular and Molecular Physiology · doi:10.1152/ajplung.00173.2005 · Cited by 97
Suzuki, Y., Ito, Y., Mizuno, M., Kinashi, H., Sawai, A., Noda, Y., Mizuno, T., Shimizu, H., Fujita, Y., Matsui, K., et al. (2012) · Kidney International · doi:10.1038/ki.2011.464 · Cited by 92
Frequent Blood–Brain Barrier Disruption in the Human Cerebral Cortex
Tomkins‐Netzer, O., Kaufer, D., Korn, A., Shelef, I., Golan, H., Reichenthal, E., Soreq, H., & Friedman, A. (2001) · Cellular and Molecular Neurobiology · doi:10.1023/a:1015147920283 · Cited by 92
Self-citationRestructuring the neuronal stress response with anti-glucocorticoid gene delivery
Kaufer, D., Ogle, W. O., Pincus, Z., Clark, K., Nicholas, A. C., Dinkel, K., Dumas, T. C., Ferguson, D., Lee, A. L., Winters, M. A., et al. (2004) · Nature Neuroscience · doi:10.1038/nn1296 · Cited by 84
Self-citationInhibition of the renin–angiotensin system prevents seizures in a rat model of epilepsy
Pereira, M. G. A. G., Becari, C., de Oliveira, J. A. C., Salgado, M. C. O., Garcia‐Cairasco, N., & Costa-Neto, C. M. (2010) · Clinical Science · doi:10.1042/cs20100053 · Cited by 84
Levi, H., Schoknecht, K., Prager, O., Chassidim, Y., Weissberg, I., Serlin, Y., & Friedman, A. (2012) · PLoS ONE · doi:10.1371/journal.pone.0039636 · Cited by 78
Self-citationFerrari, G. M., Terushkin, V., Wolff, M. J., Zhang, X., Valacca, C., Poggio, P., Pintucci, G., & Mignatti, P. (2012) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-11-0507 · Cited by 76
Dynamic in vivo imaging of cerebral blood flow and blood–brain barrier permeability
Prager, O., Chassidim, Y., Klein, C., Levi, H., Shelef, I., & Friedman, A. (2009) · NeuroImage · doi:10.1016/j.neuroimage.2009.08.009 · Cited by 65
Self-citationEffect of losartan on the blood–brain barrier permeability in diabetic hypertensive rats
Kaya, M., Kalaycı, R., Küçük, M., Arıcan, N., Elmas, İ., Kudat, H., & Korkut, F. (2003) · Life Sciences · doi:10.1016/j.lfs.2003.06.014 · Cited by 58
Blood-Brain Barrier Dysfunction in Epileptogenesis of the Temporal Lobe
Weissberg, I., Reichert, A., Heinemann, U., & Friedman, A. (2011) · Epilepsy Research and Treatment · doi:10.1155/2011/143908 · Cited by 55
Self-citationFüchtbauer, L. M., Groth-Rasmussen, M., Holm, T. H., Løbner, M., Toft‐Hansen, H., Khorooshi, R., & Owens, T. (2010) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2010.09.015 · Cited by 54
Küçük, M., Kaya, M., Kalaycı, R., Cimen, V., Kudat, H., Arıcan, N., Elmas, İ., & Korkut, F. (2002) · Life Sciences · doi:10.1016/s0024-3205(02)01772-1 · Cited by 49
Compensatory network alterations upon onset of epilepsy in synapsin triple knock-out mice
Ketzef, M., Kahn, J., Weissberg, I., Becker, A. J., Friedman, A., & Gitler, D. (2011) · Neuroscience · doi:10.1016/j.neuroscience.2011.05.030 · Cited by 43
Self-citationTimofeeva, O. A., & Gordon, C. J. (2001) · Brain Research · doi:10.1016/s0006-8993(00)03309-6 · Cited by 42
Łukawski, K., Janowska, A., Jakubus, T., Tochman-Gawda, A., & Czuczwar, S. J. (2010) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2010.04.053 · Cited by 38
Bastlund, J. F., Jennum, P., Mohapel, P., Vogel, V., & Watson, W. P. (2004) · Journal of Neuroscience Methods · doi:10.1016/j.jneumeth.2004.03.004 · Cited by 34
Detection of BBB disruption and hemorrhage by Gd-DTPA enhanced MRI after embolic stroke in rat
Ding, G., Jiang, Q., Li, L., Zhang, L., Zhang, Z. G., Ledbetter, K. A., Ewing, J. R., Li, Q., & Chopp, M. (2006) · Brain Research · doi:10.1016/j.brainres.2006.07.116 · Cited by 31
Wu, J., Kihara, T., Hongo, H., AKAIKE, A., Niidome, T., & Sugimoto, H. (2010) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.2010.00840.x · Cited by 30
The blood-brain barrier hypothesis in drug resistant epilepsy
Marchi, N., Granata, T., Alexopoulos, A. V., & Janigro, D. (2012) · Brain · doi:10.1093/brain/awr343 · Cited by 29
Khalil, A., Tullus, K., Bakhiet, M., BURMAN, L. G., Jaremko, G., & Brauner, A. (2000) · The Journal of Urology · doi:10.1016/s0022-5347(05)67492-7 · Cited by 25
Huang, B. S., Ahmad, M., Tan, J., & Leenen, F. H. H. (2009) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00317.2009 · Cited by 22
Khan (2000) · doi:10.1002/1531-8249(200008)48:2
Flagged first, then by citations
Cited by
Sorted by citations
Löscher, W., Potschka, H., Sisodiya, S. M., & Vezzani, A. (2020) · Pharmacological Reviews · doi:10.1124/pr.120.019539 · Cited by 967
Neuroinflammatory pathways as treatment targets and biomarkers in epilepsy
Vezzani, A., Balosso, S., & Ravizza, T. (2019) · Nature Reviews Neurology · doi:10.1038/s41582-019-0217-x · Cited by 928
Neuron–glia interactions in the pathophysiology of epilepsy
Patel, D. C., Tewari, B. P., Chaunsali, L., & Sontheimer, H. W. (2019) · Nature reviews. Neuroscience · doi:10.1038/s41583-019-0126-4 · Cited by 478
Tagge, C. A., Fisher, A. M., Minaeva, O. V., Gaudreau, A., Moncaster, J. A., Zhang, X.-L., Wojnarowicz, M. W., Casey, N. F., Lu, H., Kokiko‐Cochran, O. N., et al. (2017) · Brain · doi:10.1093/brain/awx350 · Cited by 402
Self-citationCommonalities in epileptogenic processes from different acute brain insults: Do they translate?
Klein, P., Dingledine, R. J., Aronica, E., Bernard, C., Blümcke, I., Boison, D., Brodie, M. J., Brooks‐Kayal, A. R., Engel, J., Forcelli, P. A., et al. (2017) · Epilepsia · doi:10.1111/epi.13965 · Cited by 300
Metadata
- Authors
- Bar‐Klein, G., Cacheaux, L. P., Kamintsky, L., Prager, O., Weissberg, I., Schoknecht, K., Cheng, P., Kim, S. Y., Wood, L., Heinemann, U., Kaufer, D., & Friedman, A.
- Affiliations
- Ben-Gurion University of the Negev (IL)
- University of California, Berkeley (US)
- Departments of Physiology and Cell Biology Cognitive and Brain Sciences, Zlotowski Center for Neuroscience, Ben‐Gurion University of the Negev Beer‐Sheva Israel
- Charité – Universitätsmedizin Berlin (DE)
- Helen Wills Neuroscience Institute and Department of Integrative Biology University of California, Berkeley Berkeley CA
- Corresponding author
- Friedman, Alon
- ORCID
- Venue
- Annals of Neurology
- Publisher
- Wiley
- Published
- 2014-05-28
- Volume
- 75
- Issue
- 6
- Pages
- 864-875
- ISSN
- 0364-5134 (ISSN-L)
- 1531-8249
- PMC
- PMC4077937
- OpenAlex
- W1746603715
- Cited by
- 270
- References
- 63
- Citations by year
- 2026: 18 · 2025: 11 · 2024: 28 · 2023: 24 · 2022: 23 · 2021: 26 · 2020: 29 · 2019: 30 · 2018: 15 · 2017: 26 · 2016: 17 · 2015: 13 · 2014: 10
- FWCI
- 16.78
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Annals of Neurology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (RO1/NINDS NS066005)
- United States - Israel Binational Science Foundation (2007185)
- Israel Science Foundation (713/11)
- The European Unions Seventh Framework Program (FP7/2007-2013), EPITARGET (602102)
- Topics
- Health Sciences › Medicine › Clinical Neurology › Epilepsy research and treatment
- Health Sciences › Medicine › Clinical Neurology › Traumatic Brain Injury and Neurovascular Disturbances
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Keywords
- losartan, acquired epilepsy, epileptogenesis, TGF-beta signaling, serum albumin, vascular injury, angiotensin II type 1 receptor, ALK5, astrocytes, blood-brain barrier permeability, vascular reactivity, antiepileptogenic therapy, spontaneous seizures, electrocorticography
- MeSH terms
- Animals, Animals, Newborn, Anticonvulsants, Astrocytes, Benzamides, Blood-Brain Barrier, Cells, Cultured, Cerebral Cortex, Dioxoles, Disease Models, Animal, Embryo, Mammalian, Endocytosis, Epilepsy, Male, Neurons, Phosphopyruvate Hydratase, Signal Transduction, Transforming Growth Factor beta, Rats, Wistar, Losartan, Rats
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
