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{"title"=>"In Vitro Blood-Brain Barrier Models Using Brain Capillary Endothelial Cells Isolated from Neonatal and Adult Rats Retain Age-Related Barrier Properties", "type"=>"journal", "authors"=>[{"first_name"=>"Fuyuko", "last_name"=>"Takata", "scopus_author_id"=>"6603214227"}, {"first_name"=>"Shinya", "last_name"=>"Dohgu", "scopus_author_id"=>"6508203929"}, {"first_name"=>"Atsushi", "last_name"=>"Yamauchi", "scopus_author_id"=>"35241146800"}, {"first_name"=>"Junichi", "last_name"=>"Matsumoto", "scopus_author_id"=>"35745159900"}, {"first_name"=>"Takashi", "last_name"=>"Machida", "scopus_author_id"=>"37072916300"}, {"first_name"=>"Kayoko", "last_name"=>"Fujishita", "scopus_author_id"=>"6603176182"}, {"first_name"=>"Keisuke", "last_name"=>"Shibata", "scopus_author_id"=>"35519952200"}, {"first_name"=>"Youichi", "last_name"=>"Shinozaki", "scopus_author_id"=>"35504287900"}, {"first_name"=>"Kaoru", "last_name"=>"Sato", "scopus_author_id"=>"55495488400"}, {"first_name"=>"Yasufumi", "last_name"=>"Kataoka", "scopus_author_id"=>"55485463500"}, {"first_name"=>"Schuichi", "last_name"=>"Koizumi", "scopus_author_id"=>"7202226576"}], "year"=>2013, "source"=>"PLoS ONE", "identifiers"=>{"issn"=>"19326203", "scopus"=>"2-s2.0-84873201497", "pui"=>"368246839", "doi"=>"10.1371/journal.pone.0055166", "isbn"=>"1932-6203", "sgr"=>"84873201497", "pmid"=>"23383092"}, "id"=>"dc77d49c-b893-3fda-b9cc-ae31335ac584", "abstract"=>"The blood-brain barrier (BBB) restricts the entry of circulating drugs and xenobiotics into the brain, and thus its permeability to substances is a critical factor that determines their central effects. The infant brain is vulnerable to neurotoxic substances partly due to the immature BBB. The employment of in vitro BBB models to evaluate permeability of compounds provides higher throughput than that of in vivo animal experiments. However, existing in vitro BBB models have not been able to simulate the intrinsic neonatal BBB. To establish a neonatal BBB model that mimics age-related BBB properties, the neonatal and adult in vitro BBB models were constructed with brain endothelial cells isolated from 2- and 8-week-old rats, respectively. To evaluate BBB functions, transendothelial electrical resistance, permeability of sodium fluorescein and Evans blue-albumin, and transport of rhodamine123 were measured. Radiolabelled drugs were used for BBB permeability studies in the neonatal and adult BBB models (in vitro) and in age-matched rats (in vivo). The neonatal BBB model showed lower barrier and p-glycoprotein (P-gp) functions than the adult BBB model; these were well associated with lower expressions of the barrier-related proteins and P-gp, and a different distribution pattern of immunostained barrier-related proteins. Verapamil (a P-gp inhibitor) significantly increased the influx of rhodamine 123, supporting functional P-gp expression in the neonatal BBB model. Valproic acid, but not nicotine, showed higher BBB permeability in the neonatal BBB model, which was well in accordance with the in vivo BBB property. We established a neonatal BBB model in vitro. This could allow us to assess the age-dependent BBB permeability of drugs.", "link"=>"http://www.mendeley.com/research/vitro-bloodbrain-barrier-models-using-brain-capillary-endothelial-cells-isolated-neonatal-adult-rats", "reader_count"=>67, "reader_count_by_academic_status"=>{"Professor > Associate Professor"=>5, "Researcher"=>9, "Student > Doctoral Student"=>8, "Student > Ph. D. Student"=>21, "Student > Postgraduate"=>3, "Student > Master"=>9, "Other"=>1, "Student > Bachelor"=>9, "Lecturer"=>2}, "reader_count_by_user_role"=>{"Professor > Associate Professor"=>5, "Researcher"=>9, "Student > Doctoral Student"=>8, "Student > Ph. D. Student"=>21, "Student > Postgraduate"=>3, "Student > Master"=>9, "Other"=>1, "Student > Bachelor"=>9, "Lecturer"=>2}, "reader_count_by_subject_area"=>{"Engineering"=>7, "Unspecified"=>1, "Biochemistry, Genetics and Molecular Biology"=>7, "Agricultural and Biological Sciences"=>29, "Medicine and Dentistry"=>11, "Arts and Humanities"=>2, "Neuroscience"=>3, "Pharmacology, Toxicology and Pharmaceutical Science"=>3, "Chemical Engineering"=>1, "Physics and Astronomy"=>1, "Chemistry"=>2}, "reader_count_by_subdiscipline"=>{"Engineering"=>{"Engineering"=>7}, "Medicine and Dentistry"=>{"Medicine and Dentistry"=>11}, "Neuroscience"=>{"Neuroscience"=>3}, "Chemistry"=>{"Chemistry"=>2}, "Physics and Astronomy"=>{"Physics and Astronomy"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>29}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>7}, "Unspecified"=>{"Unspecified"=>1}, "Pharmacology, Toxicology and Pharmaceutical Science"=>{"Pharmacology, Toxicology and Pharmaceutical Science"=>3}, "Chemical Engineering"=>{"Chemical Engineering"=>1}, "Arts and Humanities"=>{"Arts and Humanities"=>2}}, "reader_count_by_country"=>{"Hong Kong"=>1, "Italy"=>1, "Germany"=>1}, "group_count"=>1}

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• http://doi.org/10.1021/mp500046f
• http://doi.org/10.1371/journal.pone.0142725
• http://doi.org/10.3390/jcm8020137
• http://doi.org/10.1007/s12031-014-0294-7
• http://doi.org/10.1111/ene.13614
• http://doi.org/10.15252/embr.201338064
• http://doi.org/10.1177/0271678X16630991
• http://doi.org/10.1371/journal.pone.0177447
• http://doi.org/10.1016/j.jneumeth.2019.108525
• http://doi.org/10.1111/fcp.12175
• http://doi.org/10.1292/jvms.14-0475
• http://doi.org/10.1177/1933719114549844
• http://doi.org/10.3390/bioengineering4030077
• http://doi.org/10.3727/096368914X678337
• http://doi.org/10.1016/j.jep.2016.07.032
• http://doi.org/10.1111/jne.12186
• http://doi.org/10.1002/jcb.27162
• http://doi.org/10.1007/s11481-018-9796-3
• http://doi.org/10.1096/fj.201701290RR
• http://doi.org/10.1007/s00705-019-04175-3
• http://doi.org/10.1371/journal.pone.0122821
• http://doi.org/10.1111/jnc.14135

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Figshare

• {"files"=>["https://ndownloader.figshare.com/files/497161"], "description"=>"<p>Representative photographs showing immunofluorescent staining for claudin-5 (A & B), occludin (C & D) and ZO-1 (E & F) in RBECs on the inserts of neonatal (left panels) and adult (right panels) BBB models. Arrows indicate discontinuous lines and arrowheads indicate a zipper-like or zigzag shape distribution of tight junction-associated proteins. Inset panels show higher-magnification images of the squared region shown in each panel. Scale bars: 20 µm.</p>", "links"=>[], "tags"=>["junction-associated", "proteins", "rbecs", "neonatal", "bbb"], "article_id"=>167664, "categories"=>["Developmental Biology", "Neuroscience", "Medicine", "Pharmacology"], "users"=>["Fuyuko Takata", "Shinya Dohgu", "Atsushi Yamauchi", "Junichi Matsumoto", "Takashi Machida", "Kayoko Fujishita", "Keisuke Shibata", "Youichi Shinozaki", "Kaoru Sato", "Yasufumi Kataoka", "Schuichi Koizumi"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0055166.g003", "stats"=>{"downloads"=>1, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Distribution_of_tight_junction_associated_proteins_in_RBECs_in_neonatal_and_adult_in_vitro_BBB_models_/167664", "title"=>"Distribution of tight junction-associated proteins in RBECs in neonatal and adult <i>in vitro</i> BBB models.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-19 16:07:14"}
• {"files"=>["https://ndownloader.figshare.com/files/497344"], "description"=>"<p>The time-courses of the brain/perfusate ratios of valproic acid, nicotine and inulin in the neonatal (2 weeks, filled circles) and adult (8 weeks, open circles) rats (<i>in vivo</i>) (left panels in A, B and C, respectively). The time-courses of the transferred volume of valproic acid, nicotine and inulin in the neonatal (2 weeks, filled circles) and adult (8 weeks, open circles) BBB models (<i>in vitro</i>) (right panels in A, B and C, respectively). Data are means ± SEM (n = 3−6 (<i>in vivo</i>) and n = 4−12 from 2–3 separate experiments (<i>in vitro</i>)).</p>", "links"=>[], "tags"=>["bbb", "permeability", "valproic", "nicotine", "inulin", "neonatal", "rats", "models"], "article_id"=>167840, "categories"=>["Developmental Biology", "Neuroscience", "Medicine", "Pharmacology"], "users"=>["Fuyuko Takata", "Shinya Dohgu", "Atsushi Yamauchi", "Junichi Matsumoto", "Takashi Machida", "Kayoko Fujishita", "Keisuke Shibata", "Youichi Shinozaki", "Kaoru Sato", "Yasufumi Kataoka", "Schuichi Koizumi"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0055166.g004", "stats"=>{"downloads"=>0, "page_views"=>8, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Time_courses_of_the_BBB_permeability_to_valproic_acid_nicotine_and_inulin_in_the_neonatal_and_adult_rats_in_vivo_and_the_neonatal_and_adult_BBB_models_in_vitro_/167840", "title"=>"Time-courses of the BBB permeability to valproic acid, nicotine and inulin in the neonatal and adult rats (<i>in vivo</i>) and the neonatal and adult BBB models (<i>in vitro</i>).", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-19 16:08:10"}
• {"files"=>["https://ndownloader.figshare.com/files/496591"], "description"=>"<p>The TEER (A), the permeability of Na-F (B) and EBA (C), and the influx (luminal-to-abluminal) and efflux (abluminal-to-luminal) of rhodamine 123 (D) in the neonatal (2 weeks, filled columns) and adult (8 weeks, open columns) BBB models. Inset in panel D shows the effect of verapamil on rhodamine 123 influx in both models. Data are means ± SEM (n = 11−12 from 3 separate experiments (A, B, and C), n = 12−19 from 3–5 separate experiments (D); n = 8−20 from 2–5 separate experiments (Fig. D inset)). ^**<i>P</i><0.01, significantly different from the neonatal BBB model. ^#<i>P</i><0.05, ^##<i>P</i><0.01, significantly different from the influx of rhodamine 123.⁺⁺<i>P</i><0.01, significantly different from each corresponding control.</p>", "links"=>[], "tags"=>["properties", "neonatal", "bbb"], "article_id"=>167086, "categories"=>["Developmental Biology", "Neuroscience", "Medicine", "Pharmacology"], "users"=>["Fuyuko Takata", "Shinya Dohgu", "Atsushi Yamauchi", "Junichi Matsumoto", "Takashi Machida", "Kayoko Fujishita", "Keisuke Shibata", "Youichi Shinozaki", "Kaoru Sato", "Yasufumi Kataoka", "Schuichi Koizumi"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0055166.g001", "stats"=>{"downloads"=>1, "page_views"=>11, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_BBB_properties_in_the_neonatal_and_adult_in_vitro_BBB_models_/167086", "title"=>"BBB properties in the neonatal and adult <i>in vitro</i> BBB models.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-19 16:04:14"}
• {"files"=>["https://ndownloader.figshare.com/files/497524"], "description"=>"<p>The permeability of drugs (valproic acid (A), nicotine (B), inulin (C)) is expressed as the influx rate in the neonatal (2 weeks, filled columns) and adult (8 weeks, open columns) rats (<i>in vivo</i>: left panels) and the permeability clearance in the neonatal (2 weeks, filled columns) and adult (8 weeks, open columns) BBB models (<i>in vitro</i>: right panels). The influx rate (Kin) was evaluated from the brain tracer uptake in the perfusion period of 120 s and the permeability clearance (PS_trans) was evaluated from the transferred volume in the exposure periods of 10, 20, 30 and 40 min. Data are means ± SEM (n = 3−6, <i>in vivo</i>; and n = 4−12 from 2–3 separate experiments, <i>in vitro</i>). ^*<i>P</i><0.05, ** <i>P</i><0.01, significantly different from neonatal rats (<i>in vivo</i>) or neonatal BBB model (<i>in vitro</i>).</p>", "links"=>[], "tags"=>["influx", "rates", "drugs", "neonatal", "rats", "permeability", "clearance", "bbb", "models"], "article_id"=>168019, "categories"=>["Developmental Biology", "Neuroscience", "Medicine", "Pharmacology"], "users"=>["Fuyuko Takata", "Shinya Dohgu", "Atsushi Yamauchi", "Junichi Matsumoto", "Takashi Machida", "Kayoko Fujishita", "Keisuke Shibata", "Youichi Shinozaki", "Kaoru Sato", "Yasufumi Kataoka", "Schuichi Koizumi"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0055166.g005", "stats"=>{"downloads"=>2, "page_views"=>16, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_The_influx_rates_of_drugs_in_the_neonatal_and_adult_rats_in_vivo_and_the_permeability_clearance_of_drugs_in_the_neonatal_and_adult_BBB_models_in_vitro_/168019", "title"=>"The influx rates of drugs in the neonatal and adult rats (<i>in vivo</i>) and the permeability clearance of drugs in the neonatal and adult BBB models (<i>in vitro</i>).", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-19 16:09:11"}
• {"files"=>["https://ndownloader.figshare.com/files/496789"], "description"=>"<p>Representative images of western blots showing the expression of claudin-5, occludin, ZO-1 (top panels in A), and P-gp (top panels in B) in RBECs prepared from the neonatal (2 weeks) and adult (8 weeks) rats. β-actin is used as a loading control. Band intensities were quantified by densitometry (bottom panels in A and B) and the data are expressed as a percentage of the neonatal (2 weeks) rats. Each bar indicates mean ± SEM (n = 3 from 3 separate experiments).^*<i>P</i><0.05, ^**<i>P</i><0.01, significantly different from neonatal rats.</p>", "links"=>[], "tags"=>["junction-associated", "proteins", "p-gp", "rbecs", "prepared", "neonatal"], "article_id"=>167289, "categories"=>["Developmental Biology", "Neuroscience", "Medicine", "Pharmacology"], "users"=>["Fuyuko Takata", "Shinya Dohgu", "Atsushi Yamauchi", "Junichi Matsumoto", "Takashi Machida", "Kayoko Fujishita", "Keisuke Shibata", "Youichi Shinozaki", "Kaoru Sato", "Yasufumi Kataoka", "Schuichi Koizumi"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0055166.g002", "stats"=>{"downloads"=>0, "page_views"=>3, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Expression_of_the_tight_junction_associated_proteins_and_P_gp_in_the_RBECs_prepared_from_the_neonatal_and_adult_rats_/167289", "title"=>"Expression of the tight junction-associated proteins and P-gp in the RBECs prepared from the neonatal and adult rats.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-19 16:05:16"}

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Relative Metric

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F1000Prime