Carbon Monoxide Abrogates Ischemic Insult to Neuronal Cells via the Soluble Guanylate Cyclase-cGMP Pathway
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{"title"=>"Carbon Monoxide Abrogates Ischemic Insult to Neuronal Cells via the Soluble Guanylate Cyclase-cGMP Pathway", "type"=>"journal", "authors"=>[{"first_name"=>"Nils", "last_name"=>"Schallner", "scopus_author_id"=>"36779499700"}, {"first_name"=>"Carlos C.", "last_name"=>"Romão", "scopus_author_id"=>"7004528065"}, {"first_name"=>"Julia", "last_name"=>"Biermann", "scopus_author_id"=>"35363643600"}, {"first_name"=>"Wolf A.", "last_name"=>"Lagrèze", "scopus_author_id"=>"7003271235"}, {"first_name"=>"Leo E.", "last_name"=>"Otterbein", "scopus_author_id"=>"7003807813"}, {"first_name"=>"Hartmut", "last_name"=>"Buerkle", "scopus_author_id"=>"7003865981"}, {"first_name"=>"Torsten", "last_name"=>"Loop", "scopus_author_id"=>"7004000820"}, {"first_name"=>"Ulrich", "last_name"=>"Goebel", "scopus_author_id"=>"35363863100"}], "year"=>2013, "source"=>"PLoS ONE", "identifiers"=>{"pui"=>"368695860", "sgr"=>"84875976523", "issn"=>"19326203", "pmid"=>"23593279", "scopus"=>"2-s2.0-84875976523", "doi"=>"10.1371/journal.pone.0060672", "isbn"=>"1932-6203 (Electronic)\\r1932-6203 (Linking)"}, "id"=>"671dec0f-c061-3928-881d-f2918fc78188", "abstract"=>"PURPOSE: Carbon monoxide (CO) is an accepted cytoprotective molecule. The extent and mechanisms of protection in neuronal systems have not been well studied. We hypothesized that delivery of CO via a novel releasing molecule (CORM) would impart neuroprotection in vivo against ischemia-reperfusion injury (IRI)-induced apoptosis of retinal ganglion cells (RGC) and in vitro of neuronal SH-SY5Y-cells via activation of soluble guanylate-cyclase (sGC).\\n\\nMETHODS: To mimic ischemic respiratory arrest, SH-SY5Y-cells were incubated with rotenone (100 nmol/L, 4 h) ± CORM ALF186 (10-100 µmol/L) or inactivated ALF186 lacking the potential of releasing CO. Apoptosis and reactive oxygen species (ROS) production were analyzed using flow-cytometry (Annexin V, mitochondrial membrane potential, CM-H2DCFDA) and Western blot (Caspase-3). The impact of ALF186± respiratory arrest on cell signaling was assessed by measuring expression of nitric oxide synthase (NOS) and soluble guanylate-cyclase (sGC) and by analyzing cellular cGMP levels. The effect of ALF186 (10 mg/kg iv) on retinal IRI in Sprague-Dawley rats was assessed by measuring densities of fluorogold-labeled RGC after IRI and by analysis of apoptosis-related genes in retinal tissue.\\n\\nRESULTS: ALF186 but not inactivated ALF186 inhibited rotenone-induced apoptosis (Annexin V positive cells: 25 ± 2% rotenone vs. 14 ± 1% ALF186+rotenone, p<0.001; relative mitochondrial membrane potential: 17 ± 4% rotenone vs. 55 ± 3% ALF186+rotenone, p<0.05). ALF186 increased cellular cGMP levels (33±5 nmol/L vs. 23±3 nmol/L; p<0.05) and sGC expression. sGC-inhibition attenuated ALF186-mediated protection (relative mitochondrial membrane potential: 55±3% ALF186+rotenone vs. 20 ± 1% ODQ + ALF186+rotenone, p<0.05). ALF186 protected RGC in vivo (IRI 1255 ± 327 RGC/mm(2) vs. ALF186 + IRI 2036 ± 83; p<0.05) while sGC inhibition abolished the protective effects of ALF186 (ALF186 + IRI 2036 ± 83 RGC/mm(2) vs. NS-2028 + ALF186 + IRI 1263 ± 170, p<0.05).\\n\\nCONCLUSIONS: The CORM ALF186 inhibits IRI-induced neuronal cell death via activation of sGC and may be a useful treatment option for acute ischemic insults to the retina and the brain.", "link"=>"http://www.mendeley.com/research/carbon-monoxide-abrogates-ischemic-insult-neuronal-cells-via-soluble-guanylate-cyclasecgmp-pathway", "reader_count"=>37, "reader_count_by_academic_status"=>{"Unspecified"=>2, "Professor > Associate Professor"=>3, "Student > Doctoral Student"=>1, "Researcher"=>7, "Student > Ph. D. Student"=>6, "Student > Postgraduate"=>4, "Student > Master"=>7, "Other"=>1, "Student > Bachelor"=>5, "Professor"=>1}, "reader_count_by_user_role"=>{"Unspecified"=>2, "Professor > Associate Professor"=>3, "Student > Doctoral Student"=>1, "Researcher"=>7, "Student > Ph. D. Student"=>6, "Student > Postgraduate"=>4, "Student > Master"=>7, "Other"=>1, "Student > Bachelor"=>5, "Professor"=>1}, "reader_count_by_subject_area"=>{"Unspecified"=>3, "Biochemistry, Genetics and Molecular Biology"=>5, "Agricultural and Biological Sciences"=>15, "Medicine and Dentistry"=>11, "Neuroscience"=>2, "Chemistry"=>1}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>11}, "Neuroscience"=>{"Neuroscience"=>2}, "Chemistry"=>{"Chemistry"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>15}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>5}, "Unspecified"=>{"Unspecified"=>3}}, "reader_count_by_country"=>{"Germany"=>1}, "group_count"=>2}

Scopus | Further Information

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/1018366"], "description"=>"<p>Retinal expression of caspase-3 (<b>A</b>; n = 6; mean±SD.; * = p<0.05 IRI vs. ALF186+IRI and ALF186+IRI vs. NS-2028+ALF186+IRI), Bax (<b>B</b>; n = 6; mean±SD; * = p<0.05 IRI vs. ALF186+IRI and ALF186+IRI vs. NS-2028+ALF186+IRI), Bcl-2 (<b>C</b>; n = 6; mean±SD), sGC α<sub>1</sub> subunit (<b>D</b>; n = 6; mean±SD) and sGC β<sub>1</sub> subunit (<b>E</b>; n = 6; mean±SD) mRNA expression in ischemic retinal tissue in relation to the corresponding non-ischemic retinae analyzed by RT-PCR.</p>", "links"=>[], "tags"=>["Model organisms", "Animal models", "rat", "Molecular cell biology", "cytometry", "flow cytometry", "Signal transduction", "Signaling in cellular processes", "Antiapoptotic signaling", "cGMP signaling", "Cell death", "Cellular stress responses", "neuroscience", "Molecular neuroscience", "Signaling pathways", "Neurochemistry", "Neurochemicals", "Nitric oxide", "Drugs and devices", "Neuropharmacology", "neurology", "Cerebrovascular diseases", "Ischemic stroke", "Neuro-ophthalmology", "ophthalmology", "Retinal disorders", "alf186", "retinal", "bcl-2", "sgc-subunit"], "article_id"=>677673, "categories"=>["Medicine", "Biological Sciences"], "users"=>["Nils Schallner", "Carlos C. Romão", "Julia Biermann", "Wolf A. Lagrèze", "Leo E. Otterbein", "Hartmut Buerkle", "Torsten Loop", "Ulrich Goebel"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0060672.g008", "stats"=>{"downloads"=>0, "page_views"=>9, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Effect_of_ALF186_on_retinal_caspase_3_Bax_Bcl_2_and_sGC_subunit_gene_expression_analyzed_by_RT_PCR_/677673", "title"=>"Effect of ALF186 on retinal caspase-3, Bax, Bcl-2 and sGC-subunit gene expression analyzed by RT-PCR.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-04-08 02:07:53"}
  • {"files"=>["https://ndownloader.figshare.com/files/1018362"], "description"=>"<p><b>A:</b> Representative images from flat mounts with fluorogold-labeled retinal ganglion cells 7 days after IRI, ALF186 treatment and sGC inhibition with NS-2028. Scale bar 100 µm. <b>B:</b> Quantification of retinal ganglion cell density [cells/mm<sup>2</sup>] 7 days after IRI, ALF186 treatment and sGC inhibition <i>in vivo</i> (n = 6 per group; mean±SD; * = p<0.05 IRI vs. ALF186+IRI and ALF186+IRI vs. NS-2028+ALF186+IRI).</p>", "links"=>[], "tags"=>["Model organisms", "Animal models", "rat", "Molecular cell biology", "cytometry", "flow cytometry", "Signal transduction", "Signaling in cellular processes", "Antiapoptotic signaling", "cGMP signaling", "Cell death", "Cellular stress responses", "neuroscience", "Molecular neuroscience", "Signaling pathways", "Neurochemistry", "Neurochemicals", "Nitric oxide", "Drugs and devices", "Neuropharmacology", "neurology", "Cerebrovascular diseases", "Ischemic stroke", "Neuro-ophthalmology", "ophthalmology", "Retinal disorders", "alf186", "iri", "retinal", "ganglion", "cells"], "article_id"=>677672, "categories"=>["Medicine", "Biological Sciences"], "users"=>["Nils Schallner", "Carlos C. Romão", "Julia Biermann", "Wolf A. Lagrèze", "Leo E. Otterbein", "Hartmut Buerkle", "Torsten Loop", "Ulrich Goebel"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0060672.g007", "stats"=>{"downloads"=>0, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Effect_of_ALF186_treatment_on_IRI_in_retinal_ganglion_cells_in_vivo_/677672", "title"=>"Effect of ALF186 treatment on IRI in retinal ganglion cells <i>in vivo</i>.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-04-08 02:07:52"}
  • {"files"=>["https://ndownloader.figshare.com/files/1018359"], "description"=>"<p><b>A:</b> Flow-cytometric analysis of mitochondrial membrane potential change relative to untreated cells after inhibition or induction of sGC (ΔΨ<sub>m</sub>, n = 6; mean±SD; * = p<0.05 rotenone vs. ALF186+ rotenone, ALF186+rotenone vs. ODQ+ALF186+rotenone and rotenone vs. YC-1+rotenone). <b>B:</b> Flow-cytometric analysis after Annexin V staining and incubation with the cGMP-analog 8-Br-cGMP (n = 6; mean±SD; * = p<0.05 rotenone vs. ALF186+rotenone and rotenone vs. 8-Br-cGMP+rotenone). <b>C:</b> Flow-cytometric analysis after Annexin V staining and incubation with the PKG-inhibitor KT5823 (n = 6; mean±SD; * = p<0.05 rotenone vs. ALF186+rotenone and ALF186+rotenone vs. KT5823+ALF186+rotenone).</p>", "links"=>[], "tags"=>["Model organisms", "Animal models", "rat", "Molecular cell biology", "cytometry", "flow cytometry", "Signal transduction", "Signaling in cellular processes", "Antiapoptotic signaling", "cGMP signaling", "Cell death", "Cellular stress responses", "neuroscience", "Molecular neuroscience", "Signaling pathways", "Neurochemistry", "Neurochemicals", "Nitric oxide", "Drugs and devices", "Neuropharmacology", "neurology", "Cerebrovascular diseases", "Ischemic stroke", "Neuro-ophthalmology", "ophthalmology", "Retinal disorders", "sgc", "alf186", "mediated"], "article_id"=>677670, "categories"=>["Medicine", "Biological Sciences"], "users"=>["Nils Schallner", "Carlos C. Romão", "Julia Biermann", "Wolf A. Lagrèze", "Leo E. Otterbein", "Hartmut Buerkle", "Torsten Loop", "Ulrich Goebel"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0060672.g006", "stats"=>{"downloads"=>0, "page_views"=>9, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_The_role_of_sGC_in_ALF186_mediated_effects_/677670", "title"=>"The role of sGC in ALF186 mediated effects.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-04-08 02:07:50"}
  • {"files"=>["https://ndownloader.figshare.com/files/1018356"], "description"=>"<p><b>A:</b> Representative western blot of nNOS and iNOS protein expression after ALF186 treatment. <b>B:</b> Quantification of nitric oxide production by colorimetric measurement of total nitrite after ALF186 incubation ±NOS-Inhibition by L-NAME (n = 6; fold change vs. untreated cells; mean±SD; * = p<0.05 ALF186 vs. L-NAME +ALF186). <b>C:</b> Flow-cytometric analysis of mitochondrial membrane potential change relative to untreated cells after inhibition of NOS (ΔΨ<sub>m</sub>, n = 6; mean±SD; * = p<0.05 rotenone vs. ALF186+rotenone).</p>", "links"=>[], "tags"=>["Model organisms", "Animal models", "rat", "Molecular cell biology", "cytometry", "flow cytometry", "Signal transduction", "Signaling in cellular processes", "Antiapoptotic signaling", "cGMP signaling", "Cell death", "Cellular stress responses", "neuroscience", "Molecular neuroscience", "Signaling pathways", "Neurochemistry", "Neurochemicals", "Nitric oxide", "Drugs and devices", "Neuropharmacology", "neurology", "Cerebrovascular diseases", "Ischemic stroke", "Neuro-ophthalmology", "ophthalmology", "Retinal disorders", "heme-containing", "co-target", "nos", "alf186", "mediated"], "article_id"=>677667, "categories"=>["Medicine", "Biological Sciences"], "users"=>["Nils Schallner", "Carlos C. Romão", "Julia Biermann", "Wolf A. Lagrèze", "Leo E. Otterbein", "Hartmut Buerkle", "Torsten Loop", "Ulrich Goebel"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0060672.g003", "stats"=>{"downloads"=>0, "page_views"=>3, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_The_role_of_the_heme_containing_8220_primary_8221_CO_target_NOS_in_ALF186_mediated_effects_/677667", "title"=>"The role of the heme-containing “primary” CO-target NOS in ALF186 mediated effects.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-04-08 02:07:47"}
  • {"files"=>["https://ndownloader.figshare.com/files/1018355"], "description"=>"<p><b>A:</b> Representative experiment after FITC Annexin V and propidiumiodide staining and flow-cytometric analysis. 1×10<sup>4</sup> cells in each experiment were analyzed. <b>B:</b> ALF186-mediated effect on apoptosis analyzed by Annexin V staining (top, n = 6; mean±SD; * = p<0.001 rotenone vs. ALF186 10, 50 and 100 µmol/L+rotenone) and caspase-3 cleavage (bottom, representative Western blot of caspase-3 cleavage products). <b>C:</b> Flow-cytometric analysis of mitochondrial membrane potential change relative to untreated cells (ΔΨ<sub>m</sub>, n = 6; mean±SD; * = p<0.05 rotenone vs. ALF186+ rotenone and ALF186+ rotenone vs. iALF186+ rotenone).</p>", "links"=>[], "tags"=>["Model organisms", "Animal models", "rat", "Molecular cell biology", "cytometry", "flow cytometry", "Signal transduction", "Signaling in cellular processes", "Antiapoptotic signaling", "cGMP signaling", "Cell death", "Cellular stress responses", "neuroscience", "Molecular neuroscience", "Signaling pathways", "Neurochemistry", "Neurochemicals", "Nitric oxide", "Drugs and devices", "Neuropharmacology", "neurology", "Cerebrovascular diseases", "Ischemic stroke", "Neuro-ophthalmology", "ophthalmology", "Retinal disorders", "alf186", "rotenone-induced"], "article_id"=>677666, "categories"=>["Medicine", "Biological Sciences"], "users"=>["Nils Schallner", "Carlos C. Romão", "Julia Biermann", "Wolf A. Lagrèze", "Leo E. Otterbein", "Hartmut Buerkle", "Torsten Loop", "Ulrich Goebel"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0060672.g002", "stats"=>{"downloads"=>0, "page_views"=>2, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Effect_of_ALF186_on_rotenone_induced_apoptosis_/677666", "title"=>"Effect of ALF186 on rotenone-induced apoptosis.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-04-08 02:07:46"}
  • {"files"=>["https://ndownloader.figshare.com/files/1018358"], "description"=>"<p><b>A:</b> ELISA analysis of cellular cGMP concentration after ALF186 treatment (n = 6; median±25<sup>th</sup>/75<sup>th</sup> percentile; * = p<0.05 untreated vs. ALF186 10, 50, 100 µmol/L). <b>B:</b> Analysis of cellular cGMP concentration after ALF186 treatment ± sGC-Inhibition by ODQ (n = 6; median±25<sup>th</sup>/75<sup>th</sup> percentile; * = p<0.05 untreated vs. ALF186 and ALF186 vs. ODQ +ALF186). <b>C:</b> Effect of ALF186 on sGC β<sub>1</sub> subunit mRNA (top; RT-PCR analysis, n = 6; median±25<sup>th</sup>/75<sup>th</sup> percentile; * = p<0.05 untreated vs. ALF186 50 µmol/L and rotenone vs. ALF186 50, 100 µmol/L+rotenone) and protein (bottom, representative Western Blot of sGC β<sub>1</sub> protein) expression.</p>", "links"=>[], "tags"=>["Model organisms", "Animal models", "rat", "Molecular cell biology", "cytometry", "flow cytometry", "Signal transduction", "Signaling in cellular processes", "Antiapoptotic signaling", "cGMP signaling", "Cell death", "Cellular stress responses", "neuroscience", "Molecular neuroscience", "Signaling pathways", "Neurochemistry", "Neurochemicals", "Nitric oxide", "Drugs and devices", "Neuropharmacology", "neurology", "Cerebrovascular diseases", "Ischemic stroke", "Neuro-ophthalmology", "ophthalmology", "Retinal disorders", "alf186", "cellular", "cgmp"], "article_id"=>677669, "categories"=>["Medicine", "Biological Sciences"], "users"=>["Nils Schallner", "Carlos C. Romão", "Julia Biermann", "Wolf A. Lagrèze", "Leo E. Otterbein", "Hartmut Buerkle", "Torsten Loop", "Ulrich Goebel"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0060672.g005", "stats"=>{"downloads"=>0, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Effect_of_ALF186_on_cellular_cGMP_levels_and_expression_of_sGC_/677669", "title"=>"Effect of ALF186 on cellular cGMP levels and expression of sGC.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-04-08 02:07:49"}
  • {"files"=>["https://ndownloader.figshare.com/files/1018357"], "description"=>"<p><b>A:</b> Flow-cytometric analysis of ROS production after CM-H<sub>2</sub>DCFDA staining (n = 6; mean±SD; * = p<0.05 all vs. untreated; rotenone vs. ALF186 and vs. PMA). <b>B:</b> Flow-cytometric analysis of mitochondrial membrane potential change relative to untreated cells after NADPH oxidase inhibition (ΔΨ<sub>m</sub>, n = 6; mean±SD; * = p<0.05 DPI vs. untreated; rotenone vs. ALF186+rotenone and ALF186+rotenone vs. DPI+ALF186+rotenone).</p>", "links"=>[], "tags"=>["Model organisms", "Animal models", "rat", "Molecular cell biology", "cytometry", "flow cytometry", "Signal transduction", "Signaling in cellular processes", "Antiapoptotic signaling", "cGMP signaling", "Cell death", "Cellular stress responses", "neuroscience", "Molecular neuroscience", "Signaling pathways", "Neurochemistry", "Neurochemicals", "Nitric oxide", "Drugs and devices", "Neuropharmacology", "neurology", "Cerebrovascular diseases", "Ischemic stroke", "Neuro-ophthalmology", "ophthalmology", "Retinal disorders", "alf186", "ros", "nadph", "oxidase", "mediated"], "article_id"=>677668, "categories"=>["Medicine", "Biological Sciences"], "users"=>["Nils Schallner", "Carlos C. Romão", "Julia Biermann", "Wolf A. Lagrèze", "Leo E. Otterbein", "Hartmut Buerkle", "Torsten Loop", "Ulrich Goebel"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0060672.g004", "stats"=>{"downloads"=>0, "page_views"=>7, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Influence_of_ALF186_on_ROS_production_and_role_of_NADPH_oxidase_in_ALF186_mediated_effects_/677668", "title"=>"Influence of ALF186 on ROS production and role of NADPH oxidase in ALF186 mediated effects.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-04-08 02:07:48"}
  • {"files"=>["https://ndownloader.figshare.com/files/1018354"], "description"=>"<p>Carbon monoxide liberating compound containing a central molybdenum atom.</p>", "links"=>[], "tags"=>["Model organisms", "Animal models", "rat", "Molecular cell biology", "cytometry", "flow cytometry", "Signal transduction", "Signaling in cellular processes", "Antiapoptotic signaling", "cGMP signaling", "Cell death", "Cellular stress responses", "neuroscience", "Molecular neuroscience", "Signaling pathways", "Neurochemistry", "Neurochemicals", "Nitric oxide", "Drugs and devices", "Neuropharmacology", "neurology", "Cerebrovascular diseases", "Ischemic stroke", "Neuro-ophthalmology", "ophthalmology", "Retinal disorders"], "article_id"=>677665, "categories"=>["Medicine", "Biological Sciences"], "users"=>["Nils Schallner", "Carlos C. Romão", "Julia Biermann", "Wolf A. Lagrèze", "Leo E. Otterbein", "Hartmut Buerkle", "Torsten Loop", "Ulrich Goebel"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0060672.g001", "stats"=>{"downloads"=>2, "page_views"=>38, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Chemical_structure_of_ALF186_/677665", "title"=>"Chemical structure of ALF186.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-04-08 02:07:45"}

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Relative Metric

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