title: Semi-synthetic sapogenin exerts neuroprotective effects by skewing the brain ischemia reperfusion transcriptome towards inflammatory resolution.
abstract: Stroke represents one of the first causes of mortality and morbidity worldwide. We evaluated the therapeutic potential of a novel semi-synthetic spirosteroid sapogenin derivative "S15" in a transient middle cerebral artery occlusion (tMCAO) focal ischemia model in rat. S15-treated rats had significantly reduced infarct volumes and improved neurological functions at 24h post-reperfusion, compared with ischemia. Corresponding gene expression changes in brain were characterized by mRNA sequencing and qPCR approaches. Next, we applied geneset, pathway and transcription factor motif enrichment analysis to identify relevant signaling networks responsible for neuronal damage upon ischemia-reperfusion or neuroprotection upon pretreatment with S15. As expected, ischemia-reperfusion brain damage strongly modulates transcriptional programs associated with immune responses, increased differentiation of immune cells as well as reduced (cat)ion transport and synaptic activity. Interestingly, S15-dependent neuroprotection regulates inflammation-associated genes involved in phagosome specific resolution of tissue damage, chemotaxis and anti-inflammatory alternative activation of microglia. Altogether our transcriptome wide RNA sequencing and integrated pathway analysis provides new clues in the neuroprotective properties of a novel spirosteroid S15 or neuronal damage in rat brains subjected to ischemia, which opens new perspectives for successful treatment of stroke.
authors.affiliation: Centro de Investigación y Desarrollo de Medicamentos (CIDEM), BioCubaFarma, Ave 26, No. 1605 Boyeros y Puentes Grandes, CP 10600 La Habana, Cuba. Electronic address: laura.garcia@cidem.cu.
authors.forename: Laura
authors.initials: L
authors.lastname: García-Pupo
authors.affiliation: Centro de Investigación y Desarrollo de Medicamentos (CIDEM), BioCubaFarma, Ave 26, No. 1605 Boyeros y Puentes Grandes, CP 10600 La Habana, Cuba. Electronic address: yeney.ramirez@cidem.cu.
authors.forename: Jeney Ramírez
authors.initials: JR
authors.lastname: Sánchez
authors.affiliation: Receptor Research Laboratories, Nuclear Receptor Lab, Medical Biotechnology Center, VIB, Department of Biochemistry, Ghent University, Albert Baertsoenkaai 3, B-9000 Ghent, Belgium.
authors.forename: Dariusz
authors.initials: D
authors.lastname: Ratman
authors.affiliation: Proteinscience, Proteomics and Epigenetic Signaling, Department of Biomedical Sciences, University of Antwerp, Universiteitsplein 1, 2610 Antwerp, Belgium.
authors.forename: Claudina
authors.initials: C
authors.lastname: Pérez-Novo
authors.affiliation: Proteinscience, Proteomics and Epigenetic Signaling, Department of Biomedical Sciences, University of Antwerp, Universiteitsplein 1, 2610 Antwerp, Belgium.
authors.forename: Ken
authors.initials: K
authors.lastname: Declerck
authors.affiliation: Receptor Research Laboratories, Nuclear Receptor Lab, Medical Biotechnology Center, VIB, Department of Biochemistry, Ghent University, Albert Baertsoenkaai 3, B-9000 Ghent, Belgium.
authors.forename: Karolien
authors.initials: K
authors.lastname: De Bosscher
authors.affiliation: Integrated Molecular Plant Physiology Research (IMPRES), Department of Biology, University of Antwerp, Campus Groenenborger, Groenenborgerlaan 171 G.U.613, 2020 Antwerp, Belgium.
authors.forename: Marios Nektarios
authors.initials: MN
authors.lastname: Markakis
authors.affiliation: Integrated Molecular Plant Physiology Research (IMPRES), Department of Biology, University of Antwerp, Campus Groenenborger, Groenenborgerlaan 171 G.U.613, 2020 Antwerp, Belgium.
authors.forename: Gerrit
authors.initials: G
authors.lastname: Beemster
authors.affiliation: Centro de Estudios de Productos Naturales, Facultad de Química, Universidad de la Habana, Zapata s/n entre G y Carlitos Aguirre, Vedado, Plaza de la Revolución, CP 10400 La Habana, Cuba. Electronic address: zaldo@fq.uh.cu.
authors.forename: Armando
authors.initials: A
authors.lastname: Zaldo
authors.affiliation: Centro de Investigación y Desarrollo de Medicamentos (CIDEM), BioCubaFarma, Ave 26, No. 1605 Boyeros y Puentes Grandes, CP 10600 La Habana, Cuba. Electronic address: yanier.nunez@cidem.cu.
authors.forename: Yanier
authors.initials: Y
authors.lastname: Nuñez Figueredo
authors.affiliation: Centro de Investigación y Desarrollo de Medicamentos (CIDEM), BioCubaFarma, Ave 26, No. 1605 Boyeros y Puentes Grandes, CP 10600 La Habana, Cuba. Electronic address: rdelgado@infomed.sld.cu.
authors.forename: René
authors.initials: R
authors.lastname: Delgado-Hernández
authors.affiliation: Proteinscience, Proteomics and Epigenetic Signaling, Department of Biomedical Sciences, University of Antwerp, Universiteitsplein 1, 2610 Antwerp, Belgium. Electronic address: wim.vandenberghe@uantwerpen.be.
authors.forename: Wim
authors.initials: W
authors.lastname: Vanden Berghe
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy / Q000378:metabolism*; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy / Q000378:metabolism; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000188:drug therapy / Q000378:metabolism; D012502:Sapogenins / Q000008:administration & dosage*; D020521:Stroke / Q000188:drug therapy / Q000378:metabolism*; D059467:Transcriptome
chemical_list: D018696:Neuroprotective Agents; D012502:Sapogenins
keywords: Brain; Gene expression; Inflammation; Ischemia reperfusion; Neuroprotection; Sapogenin steroid