iScience (Nov 2024)
Preclinical validation of human recombinant glutamate-oxaloacetate transaminase for the treatment of acute ischemic stroke
- María Pérez-Mato,
- Antonio Dopico-López,
- Yunus Akkoc,
- Sonia López-Amoedo,
- Clara Correa-Paz,
- María Candamo-Lourido,
- Ramón Iglesias-Rey,
- Esteban López-Arias,
- Ana Bugallo-Casal,
- Andrés da Silva-Candal,
- Susana B. Bravo,
- María del Pilar Chantada-Vázquez,
- Susana Arias,
- María Santamaría-Cadavid,
- Ana Estany-Gestal,
- Ahlem Zaghmi,
- Marc A. Gauthier,
- María Gutiérrez-Fernández,
- Abraham Martin,
- Jordi Llop,
- Cristina Rodríguez,
- Ángeles Almeida,
- Martina Migliavacca,
- Ester Polo,
- Beatriz Pelaz,
- Devrim Gozuacik,
- Naouale El Yamani,
- Tanima SenGupta,
- Elise Rundén-Pran,
- José Vivancos,
- Mar Castellanos,
- Exuperio Díez-Tejedor,
- Tomás Sobrino,
- Aharon Rabinkov,
- David Mirelman,
- José Castillo,
- Francisco Campos
Affiliations
- María Pérez-Mato
- Translational Stroke Laboratory Group (TREAT), Clinical Neurosciences Research Laboratory (LINC), Health Research Institute of Santiago de Compostela (IDIS), 15706 Santiago de Compostela, Spain; Neurological Sciences and Cerebrovascular Research Laboratory, Department of Neurology, Neurology and Cerebrovascular Disease Group, Neuroscience Area of Hospital La Paz Institute for Health Research – IdiPAZ (La Paz University Hospital- Universidad Autónoma de Madrid), 28029 Madrid, Spain
- Antonio Dopico-López
- Translational Stroke Laboratory Group (TREAT), Clinical Neurosciences Research Laboratory (LINC), Health Research Institute of Santiago de Compostela (IDIS), 15706 Santiago de Compostela, Spain
- Yunus Akkoc
- Koç University Research Center for Translational Medicine (KUTTAM), Istanbul 34450, Turkey; Department of Medical Biology, Koç University School of Medicine, Istanbul 34450, Turkey
- Sonia López-Amoedo
- Translational Stroke Laboratory Group (TREAT), Clinical Neurosciences Research Laboratory (LINC), Health Research Institute of Santiago de Compostela (IDIS), 15706 Santiago de Compostela, Spain
- Clara Correa-Paz
- Translational Stroke Laboratory Group (TREAT), Clinical Neurosciences Research Laboratory (LINC), Health Research Institute of Santiago de Compostela (IDIS), 15706 Santiago de Compostela, Spain
- María Candamo-Lourido
- Translational Stroke Laboratory Group (TREAT), Clinical Neurosciences Research Laboratory (LINC), Health Research Institute of Santiago de Compostela (IDIS), 15706 Santiago de Compostela, Spain
- Ramón Iglesias-Rey
- Neuroimaging and Biotechnology Laboratory Group (NOBEL), Clinical Neurosciences Research Laboratory (LINC), Health Research Institute of Santiago de Compostela (IDIS), 15706 Santiago de Compostela, Spain
- Esteban López-Arias
- Translational Stroke Laboratory Group (TREAT), Clinical Neurosciences Research Laboratory (LINC), Health Research Institute of Santiago de Compostela (IDIS), 15706 Santiago de Compostela, Spain
- Ana Bugallo-Casal
- Translational Stroke Laboratory Group (TREAT), Clinical Neurosciences Research Laboratory (LINC), Health Research Institute of Santiago de Compostela (IDIS), 15706 Santiago de Compostela, Spain
- Andrés da Silva-Candal
- Neurology Service, University Hospital Complex of A Coruña, A Coruña Biomedical Research Institute, 15006 A Coruña, Spain
- Susana B. Bravo
- Proteomic Unit, Health Research Institute of Santiago de Compostela (IDIS), 15706 Santiago de Compostela, Spain
- María del Pilar Chantada-Vázquez
- Proteomic Unit, Health Research Institute of Santiago de Compostela (IDIS), 15706 Santiago de Compostela, Spain; Research Unit, Lucus Augusti University Hospital (HULA), Servizo Galego de Saúde (SERGAS), 27002 Lugo, Spain
- Susana Arias
- Stroke Unit, Department of Neurology, Hospital Clínico Universitario, 15706 Santiago de Compostela, Spain
- María Santamaría-Cadavid
- Stroke Unit, Department of Neurology, Hospital Clínico Universitario, 15706 Santiago de Compostela, Spain
- Ana Estany-Gestal
- Unit of Methodology of the Research, Health Research Institute of Santiago de Compostela (IDIS), 15706 Santiago de Compostela, Spain
- Ahlem Zaghmi
- Institut National de la Recherche Scientifique (INRS), EMT Research Center, Varennes, QC J3X 1S2, Canada; Rheumatology Unit, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, 171 77 Stockholm, Sweden
- Marc A. Gauthier
- Institut National de la Recherche Scientifique (INRS), EMT Research Center, Varennes, QC J3X 1S2, Canada
- María Gutiérrez-Fernández
- Neurological Sciences and Cerebrovascular Research Laboratory, Department of Neurology, Neurology and Cerebrovascular Disease Group, Neuroscience Area of Hospital La Paz Institute for Health Research – IdiPAZ (La Paz University Hospital- Universidad Autónoma de Madrid), 28029 Madrid, Spain
- Abraham Martin
- Achucarro Basque Center for Neuroscience, 48940 Leioa, Spain; Ikerbasque Basque Foundation for Science, 48009 Bilbao, Spain
- Jordi Llop
- CIC biomaGUNE, Basque Research and Technology Alliance (BRTA), 20014 San Sebastian, Spain
- Cristina Rodríguez
- Institute of Functional Biology and Genomics (IBFG), CSIC, University of Salamanca, 37007 Salamanca, Spain; Institute of Biomedical Research of Salamanca (IBSAL), University Hospital of Salamanca, CSIC, University of Salamanca, 37007 Salamanca, Spain
- Ángeles Almeida
- Institute of Functional Biology and Genomics (IBFG), CSIC, University of Salamanca, 37007 Salamanca, Spain; Institute of Biomedical Research of Salamanca (IBSAL), University Hospital of Salamanca, CSIC, University of Salamanca, 37007 Salamanca, Spain
- Martina Migliavacca
- Center for Research in Biological Chemistry and Molecular Materials (CiQUS), University of Santiago de Compostela, 15705 Santiago de Compostela, Spain
- Ester Polo
- Center for Research in Biological Chemistry and Molecular Materials (CiQUS), University of Santiago de Compostela, 15705 Santiago de Compostela, Spain
- Beatriz Pelaz
- Center for Research in Biological Chemistry and Molecular Materials (CiQUS), University of Santiago de Compostela, 15705 Santiago de Compostela, Spain
- Devrim Gozuacik
- Koç University Research Center for Translational Medicine (KUTTAM), Istanbul 34450, Turkey; Department of Medical Biology, Koç University School of Medicine, Istanbul 34450, Turkey
- Naouale El Yamani
- Health Effects Laboratory, Department for Environmental Chemistry, NILU-Norwegian Institute for Air Research, 2027 Kjeller, Norway
- Tanima SenGupta
- Health Effects Laboratory, Department for Environmental Chemistry, NILU-Norwegian Institute for Air Research, 2027 Kjeller, Norway
- Elise Rundén-Pran
- Health Effects Laboratory, Department for Environmental Chemistry, NILU-Norwegian Institute for Air Research, 2027 Kjeller, Norway
- José Vivancos
- Stroke Unit, Department of Neurology, Hospital Universitario de La Princesa & Instituto de Investigación Sanitaria La Princesa, 28006 Madrid, Spain
- Mar Castellanos
- Neurology Service, University Hospital Complex of A Coruña, A Coruña Biomedical Research Institute, 15006 A Coruña, Spain
- Exuperio Díez-Tejedor
- Neurological Sciences and Cerebrovascular Research Laboratory, Department of Neurology, Neurology and Cerebrovascular Disease Group, Neuroscience Area of Hospital La Paz Institute for Health Research – IdiPAZ (La Paz University Hospital- Universidad Autónoma de Madrid), 28029 Madrid, Spain
- Tomás Sobrino
- NeuroAging Group (NEURAL), Clinical Neurosciences Research Laboratory (LINC), Health Research Institute of Santiago de Compostela (IDIS), 15706 Santiago de Compostela, Spain; Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, 28029 Madrid, Spain
- Aharon Rabinkov
- Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot 7610001, Israel
- David Mirelman
- Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot 7610001, Israel
- José Castillo
- Neuroimaging and Biotechnology Laboratory Group (NOBEL), Clinical Neurosciences Research Laboratory (LINC), Health Research Institute of Santiago de Compostela (IDIS), 15706 Santiago de Compostela, Spain
- Francisco Campos
- Translational Stroke Laboratory Group (TREAT), Clinical Neurosciences Research Laboratory (LINC), Health Research Institute of Santiago de Compostela (IDIS), 15706 Santiago de Compostela, Spain; Corresponding author
- Journal volume & issue
-
Vol. 27,
no. 11
p. 111108
Abstract
Summary: The blood enzyme glutamate-oxaloacetate transaminase (GOT) has been postulated as an effective therapeutic to protect the brain during stroke. To demonstrate its potential clinical utility, a new human recombinant form of GOT (rGOT) was produced for medical use.We tested the pharmacokinetics and evaluated the protective efficacy of rGOT in rodent and non-human primate models that reflected clinical stroke conditions.We found that continuous intravenous administration of rGOT within the first 8 h after ischemic onset significantly reduced the infarct size in both severe (30%) and mild lesions (48%). Cerebrospinal fluid and proteomics analysis, in combination with positron emission tomography imaging, indicated that rGOT can reach the brain and induce cytoprotective autophagy and induce local protection by alleviating neuronal apoptosis.Our results suggest that rGOT can be safely used immediately in patients suspected of having a stroke. This study requires further validation in clinical stroke populations.
