Preclinical validation of human recombinant glutamate-oxaloacetate transaminase for the treatment of acute ischemic stroke
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.
Authors
- María Gutiérrez‐Fernández (ORCID: https://orcid.org/0000-0002-6615-4729)
- Beatriz Pelaz (ORCID: https://orcid.org/0000-0002-4626-4576)
- Ester Polo (ORCID: https://orcid.org/0000-0001-8870-5280)
- Naouale El Yamani (ORCID: https://orcid.org/0000-0001-5456-8230)
- Martina Migliavacca (ORCID: https://orcid.org/0000-0003-3125-3548)
- Exuperio Díez‐Tejedor (ORCID: https://orcid.org/0000-0003-2295-1707)
- Sonia López-Amoedo (ORCID: https://orcid.org/0000-0002-0497-4393)
- María Candamo-Lourido (ORCID: https://orcid.org/0000-0001-6539-5574)
- María Pérez‐Mato
- Marc A. Gauthier (ORCID: https://orcid.org/0000-0002-5408-6570)
- Ana Estany‐Gestal (ORCID: https://orcid.org/0000-0001-7997-3603)
- Yunus Akkoç (ORCID: https://orcid.org/0000-0001-5379-6151)
- María del Pilar Chantada‐Vázquez (ORCID: https://orcid.org/0000-0001-8652-4961)
- Jordi Llop (ORCID: https://orcid.org/0000-0002-0821-9838)
- Devrim Gözüaçık (ORCID: https://orcid.org/0000-0001-7739-2346)
- Antonio Dopico‐López
- Susana B. Bravo (ORCID: https://orcid.org/0000-0001-7615-3079)
- Ana Bugallo-Casal (ORCID: https://orcid.org/0000-0003-2766-6585)
- Ángeles Almeida (ORCID: https://orcid.org/0000-0003-0485-8904)
- Elise Rundén‐Pran (ORCID: https://orcid.org/0000-0002-5541-4513)
- Abraham Martín (ORCID: https://orcid.org/0000-0002-5357-4935)
- José Vivancos (ORCID: https://orcid.org/0000-0002-9339-2917)
- Cristina Rodríguez (ORCID: https://orcid.org/0000-0003-1588-5801)
- Andrés da Silva‐Candal (ORCID: https://orcid.org/0000-0001-5014-2224)
- Tomás Sobrino (ORCID: https://orcid.org/0000-0002-9760-8690)
- Mar Castellanos (ORCID: https://orcid.org/0000-0003-3116-1352)
- María Santamaría-Cadavid
- Ahlem Zaghmi
- Ramón Iglesias‐Rey (ORCID: https://orcid.org/0000-0002-9985-9135)
- David Mirelman
- Tanima SenGupta
- José Castillo (ORCID: https://orcid.org/0000-0002-6685-3001)
- Esteban López‐Arias (ORCID: https://orcid.org/0000-0002-0242-3600)
- Clara Correa‐Paz (ORCID: https://orcid.org/0000-0001-8940-1852)
- Francisco Campos (ORCID: https://orcid.org/0000-0001-8665-1039)
- Susana Arias (ORCID: https://orcid.org/0000-0002-1620-4062)
- Aharon Rabinkov
Institutions
- Ikerbasque (ES)
- Karolinska University Hospital (SE)
- Koç University (TR)
- Universidad de Salamanca (ES)
- Universidade de Santiago de Compostela (ES)
- Hospital Universitario La Paz (ES)
- Instituto de Salud Carlos III (ES)
- Institut National de la Recherche Scientifique (CA)
- Biomedical Research Networking Center on Neurodegenerative Diseases (ES)
- CIC biomaGUNE (ES)
- Complejo Hospitalario Universitario de Santiago (ES)
- Achucarro Basque Center for Neuroscience (ES)
- Hospital La Paz Institute for Health Research (ES)
- Center for Research in Molecular Medicine and Chronic Diseases (ES)
- Centro de Investigación Biomédica en Red (ES)
- Hospital Universitario de La Princesa (ES)
- Instituto de Investigación Biomédica de Salamanca (ES)
- Hospital Universitario Lucus Augusti (ES)
- Instituto de Investigación Sanitaria de Santiago (ES)
- Instituto de Biología Funcional y Genómica (ES)
- Servicio Gallego de Salud (ES)
- Weizmann Institute of Science (IL)
- Universidad Autónoma de Madrid (ES)
- NILU (NO)
Publication Details
- Journal
- iScience
- Published
- 2024-10-09
- DOI
- https://doi.org/10.1016/j.isci.2024.111108
- Citations
- 5
- Primary Topic
- Neurological Disease Mechanisms and Treatments
- Type
- article
- Field-Weighted Citation Impact
- 1.24
Funders
- Fundación Mutua Madrileña
- EuroNanoMed III
- European Commission
- Ministerio de Ciencia e Innovación
- Consellería de Economía, Emprego e Industria, Xunta de Galicia
- Xunta de Galicia
- Fonds de Recherche du Québec - Santé
- Instituto de Salud Carlos III
- European Regional Development Fund
- Agencia Estatal de Investigación