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World J Clin Cases. Apr 6, 2025; 13(10): 101647
Published online Apr 6, 2025. doi: 10.12998/wjcc.v13.i10.101647
Role of nitric oxide in cerebral ischemia/reperfusion injury: A biomolecular overview
Roberto Anaya-Prado, Abraham I Canseco-Villegas, Roberto Anaya-Fernández, Michelle Marie Anaya-Fernandez, Miguel A Guerrero-Palomera, Citlalli Guerrero-Palomera, Ivan F Garcia-Ramirez, Daniel Gonzalez-Martinez, Consuelo Cecilia Azcona-Ramírez, Claudia Garcia-Perez, Airim L Lizarraga-Valencia, Aranza Hernandez-Zepeda, Jacqueline F Palomares-Covarrubias, Jorge HA Blackaller-Medina, Jacqueline Soto-Hintze, Mayra C Velarde-Castillo, Dayri A Cruz-Melendrez
Roberto Anaya-Prado, Department of Research & Department of Surgery, School of Medicine and Health Sciences, Tecnologico de Monterrey, Corporate Hospitals Puerta de Hierro, Zapopan 45116, Jalisco, Mexico
Roberto Anaya-Prado, Direction of Research and Education, Corporate Hospitals Puerta de Hierro, Zapopan 45116, Jalisco, Mexico
Abraham I Canseco-Villegas, Jacqueline Soto-Hintze, Department of Research, School of Medicine and Health Sciences, Tecnologico de Monterrey, Zapopan 45116, Jalisco, Mexico
Abraham I Canseco-Villegas, Roberto Anaya-Fernández, Michelle Marie Anaya-Fernandez, Jacqueline F Palomares-Covarrubias, Jacqueline Soto-Hintze, Mayra C Velarde-Castillo, Division of Research and Education, Corporate Hospitals Puerta de Hierro, Zapopan 45116, Jalisco, Mexico
Roberto Anaya-Fernández, Mayra C Velarde-Castillo, Dayri A Cruz-Melendrez, Division of Research, School of Medicine, University of Guadalajara, Guadalajara 44340, Jalisco, Mexico
Michelle Marie Anaya-Fernandez, Miguel A Guerrero-Palomera, Citlalli Guerrero-Palomera, Ivan F Garcia-Ramirez, Daniel Gonzalez-Martinez, Consuelo Cecilia Azcona-Ramírez, Airim L Lizarraga-Valencia, Aranza Hernandez-Zepeda, Jacqueline F Palomares-Covarrubias, Division of Research, School of Medicine, Autonomous University of Guadalajara, Zapopan 45116, Jalisco, Mexico
Miguel A Guerrero-Palomera, Citlalli Guerrero-Palomera, Daniel Gonzalez-Martinez, Consuelo Cecilia Azcona-Ramírez, Claudia Garcia-Perez, Airim L Lizarraga-Valencia, Aranza Hernandez-Zepeda, Jorge HA Blackaller-Medina, Dayri A Cruz-Melendrez, Research & Education, Corporate Hospitals Puerta de Hierro, Zapopan 45116, Jalisco, Mexico
Ivan F Garcia-Ramirez, Division of Research, Corporate Hospitals Puerta de Hierro, Zapopan 45116, Jalisco, Mexico
Jorge HA Blackaller-Medina, Research, School of Medicine, UNIVA University, Zapopan 45116, Jalisco, Mexico
Author contributions: Anaya-Prado R, Canseco-Villegas AI, Anaya-Fernández R, Anaya-Fernandez MM designed research; Guerrero-Palomera MA, Guerrero-Palomera C, Garcia-Ramirez IF, Gonzalez-Martinez D, Azcona-Ramírez CC, Garcia-Perez C, Lizarraga-Valencia AL, Hernandez-Zepeda A performed research; Palomares-Covarrubias JF, Blackaller-Medina JHA, Soto-Hintze J, Velarde-Castillo MC, Cruz-Melendrez DA contributed new analytic tools; Anaya-Prado R, Canseco-Villegas AI, Anaya-Fernández R, Garcia-Ramirez IF, Guerrero-Palomera MA analyzed data; Canseco-Villegas AI, Anaya-Fernández R, Anaya-Fernandez MM, Soto-Hintze J wrote the paper. All authors contributed equally to the conception, literature review, drafting, the overall content and revising of the article. We all approved the version of the manuscript to be published.
Conflict-of-interest statement: The authors have declared that no competing interest exists.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Roberto Anaya-Prado, MD, MSc, PhD, Professor, Department of Research & Department of Surgery, School of Medicine and Health Sciences, Tecnologico de Monterrey, Corporate Hospitals Puerta de Hierro, Blvd Puerta de Hierro, No. 5150 Int 201B, Fraccionamiento Puerta de Hierro, Zapopan 45116, Jalisco, Mexico. robana1112@gmail.com
Received: September 25, 2024
Revised: November 19, 2024
Accepted: December 2, 2024
Published online: April 6, 2025
Processing time: 84 Days and 9.1 Hours
Abstract

Nitric oxide (NO) is a gaseous molecule produced by 3 different NO synthase (NOS) isoforms: Neural/brain NOS (nNOS/bNOS, type 1), endothelial NOS (eNOS, type 3) and inducible NOS (type 2). Type 1 and 3 NOS are constitutively expressed. NO can serve different purposes: As a vasoactive molecule, as a neurotransmitter or as an immunomodulator. It plays a key role in cerebral ischemia/reperfusion injury (CIRI). Hypoxic episodes simulate the production of oxygen free radicals, leading to mitochondrial and phospholipid damage. Upon reperfusion, increased levels of oxygen trigger oxide synthases; whose products are associated with neuronal damage by promoting lipid peroxidation, nitrosylation and excitotoxicity. Molecular pathways in CIRI can be altered by NOS. Neuroprotective effects are observed with eNOS activity. While nNOS interplay is prone to endothelial inflammation, oxidative stress and apoptosis. Therefore, nNOS appears to be detrimental. The interaction between NO and other free radicals develops peroxynitrite; which is a cytotoxic agent. It plays a main role in the likelihood of hemorrhagic events by tissue plasminogen activator (t-PA). Peroxynitrite scavengers are currently being studied as potential targets to prevent hemorrhagic transformation in CIRI.

Keywords: Nitric oxide; Cerebral ischemia/reperfusion injury; Nitric oxide synthase; Reactive nitrogen species; Nitrosylation

Core Tip: Nitric oxide (NO) plays a key role in cerebral ischemia/reperfusion injury (CIRI). Ischemic episodes lead to mitochondrial and phospholipid damage. While reperfusion is associated with neuronal damage by promoting lipid peroxidation, nitrosylation and excitotoxicity. Neural NO synthase (nNOS) interplay is prone to endothelial inflammation, oxidative stress and apoptosis. Therefore, nNOS appears to be detrimental. The interaction between NO and other free radicals develops peroxynitrite. And, limiting the negative effects of NO-derived compounds has been implemented as an important strategy to improve neurological outcomes after CIRI.