Lorena Barata1, Luis Arruza2, Maria-José Rodríguez2, Esther Aleo2, Eva Vierge2, Enrique Criado2, Elena Sobrino3, Carlos Vargas4, María Ceprián5, Ana Gutiérrez-Rodríguez4, William Hind6, José Martínez-Orgado7. 1. Instituto de Investigación Sanitaria San Carlos (IdISSC), Madrid, Spain; Instituto de Investigación Puerta de Hierro Majadahonda, Spain. 2. Servicio de Neonatología, Hospital Clínico San Carlos - IdISSC, Madrid, Spain. 3. Instituto de Investigación Puerta de Hierro Majadahonda, Spain. 4. Instituto de Investigación Sanitaria San Carlos (IdISSC), Madrid, Spain. 5. Instituto de Investigación Sanitaria San Carlos (IdISSC), Madrid, Spain; Departamento de Bioquímica y Biología Molecular, CIBERNED, IRICYS. Facultad de Medicina, Universidad Complutense de Madrid, Spain. 6. GW Research Ltd, Cambridge, UK. 7. Instituto de Investigación Sanitaria San Carlos (IdISSC), Madrid, Spain; Servicio de Neonatología, Hospital Clínico San Carlos - IdISSC, Madrid, Spain. Electronic address: jose.martinezo@salud.madrid.org.
Abstract
OBJECTIVE: Hypothermia, the gold standard after a hypoxic-ischemic insult, is not beneficial in all treated newborns. Cannabidiol is neuroprotective in animal models of newborn hypoxic-ischemic encephalopathy. This study compared the relative efficacies of cannabidiol and hypothermia in newborn hypoxic-ischemic piglets and assessed whether addition of cannabidiol augments hypothermic neuroprotection. METHODS: One day-old HI (carotid clamp and FiO2 10% for 20 min) piglets were randomized to vehicle or cannabidiol 1 mg/kg i.v. u.i.d. for three doses after being submitted to normothermia or 48 h-long hypothermia with a subsequent rewarming period of 6 h. Non-manipulated piglets (naïve) served as controls. Hemodynamic or respiratory parameters as well as brain activity (aEEG amplitude) were monitored throughout the experiment. Following termination, brains were obtained for histological (TUNEL staining, apoptosis; immunohistochemistry for Iba-1, microglia), biochemical (protein carbonylation, oxidative stress; and TNFα concentration, neuroinflammation) or proton magnetic resonance spectroscopy (Lac/NAA: metabolic derangement; Glu/NAA: excitotoxicity). RESULTS: HI led to sustained depressed brain activity and increased microglial activation, which was significantly improved by cannabidiol alone or with hypothermia but not by hypothermia alone. Hypoxic-ischemic-induced increases in Lac/NAA, Glu/NAA, TNFα or apoptosis were not reversed by either hypothermia or cannabidiol alone, but combination of the therapies did. No treatment modified the effects of HI on oxidative stress or astroglial activation. Cannabidiol treatment was well tolerated. CONCLUSIONS: cannabidiol administration after hypoxia-ischemia in piglets offers some neuroprotective effects but the combination of cannabidiol and hypothermia shows some additive effect leading to more complete neuroprotection than cannabidiol or hypothermia alone.
OBJECTIVE:Hypothermia, the gold standard after a hypoxic-ischemic insult, is not beneficial in all treated newborns. Cannabidiol is neuroprotective in animal models of newborn hypoxic-ischemic encephalopathy. This study compared the relative efficacies of cannabidiol and hypothermia in newborn hypoxic-ischemic piglets and assessed whether addition of cannabidiolaugments hypothermic neuroprotection. METHODS: One day-old HI (carotid clamp and FiO2 10% for 20 min) piglets were randomized to vehicle or cannabidiol 1 mg/kg i.v. u.i.d. for three doses after being submitted to normothermia or 48 h-long hypothermia with a subsequent rewarming period of 6 h. Non-manipulated piglets (naïve) served as controls. Hemodynamic or respiratory parameters as well as brain activity (aEEG amplitude) were monitored throughout the experiment. Following termination, brains were obtained for histological (TUNEL staining, apoptosis; immunohistochemistry for Iba-1, microglia), biochemical (protein carbonylation, oxidative stress; and TNFα concentration, neuroinflammation) or proton magnetic resonance spectroscopy (Lac/NAA: metabolic derangement; Glu/NAA: excitotoxicity). RESULTS:HI led to sustained depressed brain activity and increased microglial activation, which was significantly improved by cannabidiol alone or with hypothermia but not by hypothermia alone. Hypoxic-ischemic-induced increases in Lac/NAA, Glu/NAA, TNFα or apoptosis were not reversed by either hypothermia or cannabidiol alone, but combination of the therapies did. No treatment modified the effects of HI on oxidative stress or astroglial activation. Cannabidiol treatment was well tolerated. CONCLUSIONS:cannabidiol administration after hypoxia-ischemia in piglets offers some neuroprotective effects but the combination of cannabidiol and hypothermia shows some additive effect leading to more complete neuroprotection than cannabidiol or hypothermia alone.
Authors: Aarón Del Pozo; María Villa; Carlos Vargas; David Castejón; M Encarnación Fernández-Valle; Ana Gutiérrez-Rodríguez; José Martínez-Orgado Journal: Pediatr Res Date: 2022-04-15 Impact factor: 3.756
Authors: Luis Arruza; Lorena Barata; Eva Vierge; Maria José Rodríguez; Aaron Del Pozo; William Hind; José Martínez-Orgado Journal: Front Pediatr Date: 2022-06-06 Impact factor: 3.569
Authors: Nilson C Ferreira-Junior; Alline C Campos; Francisco S Guimarães; Elaine Del-Bel; Patrícia M da R Zimmermann; Liberato Brum Junior; Jaime E Hallak; José A Crippa; Antonio W Zuardi Journal: Braz J Psychiatry Date: 2019-07-15 Impact factor: 2.697