Isoflurane Provides Neuroprotection in Neonatal Hypoxic Ischemic Brain Injury

Burchell, Sherrefa R.; Dixon, Brandon; Tang, Jiping; Zhang, Junyi

doi:10.2310/jim.0b013e3182a07921

Cited by 52 publications

(36 citation statements)

References 49 publications

(97 reference statements)

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“…Anesthesia was provided with isoflurane which may have protective properties; 32, 33 however, isoflurane was provided to all animals in both groups, yet survival only occurred in the BP care group. 30, 31 Finally, our study was not blinded, so objective measures for rate, depth, leaning and ventilation, and strict adherence to a prospective post-cardiac arrest protocol were implemented to minimize risk for bias.…”

Section: Discussionmentioning

confidence: 99%

Blood Pressure– and Coronary Perfusion Pressure–Targeted Cardiopulmonary Resuscitation Improves 24-Hour Survival From Ventricular Fibrillation Cardiac Arrest

Naim

Sutton

Friess

et al. 2016

Critical Care Medicine

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Objective Treatment algorithms for cardiac arrest are rescuer-centric and vary little from patient to patient. The objective of this study was to determine if cardiopulmonary resuscitation (CPR) targeted to arterial blood pressure and coronary perfusion pressure (CPP) rather than optimal Guideline Care would improve 24-hour survival in a porcine model of ventricular fibrillation (VF) cardiac arrest. Design Randomized interventional study Setting Preclinical animal laboratory Subjects Female 3-month old swine Interventions/Measurements After induction of anesthesia and 7 minutes of untreated VF, 16 female 3-month old swine were randomized to: 1) Blood Pressure (BP) care: titration of chest compression (CC) depth to a systolic blood pressure (SBP) of 100 mmHg and vasopressor dosing to maintain CPP >20mmHg or 2) Guideline care: CC depth targeted to 51 mm and standard Guideline vasopressor dosing. Animals received manual CPR for 10 minutes before the first defibrillation attempt and standardized post-resuscitation care for 24 hours. Main Results 24-hour survival was more likely with BP care versus Guideline care (0/8 versus 5/8, p<0.03), and all survivors had normal neurological examinations. Mean CPP prior to defibrillation was significantly higher with BP care (28±3 mmHg versus 10±6 mmHg, p<0.01). CC depth was lower with BP care (48±0.4 mmHg versus 44±0.5 mmHg, p<0.05) and number of vasopressor doses was higher with BP care (median 3 [range 1-7] versus 2 [range 2-2], p<0.01). Conclusions Individualized goal-directed hemodynamic resuscitation targeting SBP of 100 mmHg and CPP >20 mmHg improved 24-hour survival compared to Guideline care in this model of VF cardiac arrest.

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Section: Discussionmentioning

confidence: 99%

Blood Pressure– and Coronary Perfusion Pressure–Targeted Cardiopulmonary Resuscitation Improves 24-Hour Survival From Ventricular Fibrillation Cardiac Arrest

Naim

Sutton

Friess

et al. 2016

Critical Care Medicine

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“…Unilateral HI surgery techniques were employed as previously described with P10 rat pups (Burchell et al, 2013; Fathali et al, 2010). P10 pups were underwent a unilateral right common carotid ligation.…”

Section: Methodsmentioning

confidence: 99%

“…In 20–40% of HI cases, infants develop neurological disorders, such as mental retardation, epilepsy, and cerebral palsy (Vannucci et al, 1999). Various experimental therapies have been investigated for improving HI patient outcomes and quality of life, yet successful clinical translation has been limited (Burchell et al, 2013; Koenigsberger, 2000; Zanelli et al, 2009). Thus it is of the utmost importance to identify novel therapeutics with potential for clinical translation.…”

Section: Introductionmentioning

confidence: 99%

G-CSF attenuates neuroinflammation and stabilizes the blood–brain barrier via the PI3K/Akt/GSK-3β signaling pathway following neonatal hypoxia-ischemia in rats

McBride

Doycheva

et al. 2015

Experimental Neurology

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Objective Neonatal hypoxia occurs in approximately 60% of premature births and is associated with a multitude of neurological disorders. While various treatments have been developed, translating them from bench to bedside has been limited. We previously showed G-CSF administration was neuroprotective in a neonatal hypoxia-ischemia rat pup model, leading us to hypothesize that G-CSF inactivation of GSK-3β via the PI3K/Akt pathway may attenuate neuroinflammation and stabilize the Blood-Brain Barrier (BBB). Methods P10 Sprague-Dawley rat pups were subjected to unilateral carotid artery ligation followed by hypoxia for 2.5 hours. We assessed inflammation by measuring expression levels of IKKβ, NF-κB, TNF-α, IL-1β, IL-10, and IL-12, as well as neutrophil infiltration. BBB stabilization was evaluated by measuring Evans blue extravasation, and Western blot analysis of Claudin-3, Claudin-5, ICAM-1 and VCAM-1. Measurements and Main Results First, the time course study showed that p-β-Catenin/β-Catenin, IKKβ, and NF-κB expression levels peaked at 48 hours post-HI. Knockdown of GSK-3β with siRNA prevented the HI-induced increase of p-β-Catenin/β-Catenin, IKKβ, and NF-κB expression levels 48 hours after HI. G-CSF treatment reduced brain water content and neuroinflammation by downregulating IKKβ, NF-κB, TNF-α, IL-1β, and IL-12 and upregulating IL-10, thereby reducing neutrophil infiltration. Additionally, G-CSF stabilizes the BBB by downregulating VCAM-1 and ICAM-1, as well as upregulating Claudins 3 and 5 in endothelial cells. G-CSFR knockdown by siRNA and Akt inhibition by Wortmannin reversed G-CSF’s neuroprotective effects. Conclusions We demonstrate G-CSF plays a pivotal role in attenuating neuroinflammation and BBB disruption following HI by inactivating GSK-3β through the PI3K/Akt pathway.

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“…Isoflurane is a widely used inhaled anesthetic, which reduces pain sensitivity via modulation of the neurotransmitter receptors, and exerts protective properties through antioxidant and anti-inflammatory effects [11, 12]. Prospects for the clinical usage of isoflurane (1.2-2.5%) have been hampered due to its adverse systemic effects [11]; however, our previous studies have shown that subanesthetic isoflurane (0.7%) protects against zymosan-induced lung injury by upregulating antioxidant enzymes and inhibiting inflammatory responses via the reduction of iNOS induction and NO production in neutrophils [7].…”

Section: Introductionmentioning

confidence: 99%

Subanesthetic isoflurane relieves zymosan-induced neutrophil inflammatory response by targeting NMDA glutamate receptor and Toll-like receptor 2 signaling

Wang

Wang³

et al. 2016

Oncotarget

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Neutrophil release of NO/ONOO− induces endothelial cell barrier dysfunction in inflammatory acute lung injury (ALI). Previous studies using zymosan-triggered inflammation and ALI model revealed that zymosan promotes inducible NO synthase (iNOS) expression in neutrophils, and that isoflurane inhibits zymosan-induced oxidative stress and iNOS biosynthesis. However, the underlying mechanisms remain largely unknown. We found here that in zymosan-primed neutrophils, iNOS is transcriptionally activated by NF-κB, whose nuclear translocation is triggered by excessive reactive oxygen species (ROS) and consequently activated p38 MAPK. ROS production is attributed to zymosan-initiated Toll-like receptor 2 (TLR2) signaling, in which the adaptor MyD88 recruits and activates c-Src, and c-Src activates NADPH oxidase to generate ROS. Subanesthetic isoflurane counteracts the aforementioned zymosan-induced signaling by targeting N-methyl-D-aspartic acid (NMDA) glutamate receptor and thereby suppressing calcium influx and c-Src activation. Whereas iNOS accelerates NO/ONOO− production in neutrophils which eventually promote protein leak from pulmonary microvascular endothelial cells (PMVEC), isoflurane reduced NO/ONOO− release from zymosan-treated neutrophils, and thus relieves trans- PMVEC protein leak. This study provides novel insights into the roles of neutrophils and the underlying mechanisms in zymosan-induced ALI, and has implications for the therapeutic potential of subanesthetic isoflurane in attenuating inflammatory responses causing lung endothelial cell damage.

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Isoflurane Provides Neuroprotection in Neonatal Hypoxic Ischemic Brain Injury

Cited by 52 publications

References 49 publications

Blood Pressure– and Coronary Perfusion Pressure–Targeted Cardiopulmonary Resuscitation Improves 24-Hour Survival From Ventricular Fibrillation Cardiac Arrest

Blood Pressure– and Coronary Perfusion Pressure–Targeted Cardiopulmonary Resuscitation Improves 24-Hour Survival From Ventricular Fibrillation Cardiac Arrest

G-CSF attenuates neuroinflammation and stabilizes the blood–brain barrier via the PI3K/Akt/GSK-3β signaling pathway following neonatal hypoxia-ischemia in rats

Subanesthetic isoflurane relieves zymosan-induced neutrophil inflammatory response by targeting NMDA glutamate receptor and Toll-like receptor 2 signaling

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