Isoflurane anesthesia initiated at the onset of reperfusion attenuates oxidative and hypoxic-ischemic brain injury

• Published in: PloS one 2015-03, Vol.10 (3), p.e0120456
• Main Authors: Sosunov, Sergey A, Ameer, Xavier, Niatsetskaya, Zoya V, Utkina-Sosunova, Irina, Ratner, Veniamin I, Ten, Vadim S
• Format: Article
• Language: English
• Subjects: Anesthesia; Anesthetics, Inhalation; Animals; Atrophy; Attenuation; Blood flow; Blood Gas Analysis; Brain; Brain injuries; Brain injury; Cerebral blood flow; Cerebrovascular Circulation - drug effects; Counterbalances; Damage assessment; Disease Models, Animal; Electron transport; Emission analysis; Emission measurements; Emissions; Emissions (Pollution); Exposure; Halides; Head injuries; Hydrogen peroxide; Hydrogen Peroxide - metabolism; Hypoxia; Hypoxia-Ischemia, Brain - blood; Hypoxia-Ischemia, Brain - drug therapy; Hypoxia-Ischemia, Brain - metabolism; Inhibition; Injury prevention; Ischemia; Isoflurane; Isoflurane - administration & dosage; Isoflurane - pharmacology; Mechanical ventilation; Memory; Mice; Mitochondria; Mitochondria - metabolism; Mitochondrial DNA; Navigation behavior; Neonates; Neuroprotection; Neuroprotective Agents - administration & dosage; Neuroprotective Agents - pharmacology; Oxidative stress; Oxidative Stress - drug effects; Radicals; Reactive Oxygen Species - metabolism; Recovery; Reperfusion; Reperfusion Injury - blood; Reperfusion Injury - drug therapy; Reperfusion Injury - metabolism; Respiration; Respiration, Artificial; Rotenone; Ventilation
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0120456

This study demonstrates that in mice subjected to hypoxia-ischemia (HI) brain injury isoflurane anesthesia initiated upon reperfusion limits a release of mitochondrial oxidative radicals by inhibiting a recovery of complex-I dependent mitochondrial respiration. This significantly attenuates an oxidative stress and reduces the extent of HI brain injury. Neonatal mice were subjected to HI, and at the initiation of reperfusion were exposed to isoflurane with or without mechanical ventilation. At the end of HI and isoflurane exposure cerebral mitochondrial respiration, H2O2 emission rates were measured followed by an assessment of cerebral oxidative damage and infarct volumes. At 8 weeks after HI navigational memory and brain atrophy were assessed. In vitro, direct effect of isoflurane on mitochondrial H2O2 emission was compared to that of complex-I inhibitor, rotenone. Compared to controls, 15 minutes of isoflurane anesthesia inhibited recovery of the compex I-dependent mitochondrial respiration and decreased H2O2 production in mitochondria supported with succinate. This was associated with reduced oxidative brain injury, superior navigational memory and decreased cerebral atrophy compared to the vehicle-treated HI-mice. Extended isoflurane anesthesia was associated with sluggish recovery of cerebral blood flow (CBF) and the neuroprotection was lost. However, when isoflurane anesthesia was supported with mechanical ventilation the CBF recovery improved, the event associated with further reduction of infarct volume compared to HI-mice exposed to isoflurane without respiratory support. Thus, in neonatal mice brief isoflurane anesthesia initiated at the onset of reperfusion limits mitochondrial release of oxidative radicals and attenuates an oxidative stress. This novel mechanism contributes to neuroprotective action of isoflurane. The use of mechanical ventilation during isoflurane anesthesia counterbalances negative effect of isoflurane anesthesia on recovery of cerebral circulation which potentiates protection against reperfusion injury.