Xenon Provides Short-Term Neuroprotection in Neonatal Rats When Administered After Hypoxia-Ischemia

Abstract

Background and Purpose-Brain injury after hypoxic-ischemic insults evolves via an apoptotic/necrotic cascade.Glutamate over release and N-methyl-D-aspartate (NMDA) receptor over activation (excitotoxicity) are believed to trigger this process. Xenon is a nontoxic anesthetic gas that reduces neurotransmitter release and functionally antagonizes NMDA receptors. Administering xenon to hypoxic-ischemic newborns might be clinically effective if the neurotoxic processes continue evolving after delivery. We sought to determine whether xenon administration after the initial hypoxic-ischemic insult was neuroprotective. Methods-Fifty 7-day-old rats received a 90-minute hypoxic insult after unilateral carotid ligation. They were then randomized to breathe 1 of 2 gas mixtures for 3 hours: 50% Xe/30% O 2 /20% N 2 or 30% O 2 /70% N 2 . Results-One week after hypoxic-ischemic survival, significant global protection was seen in the xenon group (80% less injury); cortex/white matter (88% versus 25%), hippocampus (62% versus 0%), basal ganglia (81% versus 25%), and thalamus (50% versus 0%; percentage of global damage score in nonxenon versus xenon groups, respectively). Conclusions-Three hours of xenon administration commenced after hypoxia-ischemia in neonatal rats provides short-term neuroprotection. This finding suggests that treatment with xenon after perinatal asphyxia would also be neuroprotective. Because xenon does not cause other neurotoxic effects and has demonstrated minimal side effects in extensive anesthesia studies, it would make an ideal candidate for the treatment after human perinatal hypoxia-ischemia.

Cooling Combined with Immediate or Delayed Xenon Inhalation Provides Equivalent Long-Term Neuroprotection after Neonatal Hypoxia—Ischemia

“…This combination has the potential to improve the otherwise bleak outcome after perinatal asphyxia. Considering that HT is currently becoming standard of care after HI injury in both adults after cardiac arrest (Polderman, 2008) and newborns after perinatal asphyxia (Hoehn et al, 2008) and that Xe significantly enhances this effect (Dingley et al, 2006;Hobbs et al, 2008a;Ma et al, 2005;Martin et al, 2007), we have compared three different Xe delivery strategies in combination with the established HT treatment. As Xe is very expensive and is likely only to be delivered in specialist centers for combination with HT, patient transport is required and two important questions arise:…”

“…In recent studies, we have shown that immediate delivery of 3 h Xe at normothermia was very neuroprotective in the short term (1-week survival) (Dingley et al, 2006), but not after long-term survival (Hobbs et al, 2008a). Therefore, we did not include a Figure 4 Mean (s.e.m.)…”

“…Four areas of the brain were examined (cortex, basal ganglia, thalamus, and hippocampus) by an investigator blinded to the treatment allocation. The severity of damage was graded from 0.0 (no injury) to 4.0 (maximum injury), with 0.5 intervals for each of the four regions, giving a nine-step scale adapted from a scoring scale used to assess injury 1 week after HI that has been validated against cell counting previously by us and used by others (Dingley et al, 2006;Haaland et al, 1997;Hobbs et al, 2008a;Thoresen et al, 1996a;Thoresen et al, 1996c;Trescher et al, 1997).…”

“…Xenon (Xe), a noble gas with anesthetic properties, has shown great promise as a neuroprotectant in both in vitro and in vivo experimental studies, especially when combined with deliberate cooling (Dingley et al, 2006;Hobbs et al, 2008a;Ma et al, 2005;Ma et al, 2002;Ma et al, 2003;Martin et al, 2007;Petzelt et al, 2003). Xenon is also attractive in this role because of its lack of chemical reactivity and lack of clinical side effects (Dingley et al, 2001;Marx et al, 1997;Preckel et al, 2004;Rossaint et al, 2003), rapid reversibility, and lack of fetotoxicity (Burov et al, 2002;Lane et al, 1980).…”

Adding 5 h delayed xenon to delayed hypothermia treatment improves long-term function in neonatal rats surviving to adulthood

“…Xenon has proven to be neuroprotective both in vivo and in vitro with minimal adverse effects (10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21). We and others have previously reported that adding immediate xenon to HT enhanced the neuroprotective effects of HT after induced hypoxia-ischemia in neonatal rats (12,13,15,20) and newborn pigs (21). In neonatal rats, xenon, when added to immediate hypothermia, either immediately or after a 2 h delay, increases neuroprotection (20).…”