Is Xenon a Future Neuroprotectant?

Pamela Sun; Jianteng Gu; Mervyn Maze; Daqing Ma

Disclosures

Future Neurology. 2009;14(4):483-492. 

In This Article

Neuroprotective Paradigms

Stroke

Stroke is the third most common cause of death in the world and is also associated with loss of function, independence and quality of life.[84] It poses a substantial burden on the healthcare system, requiring prolonged hospitalization and rehabilitation.[85]

Approximately 6.5–15% of all strokes occur in hospitalized patients, many of whom are undergoing surgical procedures.[86] Among several high-risk surgical interventions, cardiac surgery remains the most commonly reported risk factor for postoperative stroke, with an incidence ranging from 1.3 to 4.3%.[87] Accordingly, this group of patients may potentially benefit from the application of protective strategies against acute neurological injury. To date, therapeutic approaches for stroke have focused on thrombolysis and supportive therapy.[88] The application of these treatments is limited to a postinjury setting when the damage has occurred. Although multiple randomized control studies have shown a considerable neurological benefit with thrombolytic therapy,[89,90] its use is restricted by the narrow therapeutic window and considerable side effects, particularly with a hemorrhagic stroke.[91]

Xenon may play an important role in the treatment of stroke. Administration of 70% xenon improved both histological and functional outcome in a transient middle cerebral artery occlusion (MCAO) ischemia in mice.[71,92] Recently, a subanesthetic concentration of 50% xenon was seen to provide global neuroprotection for up to 4 h in vitro and 2 h in vivo after insult in a similar model in rats. It was suggested that this may translate into an administration of approximately 19% xenon in a therapeutic window of approximately 8–12 h after ischemic brain injury in humans.[73] Further experiments in relevant animal models and clinical trials are required to warrant xenon's therapeutic usage.

Perinatal Hypoxic–Ischemic Injury

Acute disruption of cerebral blood flow in perinatal H/I, is also major critical event with detrimental effects. Slight disruption in cerebral blood flow can cause an OGD for the neuronal cell, triggering necrosis and apoptosis caused by glutamateric excitotoxicity in the brain, resulting in a neurological injury in the newborn.[93]

Between one and six in 1000 live births experience an H/I incident, with a mortality of 15–20%. Between 20 and 40% of the surviving children develop permanent neurological defects including cerebral palsy, cognitive deficits, epilepsy and mental retardation.[93,94] Perinatal H/I remains a frequent cause of acute mortality and chronic neurological morbidity in infants and children all over the world,[95] and should be avoided by early prevention or rapid treatment.

During H/I, there are a number of patholophysiologic events leading to cell death, which are not entirely understood. H/I causes tissue damage through selective neuronal necrosis or infarction. The ischemic penumbra consists of neurons undergoing programmed cell death via apoptosis or necrosis.[95] The depletion of cellular energy stores associated with H/I results in membrane depolarization and ionic disruptions. Energy-dependent reuptake mechanisms are compromised and extracellular glutamate excitotoxicity overactivates the NMDA receptors.[96] Apoptosis plays a major role and is potentially more significant than the necrosis that occurs after the injury.[94] Various pharmacological agents, such as inhibitors of oxygen free radical generation, antagonists of excitatory amino acid systems, calcium-channel blockers, nitric oxide synthase inhibitors have been examined[95] with little beneficial effects found, whilst mild hypothermia (reduction in body temperature of approximately 3°C) has proven to reduce cerebral injury.[97]

Remarkably, xenon has been found to offer short-term neuroprotection with significant global protection in the rodent cortex, hippocampus, basal ganglia and thalamus when administered 90 min after H/I insult.[98] A combination of xenon and hypothermia after OGD in vivo and after H/I in vitro studies in neonatal rats has been demonstrated to confer synergistic neuroprotection with preservation of hemisphere weight and reduction in morphology and functional neurological disruption up to 30 days after injury.[99] This has been recently confirmed by complete function restoration, which is sustained long term, accompanied by a 71% reduction in global histopathology after H/I in neonatal rats.[100] Such long-term neuroprotection is extended to treatment of hypothermia combined with immediate or delayed xenon administration.[101] Asynchronous administration of xenon and hypothermia, even at a 5-h interval, provided a significant reduction in infarct volume in neonatal rats; allowing a more practical and cost-effective management of neonatal asphyxia with hypothermia administered at the site of delivery and xenon later if necessary.[102] The administration of xenon, synergistic with hypothermia, remains a very promising neuroprotective strategy worthy of clinical trials into the treatment of perinatal H/I.

Global Ischemia Induced by Cardiac Arrest

Similar to stroke, cardiac arrest also has devastating consequences. Approximately 800,000 people per annum suffer from sudden cardiac death in the western world.[103] Of the patients undergoing noncardiac surgery, 1–5% suffer a cardiac adverse event within 30 days.[104,105] The majority of these patients die within 30 days of their operation.[106] Albeit infrequent, cardiac adverse events remain a fatal complication in the surgical population and leave most patients severely neurologically disabled or comatose.[107]

Xenon has been shown to have cardioprotective effects in both pre- and post-ischemia conditioning.[108] Administrated 1 h after cardiac arrest in a porcine model, xenon conferred a reduction in neurohistopathological damage with a transient improvement in function outcome. Xenon reduced apoptotic cells in hippocampal, striatal and putamen areas and perivascular inflammation in the striatal area, as well as increased astrogliosis and microgliosis in the CA1, CA and three out of four hippocampus, resulting in preservation of neurocognitive function, especially that for visual–spatial tasks.[109]

Furthermore, xenon attenuated cerebral damage compared with total intravenous anesthesia in vivo during cerebral reperfusion after cardiac arrest in a porcine model.[110] Recently, a landmark Phase I study has demonstrated that xenon was safe and effective in coronary artery bypass patients while on cardiopulmonary bypass –such evidence merits a large placebo-controlled and randomized clinical trial to investigate the potential neuroprotection effects offered by xenon.[111]

Preventing Neurotoxic Effects Induced by Other Anesthetics

For many years, it was believed that general anesthetics exert a reversible effect on the CNS. However, increasing evidence suggests that general anesthetics exert long-term effects on the CNS, depending on the age of the subjects.

In the early development of the brain, there is an important period termed, the synaptogenesis period (also known as the brain growth-spurt period), which occurs in different mammalian species at different times relative to birth. In rodents, it begins 1 or 2 days before birth and ends 2 weeks after, whereas in humans it starts at the beginning of the third trimester and ends several years after birth.[112] During synaptogenesis, the ability of a neuron to communicate with its environment and other neurons is critical for ensuring that cell function is appropriately developed. However, perturbation of this normal communication may be capable of producing long-lasting undesirable effects, which has been well demonstrated by an elegant study on fetal alcohol syndrome.[113] Assuming that alcohol is similar to anesthetics, both in their behavioral and molecular effects, several subsequent studies demonstrated that various anesthetic agents and cocktails also induce the same response when administered postnatally.[114–117] Conversely, recent work from our laboratory, as confirmed by Cattano et al. under similar experimental conditions in other neonatal rodents,[78] has verified that the anesthetic gas xenon mitigated isoflurane/nitrous oxide-induced apoptotic neurodegeneration in neonates.

Traumatic Brain Injury

Traumatic brain injury is common, from mild to severe, it affects as many as 1.5-million sufferers per year in the USA.[118] Recent evidence from an in vitro murine model has first described desirable effects of a reduction in secondary injury developed following initial trauma, even when administered 3 h post-trauma. For xenon (75% atm), total traumatic brain injury was attenuated twofold, while secondary injury was reduced more than fourfold.[119] Such a fascinating and promising therapeutic option for limiting the consequence of head trauma warrants further animal and clinical trials and may become an important addition to the existing neuroprotective paradigms.

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