Is Xenon a Future Neuroprotectant?

Pamela Sun; Jianteng Gu; Mervyn Maze; Daqing Ma


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

In This Article

NMDA Receptor & Glutamate Excitotoxicity

Glutamate is a predominant excitatory neurotransmitter in the mammalian CNS.[4] When intensely activated, it can be toxic to neurons in a range of acute CNS injury conditions,[5] including stroke,[6] hypoglycemia,[7] trauma[8] and status epilepticus.[9] Excess glutamate is also implicated in neurodegenerative conditions[10] with involvement of the NMDA subtype.[11,12]

Neuronal function and survival relies on a constant supply of oxygen and glucose to produce ATP through glycolysis and mitochondrial respiration. In ischemia and hypoglycemia, energy deficiency results in the dysfunction of the presynaptic neurotransmitter release and leads to a net increase in extracellular glutamate, causing neurotoxicity.[13] Excess glutamate activates its postsynaptic receptors, namely NMDA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) and kainate (KA). The activation of AMPA receptors depolarizes the cell and simultaneously unblocks the NMDA channels (by the removal of the Mg2+ block), thus permitting Ca2+ entry. Depolarization opens voltage-activated calcium channels, allowing an influx of Ca2+ ions, as well as H2O molecules, down the osmotic gradient into the cell,[14–16] subjecting the cells to cytotoxicity.

The endoplasmic reticulum and mitochondria act as vast storage and regulators for Ca2+ ions. Beyond a critical point, calcium overload disrupts mitochondrial function. It promotes intracellular enzyme activation systems including lipases, proteases and endonucleases, which cause an overwhelming production of free oxygen radicals, synthesis of nitric oxide,[17] mitogen-activated protein kinase (MAPK)[18] and related toxic reaction products, leading to acute neuronal death.[11,19–21] The inner mitochondrial membrane is also disrupted and causes the oxidation of the proteins involved in ATP production,[22] reducing energy available for membrane pumps and resulting in apoptosis.

Apoptosis is often associated with excitotoxicity, although the link is not well established. A multistep mechanism regulates apoptosis,[23] involving the presence of at least two distinct checkpoints – one controlled by the bcl-2/bax family of proteins[24] and the other by the cysteine proteases or caspases. Blocking apoptosis by interfering at specific points on these pathways represents an attractive strategy for developing neuroprotective drugs; one that has yet to be fully investigated.

Severe insults due to hypoxia or ischemia result in necrosis, followed by a process of delayed secondary injury in the penumbra zone – an area surrounding the most severe damage that is initially spared. Some of the cell death in the penumbra appears to be caspase-mediated and may be of a more apoptotic type.[25–27] Further damage can occur upon reperfusion, caused by an influx of reactive oxygen species when oxygen is restored.

Furthermore, there is mounting evidence for the hypothesis that multiple cell insults causing necrosis, when administered at 'subnecrotic' levels, may instead induce apoptosis.[28] Glutamate excitotoxic neuronal death has been shown to occur through both necrosis and apoptosis, depending on the intensity[29,30] and duration of the insult.[31] Apoptosis appears to predominate after exposure to low concentrations of glutamate in a time-delayed course, whereas an acute exposure to high concentrations of glutamate leads to necrosis.[32,33] Apoptotic cell death occurs if the NMDA-receptor dependent insult is less severe, mitochondrial-depolarization is incomplete or transient, or cellular ATP levels are sufficient to support the active processes associated with apoptosis. The mechanisms behind NMDA-receptor-dependent apoptosis are unclear but seem to involve the release of apoptotic factors, for example, cytochrome C[34] from Ca2+ loaded mitochondria, and the activation of stress-induced pathways such as p38 MAPK[35] and c-Jun-N-terminal kinase.[36] However, this is evidently dependent on whether functional mitochondria still exist.[37,38] Mitochondria monitor the Ca2+ influx and its initial depolarization of NMDA receptors. Severe depletion of mitochondrial ATP synthase in depolarized mitochondria further limits the ability of cells to regulate intracellular Ca2+ levels, leading to cell death by necrosis.

Both apoptotic and necrotic cell deaths are closely linked and follow a certain spatial orientation within the brain, demonstrated in various tissues within the CNS, including the hippocampus, which appears to be an important component in both acute and chronic neurodegenerative conditions.[39] The delayed injury often takes hours to develop and provides a window for therapeutic intervention.

Extracellular glutamate and intracellular Ca2+ are arguably the two most ubiquitous chemical signals underlying brain function. Thus, it is disconcerting that they are stored in dangerously high amounts in subcellular organelles. Defence against excitotoxicity is clearly essential for the prevention of brain injury. Dead neuronal cells are irreplaceable and are implicated with irreversible and devastating functional consequences. The high incidence and social impact of neurodegenerative brain disorders, particularly in the aging population, have promoted a huge research effort in recent years.

One therapeutic approach is to address glutamate excitotoxicity[40] and prevent progressive cell death. The role of NMDA-receptor activation in excitotoxicity has led to investigation using NMDA antagonists as possible neuroprotectants. A vast array of evidence has demonstrated that NMDA antagonists, such as MK801, phencyclidine and ketamine, can be neuroprotective in both in vitro and in vivo modes of neuronal death.[41–43] NMDA antagonists have also been proven to reduce deterioration in cognitive function after cardiopulmonary bypass.[44] Despite these promising beneficial effects, their use has been abandoned[45] owing to profound psychotomimetic reactions observed in humans[46–48] and abnormal locomotor activities in rodents.[49,50] NMDA antagonists, at doses in the neuroprotective range,[51] were discovered to cause pathophysiologic changes in cerebrocortical neurons in the area of the posterior cingulate (PC) and retrosplenial cortices (RS) in rats. These areas are thought to be involved in abnormal behavioral activity. Ketamine may also increase the cerebral metabolic rate for glucose,[52] an undesirable effect in the ischemic brain. In addition, most NMDA antagonists do not readily cross the BBB,[44] which means large doses and hence greater systemic toxicity, are necessary to achieve the required neuroprotective effects.[45]

However, even at a subanesthetic dose, xenon readily crosses the BBB to provide NMDA-receptor antagonism and neuroprotection, without any of the neuronal side effects.[53–55]