Recent advances in the neuroprotective effects of medical gases

Yue-Zhen Wang,Ting-Ting Li,Hong-Ling Cao,Wan-Chao Yang

Department of Anesthesiology,The 2nd Affiliated Hospital of Harbin Medical University,Harbin,Heilongjiang Province,China

Abstract

Key words:hydrogen; hydrogen sulphide; hyperbaric oxygen; inert gases; nitric oxide; isofl urane; sevofl urane; traumatic brain injury; ischemia/reperfusion; subarachnoid hemorrhage

INTR ODUCTION

Central nervous system injuries are a leading cause of death and disability worldwide.1In China,brain injury is one of the major causes of clinical mortality and long-term disability.2With China's economic development,an increase in traffic accidents and brain trauma has been observed over the past few years.2-4Stroke is another health burden in China as it accounts for 80% of deaths and 70% of disability-adjusted life-years lost.5Additionally,the growth in the aging population of China has led to an increase in the occurrence of neurodegenerative diseases.6,7Interestingly,brain injuries often share similar underlying pathophysiological mechanisms.1Therefore,reducing neural damage through the use of neuroprotective agents will improve the patient prognosis.8,9

Medical gases are increasingly used clinically because of their special physicochemical properties and convenience in use.Medical gases exert unique neuroprotective effects against brain injury.Administration of hyperbaric oxygen (HBO) has been successfully used for the treatment of some neurological disorders.10,11Furthermore,hydrogen (H2) is emerging as an antioxidant agent with neuroprotective properties.12-14Hypercapnia,induced by a high concentration of carbon dioxide,has been demonstrated to be beneficial in the treatment of ischemic brain injuries.15-17Hydrogen sulphide (H2S) and nitric oxide (NO),which were once considered toxic,can act as signaling molecules with a promising role in brain protection.18,19In addition,clinical studies have demonstrated that inhaled anesthetics,as well as rare gases,provide a certain degree of neuroprotection.20,21In this review,we searched for neuroprotective studies on common medical gases in the past 5 years,and briefl y summarized their application and mechanisms in various neurological diseases,with gas species as a classification criterion (Table 1).It can be seen that the various medical gases reviewed play a protective role in nerve injuries,and the molecular mechanism still has a broad space for exploration.Further,we will discuss the advantages of their use and challenge their wide clinical applications.

HYPERBARIC OXYGEN

HBO treatment refers to the inhalation of pure oxygen,or a high concentration of oxygen,in a high pressure environment to treat hypoxic conditions.67HBO is the main treatment for carbon monoxide poisoning and decompression sickness.68Recently,HBO has become an issue of concern for its beneficial effects in the treatment of brain injuries.

Chen et al.22and Wee et al.23previously confirmed that infl ammation plays an important role in the pathophysiology of traumatic brain injuries (TBI) in animal models.Following TBI,a lack of interleukin (IL)-10 counters the protective effect of HBO thereby increasing the degree of brain injury.22Therefore,this anti-infl ammatory cytokine (IL-10) plays a crucial role in mediating the neuroprotective effect of HBO.The immediate inhalation of HBO (2.0 atmosphere absolute (ATA),1 ATA=1.013 kPa,100% O2) after brain injury decreases apoptosis25and reduces the expression of infl ammatorycytokines.23,24,26Moreover,HBO has been found to protect the integrity of the blood-brain barrier (BBB) and improve the patient prognosis.24,69Lin et al.11also demonstrated the positive impact of HBO administration on the behavioral and neurochemical outcomes of posttraumatic stress disorder.In mice,the continuous inhalation of HBO immediately after TBI reduces neural loss and increases the activity of astrocytes.10Moreover,continuous HBO inhalation has been shown to exert a more significant neuroprotective effect than non-continuous inhalation.10

Table 1:Neuroprotective effects of medical gases and the related mechanisms

Table 1:Continued

Clinical trials have shown that inhalation of HBO (2.0 ATA,100% O2) promotes the regeneration of cerebral blood vessels and the reconstruction of nerve fibers after TBI.9In healthy volunteers,the inhalation of HBO significantly enhances the cognitive functions and ability to perform cognitive tasks compared to the performance following inhalation of normobaric air.70In addition,long-term HBO therapy could improve post-concussion syndrome and post-traumatic stress disorder after moderate brain injury and may significantly reduce posttraumatic anxiety and suicide.Nevertheless,at present,the impact of HBO has been derived from small and uncontrolled studies or single case reports.Therefore,randomized doubleblinded clinical trials are required to enable the wide clinical application of HBO.

HYDROGEN

H2gas is chemically stable at room temperature.It has a small molecular weight and strong permeability,which enables its diffusion into the cells.In 1975,hyperbaric H2therapy was proposed as a possible anticancer agent.71However,the selective anti-oxidative effects of H2were discovered more recently,in 2007.12Ohsawa et al.12reported that H2significantly reduces the area of cerebral infarction by neutralizing toxic free radicals.Subsequent research,performed in experimental animals,found that H2has anti-infl ammatory,69,72anti-apoptotic,27,73and antioxidant28properties.Additionally,H2has been shown to have neuroprotective effects in cerebrovascular diseases and neurodegenerative diseases.32,33,35Takeuchi et al.36demonstrated that drinking hydrogen water could reduce the production of reactive oxygen species and inhibit the activation of matrix metalloproteinase-9 in the hippocampus,thereby reducing BBB damage and improving brain function.In a hypoxic-ischemic encephalopathy piglet model,treatment with H2reduced oxidative stress and improved neural recovery.74

Cerebral microvascular endothelial cells play an important role in regulating and maintaining the stability and balance of the brain neurovascular microenvironment.37Consuming hydrogen water has been shown to prevent the apoptosis of cerebral microvascular endothelial cells through the downregulation of the phosphatidylinositol 3-hydroxy kinase/protein kinase B/glycogen synthase kinase 3β (PI3K/Akt/Gsk3β) pathway,leading to a decrease in the extent of secondary brain injury.37Systemic and central nervous system infl ammation induces microglial activation,causing neuronal injury.H2inhibits microglial activation,thus protecting against brain trauma.30In a rat model of subarachnoid hemorrhage,injection of H2saline inhibits the nuclear factor-kappa B pathway and the nucleotide binding and oligomerization domain-like receptor family pyrin domain-containing three infl ammasomes,which subsequently reduces the systemic infl ammatory response and promotes the neurological function,as well as behavioural recovery.31Yoshii et al.38reported that the observed neuroprotective effect of drinking hydrogen water could be associated with the secretion of ghrelin,a gastric hormone,in the stomach.However,the mechanism of H2appears to differ between the various experimental models.For instance,H2inhibits the immuno-infl ammatory response by up-regulating the expression of regulatory T cells after cerebral ischemia/reperfusion injury.34Activation of infl ammatory mediators plays an important role in major depressive disorder.39Hydrogen water inhibits the production of IL-1β and reactive oxygen species,reduces the infl ammatory reaction,and subsequently decreases the depression behavioural scores.39In a model of cerebral infarction,glutamate producesdose-dependent neurocytotoxicity and increases the intracellular calcium level.75The neuroprotective function of hydrogen water,in this case,was found to be mediated through a reduction in glutamate-induced neural cell death and inhibition of calcium ion infl ux.75On the other hand,treatment with H2failed to relieve brain edema or exert a neuroprotective function,although it did decrease the expression of 8-hydroxy-2′-deoxyguanosine,in a rat model of intracerebral hemorrhage.This result may be attributed to the low H2concentration that was used in this study,or to the existence of a more complicated mechanism involving reactive oxygen species in intracerebral hemorrhage.76Therefore,the protective effects of H2may differ according to the dosage and/or animal model that are used.Nevertheless,H2is safe to the human body at a high concentration and it plays an antiinfl ammatory,as well as an antioxidant,role in combating cerebral ischemia/reperfusion injury.13Therefore,the protective effects of H2in TBI are dose- and time-dependent.Indeed,we observed that the inhalation of a high H2concentration exerts neuroprotective effects against TBI in diabetic mice (unpublished observations).Taken together,these findings indicate that the neuroprotective effect of H2must be replicated in clinical studies to enable its future application.

CARBON DIOXIDE

Carbon dioxide is a liposoluble gas that can cross the cell membrane and the BBB.77Therapeutic hypercapnia,through the inhalation of carbon dioxide,has been shown to exert beneficial biological functions.78-80The use of hypercapnia in organ protection has been the focus of recent research especially its effect on the brain function.15,16Hypercapnia significantly reduces the infarct size and improves the neuropathologic score (neurosensitivity,refl ex,and exercise behaviour) in a model of cerebral ischemic injury.16In addition,hypercapnia enhances the spatial memory and improves the sensorimotor impairment by regulating apoptosis,through an up-regulation of Bcl-2 and a down-regulation of Bax.17In a control case study,controlled transient hypercapnia increased the cerebral blood fl ow and cerebral oxygen saturation and reduced the possibility of secondary cerebral infarction in patients without adverse reactions.81 In a rat model of global cerebral ischemia/reperfusion,Zhou et al.40reported that moderate hypercapnia (partial pressure of carbon dioxide (PaCO2) 80-100 mmHg) had significantly improved neuroprotective effects compared to those of mild hypercapnia (PaCO260-80 mmHg); whereas severe hypercapnia (PaCO2100-120 mmHg) increased the severity of brain injury.In agreement with these findings,Yang et al.15reported that mild-to-moderate hypercapnia (PaCO260-80 mmHg and PaO2＞50 mmHg) was the optimal concentration range for neuroprotective effects.At this level,hypercapnia significantly reduces the BBB permeability as well as the brain water content,the expression of Aquaporin-4 (AQP4) and neural apoptosis.15Conversely,hypercapnia in combination with lower oxygen pressure (PaO2＜50 mmHg) may aggravate BBB destruction and edema due to cerebral ischemia/hypoxia.Therefore,the protective effect of carbon dioxide in the brain is determined by the degree of hypercapnia as well as the partial pressure of oxygen.15In our experience,we have confirmed that hypercapnia (3 hours with PaCO2levels of 80-100 mmHg) reduces brain edema,improves the BBB function,reduces the lesion volume,and improves the neurological outcome in a rat model of fl uid percussion injury (unpublished observations).Taken together,these results suggest that there is a potential neuroprotective role for “therapeutic hypercapnia” after brain injury.However,confirming these results through the use of experimental animal models will be instrumental in elucidating the neuroprotective mechanisms of hypercapnia and acidosis before conducting clinical trials.

HYDROGEN SULPHIDE

Hydrogen sulphide (H2S),an endogenous gaseous signalling conduction factor,was considered to be a toxic substance for quite a long period of time.However,recent studies have confirmed that low doses of H2S play an important role in the functioning of normal physiological processes.82-84In fact,H2S was found to be widely involved in physiological and pathophysiological processes in the brain as well as the peripheral tissues.82Following brain injury accompanied with brain edema,the expression of AQP4 increases remarkably.18,41Accumulating evidence has shown that the neuroprotective impact of H2S is mediated by its ability to increase the expression of protein kinase C and decrease the expression of matrix metalloprotein-9 through the inhibition of AQP4 expression,which in turn leads to the suppression of glial cell activation and the release of pro-infl ammatory factors.18,41,44In rats,H2S relieves cerebral vasospasm,protects neurons,preserves endothelial function,reduces cerebral edema,and inhibits apoptosis as well as the infl ammatory response.42,44Additionally,Zhang et al.47demonstrated that the administration of H2S attenuates apoptosis,inhibits the activation of autophagy and improves motor function following TBI.H2S could also improve the learning and cognitive ability as well as preserving the memory functions after brain injury.46Taken together,these results indicate that H2S can improve the sequelae of brain injury,including long-term disability.43,85Li et al.43suggested that the neuroprotective impact of H2S could be mediated through the induction of the Akt-ERK pathway.Rho-associated protein kinase 2 is a key factor that promotes neurodegeneration in Parkinson's disease.48H2S could reduce the expression of Rho-associated protein kinase 2 through microRNA-mediated protection of nerve cells.48Future research should focus on uncovering the exact role of H2S in the central nervous system with the aims of dissecting the signaling pathways involved.

NITRIC OXIDE

Like H2S,NO has previously been considered to be a toxic chemical substance.86In the 1980s,the vasodilating factor secreted by vascular endothelial cells was identified as NO.87Recent reports have suggested that NO inhalation successfully reduces the size of the necrotic area and brain edema as well as reduces BBB permeability following subarachnoid hemorrhage or TBI.19,49Thus,NO may improve neurological function and relieve secondary brain injury.49Additionally,NO inhalation may alleviate the spasm of pia mater arterioles,50 improve the neurological score,and reduce the mortality rate in mice.19The concentration of NO and inhalation time were positively correlated with its neuroprotective effects.51The neuroprotective function of NO is mediated through the improvement of the cerebral blood fl ow without causing hypotension or other significant side effects.51At present,evidence for the neuroprotective impact of NO is based on the results of animal experiments.Clinical studies are required to confirm the role of NO in TBI.Additionally,research studies examining the mechanism of action of NO as well as the toxicity and side effects of long-term use will infl uence the future therapeutic applications of NO.

VOLATILE ANESTHETIC GASES

Isoflurane

Isofl urane is a general anesthetic mainly used to start or maintain anesthesia.Following a cerebral ischemic event,microglial activation may induce neural apoptosis in the brain.53,88Isofl urane has been found to inhibit the activation of microglia through the Notch pathway,therefore,producing a decrease in apoptosis.53Additionally,Wang et al.20and Yuan et al.52demonstrated that isofl urane could alleviate the incidence of brain edema and reduce the area of reperfusion injury by down-regulating the expression of AQP4.Moreover,isofl urane inhalation up-regulates transforming growth factor-beta1 expression and down-regulates phospho-c-Jun N-terminal kinase expression,leading to an improvement in the ischemia/reperfusion injury outcome.20However,in cases of severe brain injury,long-interval isofl urane inhalation may reverse its previous protective effect and aggravate brain injury.89Therefore,future studies should focus on optimizing the ideal dose and time-frame for isofl urane inhalation to lay a solid foundation for the widespread application of isofl urane in the treatment of TBI.

Sevoflurane

To date,sevofl urane has been considered to be an ideal inhalation anaesthetic,owing to its rapid induction and revival.55In vitroexperiments have demonstrated that sevofl urane can down-regulate the expression of vascular endothelial growth factor,maintain the function of the endothelial barrier,and play a key role in injury regulation.54Cerebral ischemia often leads to the astrocyte activation and the formation of a glial scar.55In addition,sevofl urane inhalation alleviates reactive astrocytic gelatinization,reduces the effect of glial scar formation,and inhibits the activation and release of lysosomal cathepsin B,which improves the outcome of cerebral ischemia.55Sevofl urane may also attenuate the infl ammatory response.56,88However,this anesthetic neither relieves infl ammation in the brain nor significantly inhibits the activation of microglia or astrocytes.88Nevertheless,Dang et al.57demonstrated that the neuroprotective impact of sevofl urane could be attributed to the activation of microglia/macrophage migration and,thus,the promotion of brain repair.Additionally,sevofl urane postconditioning improves the cognitive performance in rats as well as promoting neural survival and decreasing apoptosis and cellular atrophy through the regulation of the PI3K/Akt pathway.58,90Conversely,several studies have reported that sevofl urane exhibit neurotoxic effects.21,91-93Inhalation of 7% sevofl urane in aged rats inhibits the expression of brainderived neurotrophic factor,aggravates postoperative cognitive dysfunction and impairs the brain function.21Moreover,sevofl urane-induced nerve injury is correlated with the used concentration.91Therefore,future research should explore the neuroprotective mechanisms of sevofl urane and optimize the concentration that is selected for research.Nevertheless,the neuroprotective effect of sevofl urane provides unique opportunities for its application by clinical anesthesiologists in cases of TBI.

INERT GASES

Helium

Helium has a lower solubility in blood than nitrogen and is often mixed with oxygen to provide a breathing gas for divers.94Angiogenesis is a natural defense mechanism that provides oxygen and nutrient supply to the injured brain.60Li et al.60demonstrated that helium exerts its neuroprotective effects by improving the neurovascular niche,as well as increasing the expression of anti-infl ammatory cytokines and BNDF.However,Aehling et al.95did not observe any beneficial effect of helium preconditioning or post-conditioning on neurological function.However,it did reduce the level of apoptosis in a rat resuscitation model.95Future studies will improve our understanding of the function of helium in neuroprotection.

Argon

The neuroprotective effects of argon have been validated in various brain injury models.96Argon improves the general condition of rats and reduces mortality by inducing the expression of Heme oxygenase 1.61,62Compared to the impact of argon alone,the combination of argon and hypothermia therapy significantly increases the expression of Heme oxygenase 1,reduces the infarct size,and provides effective protection against short-term and long-term brain injury.61Although there are still many uncertainties regarding the effect and mechanism of argon therapy,its neuroprotective role in TBI is worth further exploration.

Xenon

Xenon is an ideal anesthetic.However,the widespread clinical application of xenon is hampered by the difficulty of its separation and its scarce availability.Nevertheless,the potential neuroprotective effect of xenon has been the focus of scientific research.97Xenon alleviates oxidative stress,reduces N-methyl-D-aspartate receptor mediated neurodegeneration and exerts both neurotrophic as well as neuroprotective effects in cholinergic neurons.64,65Additionally,xenon produces neuroprotection by inhibiting the activation of microglia and reducing the level of hippocampal neural damage.66In Parkinson's disease,xenon may protect and nourish dopamine neurons,thus inhibiting the potential damage to dopaminergic neurons and astrocytes.63However,the feasibility of the widespread clinical application of xenon remains to be explored in future experiments.

PERSPECTIVES

The debate regarding the neuroprotective role of medical gases is still ongoing.To date,there are significant differences in the observed value of medical gases across different studies.However,the evidence from published studies suggests that each of the medical gases discussed in this review exert different degrees of brain protection in specific nerve injury models.It is worth mentioning that,although these gases have different uses in various types of brain injuries,the mechanisms by which these gases reduce neuronal injury at the intracellular and intercellular level are similar.The major challenge that faces this field of research is the translation from preclinical to clinical training,i.e.,the feasibility of the clinical administration of medical gases and their inclusion in individualized treatment plans.HBO should be considered to be a supportive therapeutic modality in TBI.The use of carbon dioxide in neuroprotective therapy is still at the experimental animal stage and,thus,there is an urgent need for more extensive research to determine its therapeutic value.The lack of precise methodology for the accurate estimation of H2S and NO endogenous concentrations hinders their clinical use.Volatile anesthetic gases may not be effective as single therapeutic agents.However,their use might be beneficial during neuroprotective surgeries.The clinical administration of inert gases is hampered by high costs and difficulty of their extraction.H2is a popular gas with definite roles in disease prevention and treatment and has a high safety margin.These characteristics imply that H2may revolutionize the medical field in the future.Future research should aim to clarify the specific mechanisms that underlie the action of H2.In conclusion,in this review we present recent insights into the therapeutic uses and possible applications of medical gases.Future research will focus on the precise function and molecular mechanism of each medical gas,which will lay a solid foundation for their widespread application in clinical practice.

Author contributions

Conception and literature search:YZW and TTL; drafting:YZW; revision:YZW,TTL,HLC,WCY.All authors read and approved the final version of the paper for publication.

Conflicts of interest

The authors declare no confl icts of interest.

Financial support

This work was supported by the National Natural Science Foundation of China,No.81400989 (to WCY).

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