Elsevier

Progress in Neurobiology

Volume 115, April 2014, Pages 210-245
Progress in Neurobiology

Neuroprotective gases – Fantasy or reality for clinical use?

https://doi.org/10.1016/j.pneurobio.2014.01.001Get rights and content

Highlights

  • Comprehensive review of neuroprotective gases for multiple neural diseases.

  • Summary of underlying mechanisms for their neuroprotective effects.

  • Possible limitations hindering clinical translation of neuroprotective gases.

Abstract

The neuroprotective properties for certain medical gases have been observed for decades, leading to extensive research that has been widely reported and continues to garner interest. Common gases including oxygen, hydrogen, carbon dioxide and nitric oxide, volatile anesthetics such as isoflurane, sevoflurane, halothane, enflurane and desflurane, non-volatile anesthetics such as xenon and nitrous oxide, inert gases such as helium and argon, and even gases classically considered to be toxic (e.g., hydrogen sulfide and carbon monoxide) have all been supported by the evidence alluding to their use as potential neuroprotective agents. A wide range of neural injury types such as ischemic/hemorrhagic, stroke, subarachnoid hemorrhage, traumatic brain injury, perinatal hypoxic–ischemic brain injuries, neurodegenerative disease as well as spinal cord ischemia have been used as platforms for studying the neuroprotective effects of these gases, yet until now, none of the gases has been widely introduced into clinical use specifically for protection against neural injury. Insufficient clinical data together with contradictory paradigms and results further hinders the clinical trials. However, pre-clinical models suggest that despite the various classes of gases and the broad range of injuries to which medical gases confer, protection, several underlying mechanisms for their neuroprotective properties are similar. In this review, we summarize the literature concerning the neuroprotective effect of each gas and its underlying mechanisms, extract common targets reported for the neuroprotective effects of different gases, highlight the conflicting observations from clinical trials and further discuss the possible hindrances impeding clinical applications in order to propose future research perspectives and therapeutic exploitations.

Introduction

Central nervous system (CNS) injury is a major cause of death and disability in developed countries, and represents a major economic burden in the world (Lopez et al., 2006). In the US and China, stroke is one of the most prevalent neurological injuries, striking approximately 800,000 and 2 million people per year, respectively (Roger et al., 2011). In addition, traumatic brain injury (TBI) has increased over time due to modern motor transportation and the persistence of wars. According to a meta-analysis, 12% of 25,134 adults investigated had a history of traumatic brain injury (Frost et al., 2013). Combining the incidence of stroke and TBI with other types of central nervous system injury such as spinal cord injury, perinatal hypoxia ischemia brain injury, as well as neurodegenerative diseases, the population affected by CNS injury/degeneration is substantial. Although the causes of these injuries vary, the underlying mechanisms of the injuries are often similar, leading to the concept that neuroprotective agents may be applicable to diverse CNS injury states. Two of the major working theories of neuroprotective strategies focus on (1) better preparing the CNS with activated endogenous protective mechanisms and (2) inhibiting the secondary insult in order minimize damage and promote recovery of salvageable tissue. For stroke alone, remarkable progress in the understanding of brain injury pathophysiology has led to the identification of numerous brain-protective effects in experimental models and to the implementation of more than 209 completed clinical trials (Young et al., 2007). However, no new treatment has made it from bench to bedside since tissue plasminogen activator (t-PA) was introduced in 1995 (1995). Further therapeutic options beyond t-PA are critical, as less than 5% of stroke patients are eligible for t-PA, due to its narrow therapeutic window (<4.5 h) and safety concerns (Fonarow et al., 2011). CNS injury thus remains a vexing public health problem for which the development of novel effective anti-injury strategies is a highly urgent matter.

Many pathological states emanating from different stimuli share common molecular pathways of cell injury, death, and repair. Despite the divergent and unrelated causes of acute neural injury and chronic neurodegeneration, many of the underlying mechanisms of cell injury overlap to include excitotoxicity, inflammation, and apoptosis (Dirnagl et al., 1999). Similarly, the pathways of survival and regeneration often overlap between disease states. The commonalities of these distinctly different pathological settings suggest that the options for neuroprotective strategies may not be specific to the type of injury, but rather widely compatible with various injury states. This sort of generalized adaptive response fits well with the potential use of preconditioning to induce a tolerant state. The concept of preconditioning is defined as a phenomenon that when a sub-lethal stimulus was applied before a severe injury episode, it lead to neuroprotection against lethal injuries afterwards. When the sub-lethal stimulus is applied at the onset of reperfusion and confers neuroprotection, the phenomenon is then referred to as postconditioning. As will be discussed throughout this review, numerous agents – and gases specifically – may play a neuroprotective role by functioning to condition the brain against neural injury.

Decades ago, clinical observations indicated that patients under general anesthesia are more tolerant of cerebral ischemia than unanesthetized patients (Wells et al., 1963). Following these observations, medical gases have been considered as natural candidates to promote brain protection under ischemic circumstances. More recent experimental evidence supports this concept. Volatile gases, including isoflurane, sevoflurane, halothane, enflurane and desflurane (Clarkson, 2007, Kapinya et al., 2002, Kitano et al., 2007, Wang et al., 2008a, Xiong et al., 2003), non-volatile anesthetics, like xenon (also an inert gas) and nitrous oxide, common gases like oxygen (Dong et al., 2002), inert gases (Jungwirth et al., 2006), as well as other originally presumed toxic gases like hydrogen sulfide and carbon monoxide, have been demonstrated to exert neuroprotection and thus have begun to be explored in terms of different administration regimens and mechanisms.

Among the potential therapeutic approaches targeting the ischemic cascade, medical gases have been characterized by preclinical studies to possess unique advantages over more traditional pharmacological strategies. These treatments have a wide therapeutic window and are effective when administered after an ischemic insult (Dingley et al., 2006, Erdem et al., 2005). Thus, they may be usable for patients who present to the clinic after the therapeutic time window for thrombolysis. In addition, medical gases have been found to be beneficial in models of cerebral hemorrhage (Soejima et al., 2013, Zhan et al., 2012), and therefore may be useful in patients in whom hemorrhagic stroke has not been excluded. Finally, medical gases are highly accessible and currently used in clinical settings. Taken together, medical gases present as an attractive tool for the basis of therapeutic intervention. Despite these compelling advantages, clinical translation of medical gases as neuroprotective agents have not yet been realized. In this review, we will present a comprehensive overview of the properties of these gases as well as their effects on CNS injuries, effective treatment regimens, underlying mechanisms, and clinical potential. Finally, we will discuss the current stumbling blocks in clinical application and future research perspectives for better therapeutic approaches.

Section snippets

Oxygen

Oxygen (hyperoxia, hypoxia and hyperbaric oxygen), the major component of air (20.9%), has demonstrated neuroprotective effects in various animal studies and clinical trials. However, in clinical practice, oxygen therapy is largely considered as a supportive tool rather than a formal neuroprotective strategy, despite possessing the attributes of being permeable through the blood–brain barrier (BBB), safe, well tolerated, and widely available. Due to the significant evidence that oxygen therapy

Volatile anesthetic gases

The extensive experimental work of “conditioning” strategies have led to the discovery of several pharmacological agents that are capable of recapitulating the benefits of the mechanical preconditioning strategies. Volatile anesthetics are considered to be less risk-bearing in clinical application as compared to ischemic preconditioning, particularly in the scenario of cerebral injury, as they can be administered intracerebroventricularly and provide systemic protection after inhalation (

Xenon

Xenon was discovered by chemist Sir William Ramsay in 1898 and introduced into clinical anesthesia in 1951 (Cullen and Gross, 1951). Multiple characteristics of xenon make it highly suitable for clinical use in the rapid induction of anesthesia, including low blood-gas partition coefficient (0.115) (Goto et al., 1998), rapid onset and elimination, safe cardiovascular effects, strong analgesic activity and easy permeation through the BBB (Dworschak, 2008). Given all these, xenon has become one

Noble gases

The inert or noble gases include xenon (categorized into non-volatile anesthetic in this review), helium, neon, argon, and krypton, and they exist as monatomic gases with low chemical reactivity. At the very beginning, it was believed that these inert gases were unlikely to have any biological activity. Nevertheless, evidence for the biological effects of the inert gases has emerged out of the research on the physiological changes during underwater diving. Since then, accumulating evidence

Hydrogen sulfide

As a gaseous intercellular signal transducer, hydrogen sulfide (H2S) was long considered a toxic substance, until it was more recently found to play an important role in normal physiological processes at low concentrations (Qu et al., 2008). In its physiological function, H2S is produced in astrocytes, neurons and microglia, and acts as an endogenous anti-inflammatory and neuroprotective agent (Lee et al., 2009). H2S is highly lipophilic, and can rapidly diffusing cross the cell membrane and

Neuroprotective effects and related mechanisms of gases tested in subjects with comorbidities

In clinical settings, patients with central nervous system damage or neurodegenerative diseases often present with comorbid systemic diseases such as hypertension, diabetes, hyperlipidemia, obesity and metabolic syndrome (Aviles-Olmos et al., 2013, De La Monte, 2012, de Rooij et al., 2013), termed “pathological conditions.” Compared to the normal population, the population with pathological conditions is vulnerable to neuronal injury and neurodegenerative diseases (McCormick et al., 2008, Sima,

Perspectives

As the debate continues pertaining to the role of neuroprotective gases, application methods (e.g., route, timing, generation) still vary between studies and likely contribute to the contradictory conclusions. We believe that with the appropriate application strategy, each of the gases will exert specific neuroprotective effects within specific contexts or intensities of neural injury models. In spite of their differing application paradigms in various types of neural diseases, many of the

Acknowledgments

Our research and the writing of this article were supported by grants from Innovation Team Grant (No. 2010cxtd01) from the Ministry of Education of China to Dr. Lize Xiong. Grants from Natural Science Foundation of China (No. 30930091) to Dr. Lize Xiong; No. 30972853 and No. 81128005 to Dr. Hai-Long Dong; No. 81370011 to Dr. Chong Lei; and No. 81300989 to Dr. Jiao Deng.

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