Neuroprotective gases – Fantasy or reality for clinical use?
Graphical abstract
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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2020, Brain Research BulletinCitation Excerpt :Most of the current research and knowledge is based on experimental animal studies, and very few on clinical data. Besides, although it generally seems that anaesthetics have a beneficial role for our brain tissue, there is also data raising concerns about their usage, especially on the developing and aged brain [8–11]. It is important to have an overview on the possible mechanisms of neuroprotection or neurotoxicity in each brain-type (developing, mature and aged and with or without pathologies) in order to better design future experimental and clinical research.
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These authors contributed equally to this work.