Neuroprotection of medical gases: a potential effect on treating cognitive impairments in neurological symptoms of long-COVID

Long-coronavirus disease (COVID), also known as post-acute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, refers to the persistence of symptoms beyond 12 weeks (3 months) after the initial infection with SARS-CoV-2,1 the virus responsible for coronavirus disease 19 (COVID-19). Among the myriad of symptoms associated with long-COVID, neurological manifestations have gained particular attention due to their impact on cognitive function. These neurological symptoms, often termed “brain fog,” encompass a range of cognitive impairments including confusion, short-term memory loss, difficulty concentrating, and executive dysfunction.2 Cognitive function is integral to daily life, influencing an individual’s ability to work, engage in social interactions, and maintain overall quality of life. Emerging research has highlighted the significant impact of brain fog on occupational performance, with affected individuals frequently reporting difficulties in returning to their pre-illness work roles.3 Additionally, brain fog has been closely associated with psychological conditions such as depression and poor sleep quality, further exacerbating the challenges faced by those suffering from long-COVID.4 The pathophysiology underlying long-COVID brain fog is complex and multifaceted. A proposed mechanism involves the direct entry of the SARS-CoV-2 virus into the central nervous system via multiple routes, including the olfactory nerve, trigeminal ganglia, and retrograde axonal transport. This invasion triggers neuroinflammatory processes, characterized by the activation of glial cells such as astrocytes and microglia, leading to a chronic state of inflammation within the central nervous system. This neuroinflammation, coupled with oxidative stress, is believed to be a key driver of the cognitive dysfunction observed in long-COVID patients.2 Understanding these underlying mechanisms is essential for evaluating and optimizing the neuroprotective effects of medical gases, offering a promising therapeutic avenue to alleviate neurological symptoms associated with long-COVID. Neurological symptoms of long-COVID and the potential role of medical gases: The neurological symptoms associated with long-COVID, particularly cognitive impairments collectively referred to as brain fog, represent a significant challenge for both patients and healthcare providers. These symptoms, which include confusion, short-term memory loss, and difficulty concentrating, are increasingly linked to persistent neuroinflammatory processes initiated by SARS-CoV-2. The virus’s ability to enter the central nervous system via multiple routes—such as the olfactory pathway, trigeminal ganglia, and retrograde axonal transport—triggers a cascade of inflammatory responses, activating astrocytes and microglia. This ongoing inflammation, coupled with oxidative stress, is believed to contribute to the cognitive dysfunctions observed in long-COVID. Given the profound impact these symptoms have on individuals’ quality of life and daily functioning, identifying effective therapeutic interventions is crucial. The exploration of medical gases, including volatile anesthetics and inert gases, offers a promising avenue for addressing the neurological manifestations of long-COVID. Volatile anesthetics like isoflurane, sevoflurane, and desflurane, which have demonstrated neuroprotective effects in various preclinical studies, could be particularly beneficial in this context. These agents modulate critical cellular pathways involved in neuroinflammation and oxidative stress, such as the Toll-like receptor (TLR)-4/nuclear factor-κB and hypoxia-inducible factor 1-alpha/extracellular signal-regulated kinase 1/2 (ERK1/2) pathways, potentially mitigating the underlying mechanisms of brain fog. Additionally, inert gases like xenon and argon, known for their ability to reduce neuroinflammation and oxidative damage, could further enhance cognitive recovery in long-COVID patients. By targeting the specific pathophysiological processes that contribute to long-COVID brain fog, these gases may pave the way for novel therapeutic strategies, offering hope for patients struggling with the enduring cognitive effects of this condition. Further research is warranted to translate these findings into clinical practice and optimize treatment protocols for long-COVID-related neurological symptoms (Figure 1).Figure 1: Pathophysiological mechanisms of long-COVID neurological manifestations and neuroprotective effects of medical gases.Schematic representation of SARS-CoV-2 neuroinvasion pathways and the neuroprotective mechanisms of medical gases in long-COVID brain fog. (A) Pathophysiology: SARS-CoV-2 enters the CNS via three main routes: the olfactory pathway (through the nose), trigeminal ganglia, and retrograde axonal transport. This neuroinvasion leads to neuroinflammation (characterized by activated microglia and astrocytes releasing inflammatory cytokines) and oxidative stress (with increased reactive oxygen species and cell apoptosis). (B) Medical gases intervention: Different medical gases exert neuroprotective effects through specific molecular mechanisms. Hyperbaric oxygen (O2) upregulates oxygen- and pressure-sensitive genes and promotes stem cell proliferation and neurogenesis, leading to enhanced neuroplasticity and improved cognitive function. Hydrogen (H) upregulates regulatory T cells (T-reg) and inhibits IL-1β and ROS production, reducing neuroinflammation. Xenon (Xe) inhibits NMDA receptors at the glycine site, reducing excitotoxicity and preserving neuronal function. Argon (Ar) modulates TLR2/4, activates the ERK1/2 pathway, and upregulates Nrf2, resulting in reduced oxidative stress and inhibition of apoptosis. Volatile anesthetics (isoflurane/sevoflurane/desflurane) inhibit the TLR-4/NF-κB pathway and activate HIF-1α, attenuating inflammatory responses and reducing pro-inflammatory cytokines. Collectively, these interventions contribute to improved neurological outcomes in long-COVID patients experiencing brain fog. Created with BioRender.com. CNS: Central nervous system; COVID-19: coronavirus disease 19; ERK1/2: extracellular signal-regulated kinase 1/2; HIF-1α: hypoxia-inducible factor 1-alpha; IL: interleukin; NF: nuclear factor; NMDA: N-methyl-D-aspartate; Nrf2: nuclear factor erythroid 2-related factor 2; ROS: reactive oxygen species; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2; TLR: Toll-like receptor.Neuroprotective effect of hyperbaric oxygen therapy in long-COVID: In recent years, there has been growing interest in the potential use of medical gases for neuroprotection,5 particularly in the context of conditions characterized by neuroinflammation and oxidative stress, such as long-COVID. Medical gases are increasingly recognized for their ability to modulate various biological processes, offering novel therapeutic avenues for a range of neurological conditions. Among these gases, hyperbaric oxygen therapy (HBOT) has already been introduced into clinical practice for long-COVID patients, with promising results in improving cognitive function. Hyperbaric oxygen therapy involves the administration of 100% oxygen at pressures higher than atmospheric pressure, significantly enhancing oxygen delivery to tissues. The therapeutic effects of HBOT are thought to be mediated through several mechanisms, including the upregulation of oxygen- and pressure-sensitive genes, promotion of stem cell proliferation, and stimulation of neurogenesis. These processes contribute to enhanced neuroplasticity,6 facilitating the repair and regeneration of damaged neural tissues.7 Studies have demonstrated that HBOT can improve cognitive function in long-COVID patients,8 suggesting that this therapy may counteract the effects of neuroinflammation and oxidative stress that underlie brain fog. In addition to hyperbaric oxygen, other medical gases such as hydrogen, xenon, and argon have shown potential for neuroprotection in conditions with similar brain vascular damage. Hydrogen, for example, has been found to exert anti-inflammatory effects by upregulating regulatory T cells and inhibiting the production of pro-inflammatory cytokines such as interleukin-1β and reactive oxygen species. However, the neuroprotective efficacy of hydrogen has been inconsistent, with some studies failing to demonstrate significant benefits.9 These discrepancies are often attributed to variations in hydrogen concentration, underscoring the importance of optimizing dosage to achieve therapeutic effects. Inert gases – a novel approach to neuroprotection: Inert gases, particularly xenon and argon, have emerged as promising candidates for neuroprotection, especially in the context of perioperative neurocognitive disorders, which share similarities with the brain fog observed in long-COVID. Xenon, a noble gas with unique physicochemical properties, exerts its neuroprotective effects primarily through its action on N-methyl-D-aspartate receptors. By inhibiting N-methyl-D-aspartate receptors at the glycine site, xenon reduces excitotoxicity, a key contributor to neuronal injury in various neurological conditions. Notably, neuroprotective effects of xenon are achieved with minimal impact on γ-aminobutyric acid receptors, which helps to preserve overall neuronal function. Argon, another inert gas, has demonstrated neuroprotective properties through its ability to modulate Toll-like receptors (TLR2 and TLR4) and activate the ERK1/2 pathway. Activation of ERK1/2 leads to the upregulation of antioxidant proteins such as nuclear factor erythroid 2-related factor 2 and B-cell lymphoma 2 (Bcl-2), which play critical roles in reducing oxidative stress and inhibiting apoptosis. Additionally, argon has been shown to decrease the activity of caspase-3, an enzyme involved in the execution phase of apoptosis, thereby promoting cell survival and protecting neural tissues from ischemic and traumatic injury. These mechanisms suggest that xenon and argon could potentially mitigate the neuroinflammatory and oxidative processes that contribute to long-COVID brain fog.10 Volatile anesthetics – expanding the therapeutic potential: Volatile anesthetics, including isoflurane, sevoflurane, and desflurane, are halogenated ethers widely used for the induction and maintenance of general anesthesia. These agents are characterized by their rapid onset and offset of action, making them highly versatile in surgical settings. Beyond their anesthetic properties, volatile anesthetics have demonstrated unique neuroprotective capabilities, distinguishing them from other classes of anesthetics. Sevoflurane, in particular, has been extensively studied for its neuroprotective effects. It has been shown to inhibit the TLR-4/nuclear factor-κB pathway, leading to a reduction in the production of pro-inflammatory cytokines and attenuating the inflammatory response following ischemic injury. Isoflurane has been linked to the activation of hypoxia-inducible factor 1-alpha and ERK1/2 pathways, both of which are crucial for neuronal survival under conditions of hypoxia and ischemia. Desflurane, although less frequently studied, has demonstrated significant neuroprotective properties, including the reduction of infarct size and improvement in neurological outcomes following ischemic injury. These findings suggest that volatile anesthetics may have a broader application beyond anesthesia, offering potential therapeutic benefits for conditions characterized by neuroinflammation and oxidative stress, such as long-COVID11 (Figure 1). Conclusion: Long-COVID presents a multifaceted challenge, particularly with the emergence of neurological symptoms such as brain fog that significantly impair cognitive function and overall quality of life. As research continues to unravel the complex pathophysiology of these symptoms, medical gases have emerged as a promising therapeutic avenue. Hyperbaric oxygen therapy has already shown the potential in improving cognitive function in long-COVID patients by enhancing tissue oxygenation and promoting neurogenesis. Inert gases like xenon and argon, with their ability to modulate neuroinflammatory and oxidative pathways, offer additional hope for addressing the cognitive deficits associated with long-COVID. Volatile anesthetics, widely used in clinical practice, also demonstrate significant neuroprotective properties that could be leveraged to treat long-COVID brain fog. However, the application of these medical gases in treating long-COVID remains in its early stages, and substantial research is needed to fully understand their therapeutic potential. Future studies should focus on optimizing dosing regimens, exploring combinations of medical gases, and conducting large-scale clinical trials to evaluate efficacy and safety. Additionally, understanding the precise molecular mechanisms through which these gases exert their neuroprotective effects will be crucial for developing targeted therapies that can effectively mitigate the cognitive impairments associated with long-COVID. As the medical community continues to grapple with the long-term effects of COVID-19, the exploration of medical gases as neuroprotective agents offers a promising new direction in the quest to alleviate the burden of long-COVID on patients and healthcare systems alike.