Treatments For Brain Injury: The Potential Roles Of Noble Gases

  • Shiyi Liang Medical Biosciences, Imperial College London

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Brain injury can be a serious condition where the brain matter is damaged, hence heavily impairing the cognitive and physical function of patients. Current major treatments are limited to targeting symptoms after brain injury, but the potential role of noble gases protecting nerve cells and reducing brain damage regions is researched in labs.

This article will enhance our understanding of brain injuries and offer insights into the role of noble gases in these injuries, along with considerations for the future.

Introduction 

Brain injury, or brain damage, is when a significant portion of the brain is damaged. The brain is a delicate and fragile organ which requires immediate and effective treatment after injury, regardless of its severity. Advancements in treatment modalities promise improved outcomes for individuals with brain injuries and pave the way for a deeper understanding of the intricate mechanisms involved in brain function and recovery. Exploring new treatments is vital for addressing the pressing medical challenges associated with brain injuries and enhancing the overall quality of life for affected individuals.

Types of brain injuries 

Brain injuries can be caused by both extrinsic (outside the body) and intrinsic (within the body) factors. External impact and injuries to the head could lead to traumatic brain injury, and intrinsic diseases may also cause brain injuries, including ischemic and hemorrhagic brain injury. These types of injuries are categorised as acquired brain injuries and are a separate category from congenital (present from birth) brain damage caused due to genetic factors or other innate diseases.

The use of noble gases, a group of gases that include helium, neon, argon, krypton, xenon, and sometimes radon, has shown certain neuroprotective effects (keeping brain cells safe from damage) in brain injury animal models, even though these brain injury models have different pathological mechanisms than humans. Nevertheless, this could potentially lead to new treatments for brain injury in humans. 

Traumatic brain injury 

Traumatic brain injuries (TBI) are caused by a forceful impact to one’s head, or from an object that pierces through the skull and causes damage to the brain. Some accidents, explosions or natural disasters can cause both penetrating and non-penetrating TBI. 

Typical physical signs for TBI patients include headaches, vomiting, blurred vision, or seizures. Cognitive changes can be reflected in sleep pattern changes, inability to concentrate, learning and memory difficulties, and even consciousness loss for some time. Other sensory problems include hearing loss, increased sensitivity to light and sound, and experiencing unnatural tastes in the mouth. 

Physical signs can appear immediately after injury, while cognitive and sensory changes may develop over time.1 Collision and piercing cause internal bleeding and damage to the brain matter, and can often lead to inflammation, metabolic, and morphological changes to nerve cells. 

Ischaemic brain injury (hypoxic-ischaemic brain injury)

The brain is an organ that heavily depends on sufficient blood flow, which provides glucose and oxygen, two essential parts to normal brain function. When the blood flow in the brain is restricted or cut off, ischaemic brain injury occurs. Brain ischaemia can be either global or focal, meaning that it can affect either the entire brain or a part of it. Focal brain ischemia (or multifocal - in multiple brain parts), often arises from the blockage of blood vessels in an area, by blood clots or other foreign bodies like air bubbles.2

Systemic hypotension (low blood pressure), where a malfunction in the mechanisms regulating blood pressure and heart rate leads to a decrease in systemic blood pressure, essentially restricting blood flow to the brain, primarily causes global brain ischemia. Other structural and functional heart problems, like arrhythmias (heart rhythm problems) and cardiac arrest (heart attack), can also cause global brain ischemic brain injury.2  

Haemorrhagic brain injury

Haemorrhagic brain injury refers to bleeding within the brain, which may occur due to penetrating trauma, hypertension (high blood pressure), tumours, infections, or other intrinsic factors.3 Symptoms of brain haemorrhage include sudden severe headache, loss of consciousness, blurred vision, and a stiff neck. Bleeding within the brain also has a range of complications, affecting the patients’ mental function and mood.4 The damage to the brain can be observed within minutes to hours. The bleeding increases pressure within the brain, causing direct injury. The blood is also toxic to brain cells and increases oxidative stress and inflammation.5 

A brain injury is typically hard to treat because in most cases, brain cells die very quickly, sometimes causing up to 95% damage to the brain tissue within 15 minutes, in the case of global ischaemic brain injury.6

Additionally, the blood-brain barrier, a membrane acting as a filter between the blood vessels and the brain, hinders the effective delivery of drugs to the brain. While mild brain injuries may not require specific drug interventions, prompt treatment is crucial for severe cases to prevent fatalities and mitigate potential long-term complications.1

Current treatment approaches

When serious brain injury takes place, the primary action would be to ensure sufficient oxygen supply to the brain and stabilise other organs’ function. 

For a mild brain injury, doctors do not recommend specific treatments or hospitalisation. Instead, they prescribe drugs to reduce pain and the chance of a blood clot, as well as drugs that relieve seizure symptoms. Additionally, they prescribe diuretics to reduce fluid accumulation in the body and, most importantly, within the brain.

For severe brain injuries, the patient’s conditions are evaluated, and then the treatments are selected. Surgical interventions play a critical role. Surgeons can remove debris from a skull fracture, dead brain tissue, and other foreign bodies that are a risk to the brain. This also lowers the pressure buildup in the brain by removing accumulated blood or fluids. Surgeries for haemorrhage brain injuries are necessary to repair damaged blood vessels and stop bleeding. The two widely applied surgical procedures are coiling and clipping. After surgeries, patients remain in the hospital for observation in case of a serious infection or the occurrence of thrombosis (blood clots).1 

Rehabilitation is a crucial component of the recovery process, encompassing physical, occupational, and speech therapy. Despite several advancements in treatment approaches, the variability in individual responses to treatment underlines the need for personalised and multifaceted approaches to address the diverse nature of brain injuries. The cognitive and physical symptoms after brain injury can be long-lasting and can heavily reduce life quality.1 Apart from surgeries and medication, noble gas treatment is currently being researched in most brain injury models and has shown positive outcomes. xenon and argon have shown the most significant neuroprotective effects. 

Introduction to noble gases

Noble gases, which are also called inert gases, include helium, neon, argon, krypton, xenon, and radon. They are chemically inactive and hardly react with other chemicals under normal conditions. Despite their lack of bioactivity, neon and radon are radioactive, but helium, argon, krypton and xenon have applications in medical fields. 

When organs are injured, the anti-apoptotic effect (which prevents cell death) of xenon and argon, which are used as anaesthesia agents, provides protection. Krypton is a good agent for magnetic resonance imaging.7 Helium also has an anaesthetic effect (causing lack of sensation), but can only be achieved at high pressures, up to 189 atmospheric units. Helium’s beneficial effect of protecting heart muscle cells from ischemia has stood out, and new applications in magnetic resonance imaging (MRI) screening have been discovered.8 

The neuroprotective potential of noble gases 

Xenon gas has emerged as a promising candidate with its applications in mitigating the effects of brain injury. Its unique properties make it an effective neuroprotective agent. Previously, researchers have mainly tested the effect of xenon in lab conditions. However, in recent years, they have conducted experiments on different animal models that have traumatic brain injury, ischemic brain injury, and intracerebral haemorrhage. These experiments have shown that xenon treatment improves cognitive function and reduces neural loss and inflammation.9,10,11 

Argon gas is another choice for neuroprotection after brain injury, although it is less studied than xenon. Argon also passes through the blood-brain barrier as quickly as xenon while being cheaper to use and easier to transport. There are limited and contradictory results when speaking of its neuroprotective effects, but it has been experimented with in ischaemic, haemorrhagic and traumatic brain injury animal models. The results showed better neuroprotection in ischaemic lesions, especially when inhaling for a long time (24 hours), immediately after the injury.12, 13,14 

The mechanisms of action of xenon and argon are different. Xenon inhibits the action of a specific receptor called NMDA receptor, a receptor related to memory function in the human brain. Its over-activation could lead to neuron cell death.15,16 

Argon has another downstream pathway where it inhibits two receptors that are vital components of the brain’s innate immune system, called toll-like receptors 2 and 4 (TLR2 and TLR4). Argon reduces inflammation in brain injury by suppressing the action of TLR2 and TLR4.17 Argon also activates an important factor regulating the responses to oxidative stress, called an Nrf2 factor. Therefore, nervous cells can better resist oxidants and avoid cellular damage.18 

Research and clinical studies 

There are limited clinical trials examining the neuroprotective effect of noble gases in patients with brain injury, and they are mostly focusing on xenon. One phase-2 clinical trial tested the neuroprotective effect of xenon on cardiac arrest patients, measuring the severity of ischaemic white matter brain injury after patients received xenon treatment. The result showed a trend to reduce brain damage but was not significant due to the lack of long-term survivors with severe neurological damage after suffering from cardiac arrest.19 Xenon is also tested in several other clinical trials for brain injury in newborn babies due to lack of oxygen.20 Argon has been suggested for further research in clinical settings, based on the beneficial evidence found in pre-clinical studies

The wide use of xenon and argon as anaesthesia agents reflects its safety in humans.21,22 Currently, argon and xenon are administered by inhalation in combination with oxygen at a certain percentage if given as a treatment, lasting from 3 to 24 hours.20,23 Future studies are needed to determine the most effective ratio and time of administration. 

Conclusion 

Noble gases are stable and inert gases in nature, are bioactive and have applications in the medical field, especially the anaesthetic role of xenon and argon. The neuroprotective effects of xenon and argon in patients with brain injury have not been yet extensively researched. Studies on animal models have shown their safety and efficacy in protecting the brain from further damage after the primary injury. Although several clinical studies for this purpose emerged, more trials are needed to gain a better understanding of their application.  

References

  1. National Institute of Neurological Disorders and Stroke. Traumatic brain injury (TBI) [Internet]. www.ninds.nih.gov. 2023. Available from: https://www.ninds.nih.gov/health-information/disorders/traumatic-brain-injury-tbi 
  2. DeSai C, Hays Shapshak A. Cerebral Ischemia [Internet]. PubMed. Treasure Island (FL): StatPearls Publishing; 2021. Available from: https://www.ncbi.nlm.nih.gov/books/NBK560510/ 
  3. Tenny S, Thorell W. Intracranial Hemorrhage [Internet]. PubMed. Treasure Island (FL): StatPearls Publishing; 2020. Available from: https://www.ncbi.nlm.nih.gov/books/NBK470242/ 
  4. NHS Choices. Overview - Subarachnoid haemorrhage [Internet]. NHS. 2019. Available from: https://www.nhs.uk/conditions/subarachnoid-haemorrhage/
  5. Aronowski J, Zhao X. Molecular Pathophysiology of Cerebral Hemorrhage. Stroke. 2011 Jun;42(6):1781–6.
  6. Busl KM, Greer DM. Hypoxic-ischemic Brain injury: Pathophysiology, Neuropathology and Mechanisms. Neurorehabilitation [Internet]. 2010;26(1):5–13. Available from: https://content.iospress.com/articles/neurorehabilitation/nre00531 
  7. Pavlovskaya GE, Cleveland ZI, Stupic KF, Basaraba RJ, Meersmann T. Hyperpolarized krypton-83 as a contrast agent for magnetic resonance imaging. Proceedings of the National Academy of Sciences of the United States of America [Internet]. 2005 Dec 20 [cited 2021 Oct 8];102(51):18275–9. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1317982/ 
  8. Berganza CJ, Zhang JH. The role of helium gas in medicine. Medical Gas Research. 2013;3(1):18.
  9. Sheng Siyuan P, Lei B, James Michael L, Lascola Christopher D, Venkatraman Talaignair N, Jung J, et al. Xenon Neuroprotection in Experimental Stroke. Anesthesiology. 2012 Dec 1;117(6):1262–75.
  10. Ma D, Yang H, Lynch J, Franks Nicholas P, Maze M, Grocott Hilary P. Xenon Attenuates Cardiopulmonary Bypass–induced Neurologic and Neurocognitive Dysfunction in the Rat. Anesthesiology. 2003 Mar 1;98(3):690–8.
  11. Campos-Pires R, Hirnet T, Valeo F, Ong BE, Radyushkin K, Aldhoun J, et al. Xenon improves long-term cognitive function, reduces neuronal loss and chronic neuroinflammation, and improves survival after traumatic brain injury in mice. British Journal of Anaesthesia [Internet]. 2019 Jul [cited 2023 Jan 12];123(1):60–73. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6676773/ 
  12. Aнтонова ВВ, Silachev DN, Рыжков ИА, Лапин КН, Sergey Kalabushev, Острова ИВ, et al. Three-Hour Argon Inhalation Has No Neuroprotective Effect after Open Traumatic Brain Injury in Rats. Brain Sciences [Internet]. 2022 Jul 13 [cited 2023 Nov 30];12(7):920–0. Available from: https://doi.org/10.3390%2Fbrainsci12070920 
  13. Brücken A, Pınar Kurnaz, Berne C, Matthias Derwall, Weis J, Nolte K, et al. Delayed Argon Administration Provides Robust Protection Against Cardiac Arrest-Induced Neurological Damage. Neurocritical Care. 2014 Aug 1;22(1):112–20.
  14. Ma S, Chu D, Li L, Creed JA, Ryang YM, Sheng H, et al. Argon Inhalation for 24 Hours After Onset of Permanent Focal Cerebral Ischemia in Rats Provides Neuroprotection and Improves Neurologic Outcome. Critical Care Medicine. 2019 Aug;47(8):e693–9.
  15. Harris K, Armstrong SJ, Campos-Pires R, Kiru L, Franks NP, Dickinson R. Neuroprotection against Traumatic Brain Injury by Xenon, but Not Argon, Is Mediated by Inhibition at the N-Methyl-d-Aspartate Receptor Glycine Site. Anesthesiology. 2013 Nov 1;119(5):1137–48.
  16. Sánchez-Blázquez P, Rodríguez-Muñoz M, Vicente-Sánchez A, Garzón J. Cannabinoid Receptors Couple to NMDA Receptors to Reduce the Production of NO and the Mobilization of Zinc Induced by Glutamate. Antioxidants & Redox Signaling. 2013 Nov 20;19(15):1766–82.
  17. Wang Y, Ge P, Zhu Y. TLR2 and TLR4 in the Brain Injury Caused by Cerebral Ischemia and Reperfusion. Mediators of Inflammation. 2013;2013:1–8.
  18. Yin H, Chen Z, Zhao H, Huang H, Liu W. Noble gas and neuroprotection: From bench to bedside. Frontiers in Pharmacology. 2022 Nov 29;13.
  19. Ruut Laitio, Marja Hynninen, Arola O, S. M. M. Virtanen, Riitta Parkkola, Saunavaara J, et al. Effect of Inhaled Xenon on Cerebral White Matter Damage in Comatose Survivors of Out-of-Hospital Cardiac Arrest. JAMA. 2016 Mar 15;315(11):1120–0.
  20. Dingley J, Tooley J, Liu X, Scull-Brown E, Elstad M, Chakkarapani E, et al. Xenon Ventilation During Therapeutic Hypothermia in Neonatal Encephalopathy: A Feasibility Study. Pediatrics. 2014 May 1;133(5):809–18
  21. Ristagno G, Nespoli F, Redaelli S, Ruggeri L, Fumagalli F, Olivari D. A complete review of preclinical and clinical uses of the noble gas argon: Evidence of safety and protection. Annals of Cardiac Anaesthesia. 2019;22(2):122.
  22. Esencan E, Yuksel S, Tosun YB, Robinot A, Solaroglu I, Zhang JH. XENON in medical area: emphasis on neuroprotection in hypoxia and anesthesia. Medical Gas Research [Internet]. 2013 [cited 2019 Apr 30];3(1):4. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3626616/ 
  23. Zhu Y, Mosko JJ, Chidekel A, Wolfson MR, Shaffer TH. Effects of xenon gas on human airway epithelial cells during hyperoxia and hypothermia. Journal of neonatal-perinatal medicine [Internet]. 2020 Nov 27 [cited 2023 Nov 30];13(4):469–76. Available from: https://doi.org/10.3233%2FNPM-190364 

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This content is purely informational and isn’t medical guidance. It shouldn’t replace professional medical counsel. Always consult your physician regarding treatment risks and benefits. See our editorial standards for more details.

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Shiyi Liang

Medical Biosciences, Imperial College London

Shiyi has several years of experience as a writer for health articles and science reviews. Shiyi has engaged actively in diverse research projects, spanning topics from neuroscience to endocrinology, demonstrating her meticulous approach and passion for research. She is eagerly anticipating more opportunities to delve into the realms of research and science. Furthermore, Shiyi is dedicated to creating informative scientific videos.

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