Traumatic brain injuries (TBIs) are a leading cause of death and disability.
Sports-related TBIs are estimated to be more than several million per year. The
pathophysiology of TBIs involves high levels of inflammation, oxidative stress,
dysregulation of ion homeostasis, mitochondrial dysfunction, and apoptosis. There
is also a reduction in cerebral blood flow, leading to hypoxia and reduced
removal of metabolic waste, which further exacerbates the injury. There is
currently no recognized effective medical treatment or intervention for TBIs,
which may in part be due to the difficulty of drug delivery through the
blood-brain barrier. Molecular hydrogen has recently emerged as a neuroprotective
medical gas against cerebral infarction and neurodegenerative diseases including
TBIs. Its small molecular size and nonpolar nature allow it to easily diffuse
through the blood-brain barrier, cell membranes and subcellular compartments.
Hydrogen has been shown to exert selective anti-inflammatory, antioxidant, and
anti-apoptotic effects by regulating various transcription factors and protein
phosphorylation cascades. Nitric oxide is another well-recognized medical gas
that plays divergent roles in protecting from and in the recovery of TBIs, as
well as in contributing to their pathophysiology and injury. Excessive activation
of inducible nitric oxide synthase leads to excess inflammation and
oxidative/nitrosative damage as well as a paradoxical nitric oxide depletion in
the locations it is needed. Hydrogen regulates nitric oxide production and
metabolism, which enhances its benefits while reducing its harms. A novel
Traumatic brain injuries represent a serious health concern for millions of people and are a contributing risk factor in the development of other neurodegenerative diseases. However, there are many obstacles that need to be overcome in order to address these brain injuries including diagnosis, treatment, and monitoring. This article briefly summarizes the current status and problems with diagnosing, monitoring and treating traumatic brain injuries as well as its molecular pathophysiology. We introduce a novel approach for the treatment of traumatic brain injuries using medical gases, nitric oxide and molecular hydrogen. The scientific literature of both of these gases is briefly reviewed followed by some preliminary data in which administration of both gaseous molecules through a novel functional beverage improves cognitive function.
A traumatic brain injury (TBI) occurs when the brain is injured by an external source from a significant acceleration or deacceleration, impact, or blast wave. TBIs are a leading cause of death and disability worldwide . Sports-related TBIs make up to one-third of all causes of TBIs . Mild TBIs are called concussions and are the most common types of TBIs. The Center of Disease Control estimates that there are around 300,000 sports-related concussions per year in the USA . However, this number only includes athletes who have lost consciousness, which occurs in only about 10% of concussions . The real number may be more than several million per year . The vast majority of people who suffer a TBI do not immediately die from the primary injury, i.e., the damage directly to the brain tissue and blood vessels. Instead, most consequences occur from the secondary injury largely due to excessive inflammation and production of reactive oxygen species.
The secondary injuries may result in post-concussion syndrome in which the symptoms continue to last for months to more than a year after a TBI. Frequent TBIs increase the risk for developing the neurogenerative disease, chronic traumatic encephalopathy . It normally takes eight to ten years after repetitive concussions for the stages of CTE to appear. The symptoms of these stages include confusion, headaches, memory loss, impulsive behavior, depression, suicidality, etc. .
Diagnosis of TBIs may include neuroimaging such as a computed tomography (CT) scan, functional magnetic resonance imaging (fMRI), single photon emission computed tomography (SPECT), and positron emission tomography (PET) scans. However, most concussions are not usually associated with visible lesions that can be detected by current imaging techniques . Unfortunately, there is no urine, saliva, or blood test that can confirm either the existence of a TBI or recovery from a TBI . Accordingly, cognitive functional assessments are imperative to understanding the prognosis and recovery of TBIs . The most widely used psychometric test is the “Immediate post-concussion assessment and cognitive testing” abbreviated as “ImPACT” . Another method that can be useful is a neuro-diagnostic called Brain Gauge by Cortical Metrics. This is also an FDA-approved device that has been demonstrated to be an effective tool for monitoring TBIs. It measures eight essential components of brain health including, speed, focus, fatigue, accuracy, sequencing, timing, perception, plasticity, and connectivity .
In one study, over 200 student athletes were tracked post-concussion with the
Brain Gauge and the results were compared to other methods including ImPACT and
balance testing, and it was found that the Brain Gauge was highly sensitive and
accurate in the measurements. This is largely because of the high precision and
accuracy of measuring reaction time, which is an objective indicator of
concussions and recovery . The precision (0.33 milliseconds) is approximately
Despite having a mass of only 2% of the body, the brain constitutes about 20%
of the normal resting metabolic rate. In other words, the brain consumes about
20% of the available oxygen in order to maintain normal cognitive function .
In order to receive this much oxygen, the brain receives a high proportion
As expected, traumatic brain injuries (TBIs) also dysregulate and impair cerebral blood flow . Normally cerebral autoregulation maintains adequate brain perfusion during systemic changes in blood pressure. However, TBIs impair the brain’s autoregulation of blood flow, which is correlated with poor cognitive function . The decreased cerebral blood flow predicts the severity, cognitive dysfunction, and recovery from a TBI . The reduced brain blood flow means a reduction in oxygen and glucose, which leads to a pathological energy crisis . Reduced oxygen impairs mitochondrial activity, thus decreasing adenosine triphosphate (ATP) from oxidative phosphorylation. Under low oxygen conditions, anaerobic glycolysis would normally increase to ensure sufficient ATP; however, although glycolysis increases, the lower blood supply limits glucose availability resulting in further reductions in ATP and subsequent neuronal dysfunction .
The decrease in ATP production decreases Na
Pathophysiology of TBI injury and related consequences and interventions.
Immediate treatment of a TBI is imperative to help reduce the secondary injuries previously discussed. However, there is no known effective treatment or medications for TBI. Most recommendations simply include physical rest while slowly transitioning from light work back to normal activity once it appears that cognitive function has been restored . However, this does not address the pathological cascades resulting in secondary brain injury such as oxidative stress, inflammation, reduced blood flow, metabolic dysregulation, glutamate excitotoxicity, and neuronal apoptosis. Conventional antioxidants and anti-inflammatories are often ineffective at preventing or treating human diseases , but still may have some benefit for TBI .
There have been many preclinical studies in various animal models using
different bioactive molecules. For example, in a mouse model of TBI-induced by
controlled cortical impact, treatment with Coriolus versicolor and
Hericium erinaceus from mushrooms restored behavioral alterations and
decreased the neuroinflammatory and oxidative stress . In a similar TBI-mouse
model, administration of artesunate from the Chinese plant Artemisia
annua was able to favorably modulate neurotropic factors and suppress
Molecular hydrogen (H
The chemical properties and biological effects of hydrogen make it an attractive
molecule for the treatment of TBIs. There are many therapeutic effects of H
|Phenotypic, cellular and mechanistic effects of H
|[41, 42, 43, 44, 45, 46]|
|[40, 41, 42]|
|[39, 43, 48]|
|[36, 42, 48]|
|[40, 43, 44, 48]|
|[40, 41, 48]|
|Bcl-2, B-cell lymphoma protein 2; Bax, Bcl2 associated X-protein.|
In addition to the studies directly using H
Another medical gas that has shown therapeutic effects for TBIs is nitric oxide
However, nitric oxide also has a dark side as its dysregulation mediates many of
the pathological consequences of TBIs. A decreased eNOS activity results in
decreased blood flow and subsequent reductions in oxygen and glucose
availability, and decreased removal of metabolic waste and cellular debris. The
increased inflammation leads to an increased iNOS activation, which is expressed
in macrophages and glial cells . Unlike eNOS, increased iNOS expression is often harmful
and contributes to the pathophysiology of secondary TBI injuries .
The high levels of NO
In humans suffering severe TBI, the levels of arginine and citrulline were
significantly reduced compared to the control group . Accordingly, increasing or
preserving arginine availability is paramount in improving the prognosis of TBIs.
This can be attenuated by increasing arginine availability via supplementation
. Supplementation with citrulline is more effective at increasing plasma
arginine and NO
The novel combination of these two medical gases has important clinical
implications . For example, molecular hydrogen is able to attenuate the
aforementioned dark side of nitric oxide and regulate its production and
metabolism. This includes (i) enhanced expression of protective eNOS, (ii)
decreased inflammatory mediators that impair NO
In order to evaluate the potential of an H
In order to assess the effects of the functional beverage on cognitive function related to TBIs, the FDA-approved medical device, ImPACT was used (ImPACT Applications, Inc., Coralville, IA, USA) As mentioned, this widely used computer software gives a battery of neurocognitive tests for concussion care. A clinical ImPACT report was generated, and the average value of each category was determined. The composite score consisted of five parts (memory verbal, memory visual, visual-motor speed, reaction time, and impulse control). These values were totaled to find the average so that each category as a whole can be compared directly to each other. Fig. 2 shows the results of completing the assessment with and without Hydro Shot. As noted in the figure, this novel functional beverage improved the ImPACT clinical scores indicating its ability to improve functional cognition.
Effects of functional beverage on clinical ImPACT scores. Ingestion of beverage improved ImPACT scores compared to baseline.
It was previously reported that Hydro Shot significantly improved cognitive function as assessed by Brain Gauge (Cortical Metrics, Chapel Hill, NC, USA) . As discussed earlier, the Brain Gauge cognitive assessment tool has been validated by many studies and serves as an important indicator of TBIs. Fig. 3 illustrates the effects of the novel functional beverage on cognitive function using a radar chart.
Radar charts of cognitive function. (A) Without beverage. (B) With beverage. Cognitive scores were significantly improved above baseline following ingestion of the novel beverage.
TBIs are a leading cause of death and disability worldwide . Various diagnostic and assessment tools are available including neuroimaging techniques (e.g., fMRI, CT and PET scans, etc.), and computer software neuropsychometric testing. However, neuroimaging methods are expensive, time consuming, and do not always detect the presence of existing TBIs. The neuropsychometric assessments, such as ImPACT and Brain Gauge, appear to be more accurate in diagnosing and monitoring TBIs. Brain Gauge has a high level of sensitivity, accuracy, and precision for assessing cognitive function. We report that Hydro Shot significantly improved the clinical scores using ImPACT testing as well as the Brain Gauge. The significant improvements from Hydro Shot may be due to its ability to increase nitric oxide production and subsequent cerebral blood flow as well as the neuroprotective effects of molecular hydrogen.
The level of cerebral blood flow may predict the recovery, injury severity and
cognitive function from TBIs. The reduction in cerebral blood flow is largely due
to reductions in nitric oxide. Nitric oxide plays a key role in the prognosis,
recovery, and pathogenesis of TBIs. Molecular hydrogen also has important
benefits for TBIs and concussions at improving neurological outcomes and reduced
brain damage. These benefits are primarily due to the unique properties of
hydrogen including (i) rapid diffusion and penetration through all cell membranes
and subcellular compartments (e.g., nucleus, mitochondria, and blood-brain
barrier), (ii) selective antioxidant activity, (iii) selective anti-inflammatory
activity, (iv) prevention of pathological apoptosis, (v) favorable effects on
microRNA and gene expression, (vi) improved mitochondrial function, (vii)
regulation of nitric oxide production and metabolism, (viii) enhancement of
nitric oxide’s therapeutic effects, (ix) suppression of excess iNOS activity, and
(x) protection against nitrosative stress induced by ONOO
The cellular damage induced by TBIs is due to both primary and secondary injuries to the brain. Prevention is the best strategy for primary injuries, but once it occurs, then treatment of secondary injuries is paramount. However, no approved or effective medical treatments for TBIs currently exist. The secondary injuries occur due to increased oxidative stress, inflammation, and impaired metabolism largely attributed to reductions in cerebral blood flow, which decreases glucose and oxygen availability. Cerebral blood flow also declines with age in accordance with the decline in nitric oxide levels. Physical exercise and healthy dietary choices increase global and regional cerebral blood flow and improve cognitive functioning . The studies on the effects of molecular hydrogen and nitric oxide make it an attractive combination for TBIs and concussions.
Molecular hydrogen has emerged as an important medical gas with favorable physicochemical properties that make it ideal for the treatment of secondary TBIs. This is supported by pre-clinical studies and relevant human clinical studies. Similarly, nitric oxide has essential biological effects to treat TBIs but not without undesirable side effects. The novel approach of combining molecular hydrogen with nitric oxide may significantly improve the prognosis of TBIs by exerting individual and potential synergistic therapeutic effects with hydrogen mitigating nitric oxide toxicity.
The preliminary results obtained with the novel H
CT, computed tomography; CTE, chronic traumatic encephalopathy; eNOS,
endothelial nitric oxide synthase; HIF-1, hypoxia inducible factor;
TWL, JK, MLM conceived and designed the experiments; JK and MLM performed the experiments; TWL and JK analyzed the data; TWL and JK wrote the manuscript. All authors approved the final manuscript.
We thank H2 Beverages Inc., PO Box 940283, Plano, TX 75094–0283, USA. for providing product for testing, and also Kurt H. Ruppman Sr. for supporting information.
This research received no external funding.
MLM is a scientific advisor to the company. TWL reports personal fees from medical/academic conferences including travel reimbursement, honoraria, and speaking and consultancy fees from various academic and commercial entities regarding molecular hydrogen. All other authors report no conflict of interest.