The Pathophysiology of Traumatic Brain Injuries and the Rationale Behind Creatine Supplementation as a Potential Therapy: A Review

Abstract

Traumatic brain injuries (TBI) are detrimental to the brain in a variety of ways. Mild traumatic brain injuries (mTBI) are concussions; these are common events that disrupt typical brain functioning and send millions of patients to seek acute care each year globally. Despite the frequency of mTBIs, clinicians have few tools, pharmacologic and nonpharmacologic, to promote recovery and alleviate symptoms. After a TBI, complex biomolecular signaling, diffuse axonal stretching, and glutamate excitotoxicity occur, along with other pathological sequelae. Creatine has been shown to improve cognitive functioning in healthy adults. Burgeoning research is providing evidence that creatine may enhance recovery from TBI, as it directly targets derangements from such trauma.

TBI Epidemiology

TBIs represent a leading cause of morbidity and mortality worldwide.¹ These injuries have garnered more attention from the media and public during the last decade. However, trends show that although overall TBI-associated mortality has decreased by 50% in the last century, there has been no decrease in the mortality rate since 1990.^2,3 Interestingly, despite this finding, updates to evidence-based medicine have led to overall improvements with outcomes for those suffering from a TBI.² It is estimated that 50–60 million individuals worldwide are affected by TBIs each year; approximately 50% of the world’s population will sustain a TBI in their lifetime.³ Understandably this disease process places a large burden on the health system. In fact, TBI accounts for more than 2.5 million emergency department visits annually across the globe. In addition to the work required by acute care resources, other facets of the health care system bear this load, such as rehabilitation and therapy services. In fact, 5.3 million people in the United States are living with a TBI-related disability.²

Classification of TBI

The diagnosis of TBI comprises a heterogenous array of pathologies. For that reason, it has been difficult to categorize TBIs. The classification system uses three broad categories to guide diagnosis and acute care: clinical, radiographic, and mechanistic.¹ Clinically, and commonly, the Glasgow Coma Scale (GCS) is used. A mild TBI is classified as having a GCS score of 13 to 15, a moderate TBI has a GCS score of 9 to 12, and a severe TBI has a GCS of 8 or less.¹ Radiographic methods characterize structural damage, while mechanistic classification schemes can provide valuable prognostic information.⁴ Of note, an mTBI is commonly regarded as a concussion. Other indices of severity can be used to help infer prognosis, such as the Abbreviated Injury Severity Scale (AISS), loss of consciousness, or the presence of posttraumatic amnesia.⁵

mTBI Current Treatment Strategies

Current research shows that the treatment of mTBI should be multifaceted. Early patient education on concussion and treatment strategies has been shown to improve outcomes.⁶ While brief rest following an mTBI is warranted (24–48 hours), no research has proven that further rest is required or beneficial. Rather, it is preferrable if physical and cognitive activity is restarted. Return to previous levels of activity should be reintroduced slowly and decreased if there is a rebound of mTBI symptoms.⁷ Research on treatment of post-concussive syndrome shows that disturbances in mood and sleep often follow. It is key that these are diagnosed with neuropsychological testing and adequately treated with cognitive behavioral therapy (CBT) and pharmacological agents.^6,8 Cognitive deficits that arise may be addressed with neurocognitive rehabilitation, which uses tasks to improve mental processing or give patients coping mechanisms to navigate through daily activities.⁶ Mild TBI sequelae also include damage to the vestibular system and cervical spine. As such, physical, occupational, and speech-language therapy can alleviate this dysfunction, making the return to natural aerobic exercise and typical physical activity more successful.^9,10

Thus, while many strategies can be employed to ameliorate symptoms following mTBI, there continues to be a dearth of research surrounding pharmacological treatments that directly target the biochemical causes of injury that follow physical trauma to the head.

TBI Pathophysiology

A complex biochemical cascade of inflammatory and cellular processes occurs after the initial traumatic insult to the central nervous system (Figure 1). Largely, the injuries that ensue can be divided into primary and secondary insults. Linear acceleration forces are more likely to cause superficial brain damage; gray matter that is closest to the surface is most susceptible to developing lesions. Rotational forces can potentiate damage to deep white matter and gray matter nuclei axonal tracts in the brainstem and midbrain.^11,12 The primary mechanism by which damage occurs is through diffuse axonal injury and stretching of neurons. Rather than causing immediate swelling, these shearing forces act as a catalyst for the complicated metabolic and neuroinflammatory changes that comprise the secondary injury, which is more devastating and predictive of clinical outcomes.^12–14

Figure 1.

Illustration of complex pathophysiology and sequelae of TBI including direct damage to neurons, cell energy depletion, and cytokine production. Blood brain barrier (BBB); N-methyl-D-aspartic acid (NMDA), ɣ -aminobutyric acid (AMPA), reactive oxygen species (ROS); nitric oxide (NO).

The secondary insult of a TBI is indolent and progressive, encompassing a vast network of biochemical responses. Initially, there is destruction of the primary brain lesion affected by the physical trauma; however, widespread damage to neurons and glial cells occurs later due to release of molecules and initiation of signaling cascades.¹² The diffuse stretching of axons causes direct damage to the blood-brain barrier (BBB). Subsequently, ions enter the neuron, including calcium, sodium, and potassium. Random membrane depolarization ensues, causing release of excitatory amino acids (e.g. glutamate) from voltage- and ligand-gated ion channels. A positive feedback loop occurs with other neurons firing. This system depletes ATP stores, which are unable to be readily replenished due to the damage of oxidative respiration as cerebral blood flow is compromised.¹³ Anaerobic glycolysis will increase but cannot provide adequate energy to the neuron. As such, lactic acid also builds up within the cell.¹³ Glutamate release activates receptors, N-methyl-D-aspartic acid (NMDA) and ɣ-aminobutyric acid (AMPA), to cause intracellular signaling cascades. Calcium is then release intracellularly, promoting generation of both reactive oxygen species (ROS) and nitric oxide (NO). ROS can precipitate apoptosis, cytoskeletal degradation, and membrane lipid peroxidation. These processes can further promote the production of excitatory amino acids and the release of cytokines.¹²

New insights have been made regarding the role of inflammation within the secondary injury process. This neuroinflammation was previously regarded as peripheral immune mediators entering through a fragmented BBB. However, research has since shown that this is a multifaceted web of interactions, including central and peripheral components. To begin, there is early microglial activation and neutrophil recruitment. Subsequently, lymphocytes and macrophages infiltrate. Natural killer cells, dendritic cells, and T cells also are involved. Overlaying this is concurrent pro-inflammatory and anti-inflammatory action by cytokines to both promote and reduce the neuroinflammatory response.^15–17

Overall, this orchestration of the immune system is affected by various factors, including mechanism of injury, timing, age, genetics, and sex. All the molecular and cellular participants in the process ebb and flow during the secondary injury timeline. Likely, aspects of the post-injury neuroinflammatory process are both beneficial and harmful.¹⁵

Biomarkers

There are a variety of biomarkers that are associated with TBI; these are related to the kinetic release from neurons, transfer across the BBB, and clearance from systemic circulation. Diagnostic markers include S100B, UCHL-1, and glial fibrillary acid protein (GFAP).⁴ These markers can be used as proxies for imaging, allowing for a reduction in cost and radiation exposure. Furthermore, the IL-1B gene can be used with electroencephalography (EEG) to predict risk of post-traumatic epilepsy (PTE).^4,18

Free fatty acids (FFA) and lactic acid can also be used as markers of cellular injury after a TBI. In fact, animals given creatine for two weeks prior to a TBI had lower levels of FFA and lactic acid; however, these levels were still higher than sham controls.¹⁹ Another study found reversible decreases of creatine, phosphocreatine, N-acetylaspartate (NAA), adenosine triphosphate (ATP), and adenosine diphosphate (ADP) following CNS trauma in rat models; creatine and NAA were decreased by 44.5% and 29.5%, respectively.²⁰ Later research found decreases in NAA and creatine brain levels in concussed athletes using proton magnetic resonance spectroscopy. It was therefore concluded that mTBI may cause accompanying decreases in cerebral NAA and creatine levels. Such derangements make return to baseline neuronal homeostasis more lengthy.²¹

Skeletal Muscle Creatine Compared to Brain Creatine

Creatine is naturally occurring compound that is made endogenously from the amino acids glycine, arginine, and methionine and can be produced by the kidneys, liver, pancreas, and brain. It is a commonly used ergogenic substance that helps support the creation of lean muscle mass and helps increase capacity for high-intensity, short-duration exercise²² (Figure 2.)

Figure 2.

Illustration of the creatine molecule. Creatine is an organic compound and a derivative of glycine. It is methylated and has Nitrogen (N); Hydrogen (H), O (oxygen) and it is found primarily in brain and muscle tissue and is involved in vital physiologic processes.

Largely, this compound is stored in skeletal muscle, as it has a critical role in the phosphocreatine shuttle and generation of ATP, without need for oxygen.^23,24 Creatine’s main function is to supply energy on an immediate basis for acute needs; creatine is stored as phosphocreatine and the compound’s high-energy phosphate bonds allow for fast energy regeneration.²⁵ Broadly, it helps convert ADP to ATP in addition to transferring energy from the mitochondria to the cytosol.²⁶

Over the past decade, research has shown that creatine may play a role in cognition, particularly when the brain is enduring stress.²⁶ Creatine has also been shown to be neuroprotective with regards to normal aging, brain injury, and neurodegenerative conditions.²⁷ Logically, this relationship has been translated to a therapeutic strategy for recovery from an mTBI.¹³

As previously mentioned, creatine can be endogenously synthesized by organs in the body, including the kidneys, liver, pancreas, and brain. However, skeletal muscle cannot produce creatine. Rather, the creatine synthesized by the kidneys, liver, and pancreas joins systemic circulation and then enters skeletal muscle cells through the SLC6A8 transporter.²⁴

Generation of energy is important for the brain as it consumes 20% of the body’s total energy; however, it only makes up 2% of the body’s total mass.^24,26 Unlike skeletal muscle, the brain is not fully reliant on circulating creatine from diet or supplementation as it can generate the compound endogenously. Creatine kinase, an enzyme critical to the energy generation of creatine, has a specific brain isoform, located in the cerebellum, hippocampus, pontine reticular formation, red nucleus, cerebral cortex, and choroid plexus. This underscores the fact that creatine is necessary for energy production in the central nervous system (CNS).^25,26 Additionally, the SLC6A8 creatine transporters allow creatine from exogenous sources to be utilized by the CNS.^22,25 These transporters are found on neurons and oligodendrocytes.²⁶ They are also found at the BBB; there is likely some ability for creatine to cross this complex biomechanical barrier.^24,26 Though, creatine is absorbed at significantly slower rates into the CNS compared to skeletal muscle.²² This could be a result of low permeability at the BBB or because astrocytes lack expression of the SLC6A8 creatine transporter.^24,26

Studies have shown that exogenous ingestion of creatine can increase brain levels.^22,28,29 Factors that can influence brain creatine levels include aging, amount of brain activity, amount of physical activity, mood disorders, schizophrenia, and panic disorder.²⁶ Another difference between skeletal muscle and brain levels of creatine is that, according to several studies, larger amounts of creatine are needed for a longer period of time to increase brain levels compared to skeletal muscle levels.^22,24,29,30

In a review article, Forbes et al. found that 12 studies in 11 articles showed that brain creatine content changed from −0.7% to 14.6% with oral supplementation; most of those studies reporting a 3–10% increase. Other studies found no change or even decreased brain creatine with supplementation.²⁴ A large element of brain creatine levels after supplementation depends on basal creatine levels; the potential for increase is inversely related to baseline levels.²⁵ Researchers theorize that because the brain can endogenously synthesize creatine, it may downregulate this creation when creatine supplementation occurs.²⁶ Others suggest that simply because the brain can synthesize creatine the neuronal tissue is more resistant to the uptake from systemic circulation.²⁴

Creatine Supplementation and Cognitive Function in Healthy Adults

Many studies have examined the effects of creatine on cognition in healthy patient populations. On the whole, creatine has been shown to improve cognitive processing, brain function, and recovery from trauma.²⁶ Studies have shown that these positive influences are most beneficial when the brain is experiencing stressful situations such as sleep deprivation, exercise, or hypoxia.^22,24,26 With regards to exercise, athletes have been shown to have improved cognitive performance, mental fatigue, and memory.²²

Further proof in the importance of creatine for the homeostasis of cognitive functioning exists within a variety of genetic creatine deficiency disorders: L-arginine-glycine amidino transferase (AGAT), guanidinoacetate-methyltransferase (GAMT), and SLC6A8 deficiency. Each of these disorders disrupts creatine metabolism or transport, has global effects on development, and causes intellectual disability. Critical to this connection is that the supplementation of oral creatine counteracts the effects of AGAT and GAMT, except with SLC6A8 deficiency.²⁵

Creatine Supplementation and TBI

While creatine has been shown to be efficacious for cognitive functioning, particularly in times of brain stress, significant research has shown that it can play a role in directly combating the pathophysiological changes that occur in neuronal tissue after a TBI. In fact, following a TBI, brain creatine levels are reduced.^20,21,24 Furthermore, animal model data indicate that creatine supplementation prior to TBI can decrease damage up to 50%.³¹

Two small clinical trials were performed giving children and adolescents creatine after TBI. In one study, creatine supplementation was initiated within four hours of the TBI and was administered for six months daily at 0.4g/kg in an oral suspension. Of the patients that received the supplementation, less posttraumatic headache, dizziness, and fatigue were reported compared to the group who received no creatine.³² Another investigation by the same authors with similar methodology showed that creatine could confer neuroprotective effects in children and adolescents post-TBI. In that study, patients who received the creatine supplementation had improved post-traumatic amnesia, decreased duration of intubation, intensive care unit stay, and disability. These children also had improved communication, locomotion, behavior, and cognition.³³ Importantly, both experiments found no deleterious side effects with creatine supplementation.^32,33

In terms of PTE, creatine supplementation in rat models begun one week after TBI has been shown to increase latency of first myoclonic and tonic clonic seizures. In addition, creatine was found to decrease time spent in seizures and seizure intensity. This neuroprotective effect was demonstrated even one week after creatine supplementation was discontinued.³⁴ Creatine can reduce cell loss in the hippocampus and protect against GABAergic function in the hippocampus. This is critical, as progressive neuronal damage that follows TBI for months can be related to pathologic excitotoxicity.³⁴ Another rat model study examining creatine’s effects on seizure and biomarkers found that creatine helped to reduce amounts of markers associated with protein carbonylation and lipid peroxidation, thought it did not reverse a decrease in Na⁺/K⁺ ATPase activity.³⁵ Rather than protecting against seizures, this study found that rats with creatine supplementation had decreased seizure latency at four days post-TBI and had a longer duration in tonic-clonic seizures. Therefore, there is mixed proof regarding creatine supplementation and TBI; likely the neuroprotective effects are not able to minimize all the excitatory pathways that create PTE.³⁵

After a TBI, random membrane depolarization causes neuronal firing, depleting ATP stores. Furthermore, there is reduced blood flow and hypoxia. Brain metabolism can be dysregulated for years.²⁶ However, creatine can help restore membrane potentials and act as an energy source for the cells.¹³ In a study with induced hypoxic conditions for human subjects, creatine supplementation was found to restore hypoxia-induced decrements in cognitive functioning. These patients also had an increase in corticomotor excitability. This is likely as creatine can delay hypoxia-induced membrane depolarization and maintain neuronal integrity.²³ Creatine supplementation prior to insult can also prevent impaired protein synthesis and axonal damage, protecting against synaptic transmission breakdown and the pathologic anoxic depolarizations that can cause neuronal death. Furthermore, creatine works to help the energy balance by transferring high-energy phosphates to areas of the neuron that need additional energy when oxidative phosphorylation is unable to function during hypoxia.²³ There is also a theorized state of hypermetabolism followed by hypometabolism following TBI. Due to the limited cerebral energy and injury-induced blood flow anomalies, energy supply and demand are unequal. Creatine is beneficial to this problem both prophylactically and immediately following TBI.²⁴

The impaired mitochondrial function associated with TBI can also be addressed by creatine supplementation. Creatine has been shown to help increase mitochondrial membrane potential and decrease intramitochondrial reactive oxygen species and calcium.³¹ Furthermore, it can help maintain ATP levels produced by the mitochondria. With restoration of functioning mitochondria, creatine kinase is able to catalyze the reversible conversion of creatine and ATP to ADP and phosphocreatine, thus generating energy reserves for the healing neuronal tissue.³¹ Creatine is also able to directly stimulate oxidative respiration of the mitochondria and prevent formation of mitochondria permeability transition pores (mPTP).¹³

TBI causes excesses glutamate activation of NMDA receptors. This is one arm of the complex biomolecular signaling cascade previously described that causes increased cellular calcium, neuronal damage, and death.²⁴ In cultured rat embryonal hippocampal and cortical cells subjected to glutamate or peroxide, creatine was found to act in a neuroprotectant manner. Creatine was able to antagonize the excitotoxic response of glutamate on NMDA receptors, thus preventing calcium influx and sequestration.²⁷

In addition to addressing energy, glutamate excitotoxicity, and impaired mitochondrial function, creatine has other ways it can combat TBI pathophysiology. It dampens calcium influx and reduces ROS by directly scavenging free radicals. Moreover, it prevents cerebral edema and can act as an anti-inflammatory agent.¹³

Conclusion

Overall, there is compelling evidence that creatine may act as a potential pharmacological therapy directly targeting the pathophysiologic effects of TBI. Future studies need to elucidate proper creatine supplementation protocols, including dosage amounts and intervals. While some studies have examined the effects of creatine on cognitive function, more trials are needed to analyze the connection. Further examination is also needed on the specific brain conditions that could benefit the most from creatine, in addition to post-traumatic states.²⁶