Pre-workout, protein powder, creatine. Speak with any frequent gym-goer, and these terms will likely come up. Nutritional supplements are very popular in bodybuilding and other high-intensity athletic endeavors for their physical performance benefits, but new research suggests creatine can do more than pack on muscle: it can also protect the brain. A 2014 Pakistani study demonstrated that creatine supplementation reduced brain damage and improved neurological function in mice with Hypoxic Ischemic Encephalopathy, a critical brain injury.
Hypoxic Ischemic Encephalopathy (HIE) is a rare but serious birth complication that results from insufficient blood flow to the brain. Ion gradients across cell membranes fail due to lack of oxygen, causing neurons to die (Allah et al. 2014). Although HIE only occurs in about three out of every 1000 births, 60% of infants diagnosed will die or experience severe disabilities such as cerebral palsy, epilepsy, seizures, and other cognitive impairments (Allen and Brandon 2011). Currently, there is only one standard treatment for HIE: therapeutic hypothermia, also known as brain cooling. Infant body temperature is quickly decreased and maintained for 72 hours using cooling blankets. This reduces the metabolic rate and oxygen requirements of the brain, thus reducing cellular decay due to lack of oxygen flow (Hypoxic 2021). Therapeutic hypothermia reduces mortality and morbidity by about 10% and 20%, respectively, but scientists are still trying to discover more effective treatments, one of which could be creatine (Papazian 2018).
Creatine is a natural substance found mainly in skeletal muscle cells, but also in the kidney, liver, and brain. It is commonly in the form of phosphocreatine, a creatine molecule with a phosphate group attached. Phosphocreatine’s role in the body is to restore energy-poor ADP molecules back into energy-rich ATP molecules by transferring its high energy phosphate group (Tarnopolsky 2010). This process supplies the body with power during anaerobic conditions for the few seconds before aerobic respiration kicks in. What’s interesting about creatine is that despite its consumption through fish and red meat as well as its production by the liver, pancreas, and kidney, normal human creatine stores sit only at about 60-80% saturation. As such, additional supplementation—usually 5 grams a day—can significantly increase creatine levels in the body, including those in your brain (Kreider et al. 2017). Countless studies have shown supplementation in this form poses no health risks, and the only consistent side effect is slight weight gain due to more intracellular water (Tarnopolsky 2010).
The obvious benefit of creatine is improved physical performance: during low-duration, high-intensity exercise like weightlifting, boosted phosphocreatine levels allow for more ATP energy to be produced. As such, athletes can train harder and longer, eliciting more muscle growth (Tarnopolsky 2010). A less apparent benefit of creatine is its ability to potentially act as a neuroprotector in low oxygen conditions. It can be reasoned that during HIE, when brain cells are starving for oxygen to undergo aerobic respiration, creatine can act as a buffer to supply energy for anaerobic respiration and buy the body more time to supply oxygenated blood. Furthermore, brain cells involved in learning and memory show high expression of creatine isoenzymes, indicating that creatine plays an important role in the development of these areas as well. This is exactly what Razia Allah Yar, Atif Akbar, and Furhan Iqbal from the University of Bahauddin Zakariya in Pakistan set out to research in their 2014 study. Using neonatal mice induced with HIE, they hypothesized that creatine monohydrate supplementation in experimental groups will improve performance on neurological tests compared to the control group.
To begin the study, thirty newborn mice were surgically given HIE by tying off a major artery and being temporarily subjected to low oxygen conditions. The mice were then divided into three groups: a control group fed a normal rodent diet, a group supplemented with 1% creatine, and a group supplemented with 3% creatine. Over the following days, mice were analyzed in four ways: the Rota rod test, open field test, Morris water maze test, and brain staining. The Rota rod Test measures neuromuscular coordination by placing the mice on a rotating rod and timing how long they can stay on it. The Open field test studies locomotory and exploratory behavior by individually placing mice in an open arena and monitoring their movement patterns for ten minutes. The Morris Water Maze consists of a circular pool with a hidden escape platform underwater, which can only be found using memory of spatial cues. After being trained over several days how to find the platform, mice were individually released at random locations in the pool and their escape was recorded. Variables such as latency (time taken to reach the platform), path length, rest time, and swimming speed were recorded. The final test, brain staining, involved surgically removing the mice’s brains and slicing them into sections. Sections were immersed in a solution (triphenyl tetrazolium chloride, TTC) that stains intact brain areas dark red while leaving infracted (dead) areas white (Allah et al. 2014).
Ultimately, each test demonstrated varying results of creatine effectiveness in reducing the detriments of HIE. With respect to the Rota rod test, mice supplemented with 3% creatine spent more time on rotating drum than 1% and control groups, but not enough to be statistically significant. In the open field test, 1% and 3% creatine supplementation significantly affected mobile, immobile, and freezing episodes compared to control groups. This evidence demonstrates that creatine supplementation improved locomotor and exploratory behavior following HIE. In the Morris water maze test, the 3% group swam with the highest velocity, took the shortest path, and had the most successful runs compared to the other groups, indicating that creatine supplementation improved learning and memory formation. TTC brain staining revealed a significant difference in infarct size between the 3 groups, with the 3% group having the smallest. This clearly showed that creatine makes the brain less susceptible to brain damage during HIE (Allah et al. 2014).
This study provides convincing, reasonable evidence that creatine could be a viable treatment option for HIE. The methods employed to collect data, like the Rota rod test and Morris water maze, are widely used and accepted in the research industry. Furthermore, the researchers claimed no conflicts of interest in the study, and the study itself is both repeatable and ethical. Mice were housed and handled with care, given anesthesia during induced HIE, and sacrificed humanely (Allah et al. 2014). Future tests like this one should consider implementing a larger sample size per supplement group to provide more statistically significant evidence. In addition, open field behaviors such as immobile and freezing episodes should be more clearly defined, specifically with how they relate to locomotor and exploratory behavior.
More research is needed to justify clinical usage of creatine as a treatment for HIE, however, it has great potential in the neurological healthcare field. It is inexpensive, meaning that if implemented, it would serve as a more affordable treatment option for financially struggling families. In addition, the neurological systems that creatine affects are closely linked with disorders other than HIE, including Huntington’s (Allah et al. 2014). Further creatine supplementation studies and clinical trials could reveal benefits extending into other neurological disorders that harm our society.
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