Creatine in Clinical Trials : Ischemia & Hypoxia

Clinical Scenarios Where Creatine is Being Tested

1. Muscular Dystrophy

2. Neurodegenerative Disorders

3. Ischemia and hypoxia

Creatine is a Neuroprotectant!

Creatine Enhances Brain Survival Following Reduced Blood Flow That Compromises Oxygenation

Creatine’s energy allotment is proving to have far reaching ramifications for overall health, resistance to disease and protection from cellular trauma. Below are two studies from distinct parts of the world (United States and Switzerland) showing that creatine protects brain cells from dying following reduced blood flow (ischemia) that could starve brain cells for oxygen (hypoxia) and essential nutrients.

Swiss Study: “Neuroprotection of Creatine Supplementation in Neonateal Rats with Transient Cerebral Hypoxia-Ischemia.”

The loss of oxygen to brain regions leads to energy failure, cell death and possibly chronic neurological symptoms. Low oxygen levels (hypoxia) as a result of blood flow restriction (ischemia) are especially devastating to the nervous systems of newborn infants (neonates) and can result in life-long neurological disorders such as cerebral palsy. This study examined the ability of creatine supplementation to reduce the extent of brain damage in neonateal rats after exposure to ischemia-hypoxia.

Swiss Study Design: Six day old rat pups were injected with 3 grams of creatine per kilogram of body weight for three days. Injection was necessary to assure that all specimens received a standard dose of creatine monohydrate. On the fourth day the pups were exposed to hypoxia after blocking blood flow (via the carotid artery) to the brain (I’ll spare you the bloody details of how ischemia-hypoxia was created). However, via this technique one hemisphere of the brain (ipsilateral-opposite side) is preferentially subjected to reduced blood flow. The pups were then allowed to recover for an hour before being exposed to hypoxia for 100 minutes (approximately one and a half hour). On the fifth day the brains of these pups were examined using Magnetic Resonance Imaging (MRI) and the size of the edemic brain lesions noted.

Results and Conclusions: The brain lesions observed in rats that had been previously supplemented with creatine were 25% smaller than those present in non-supplemented rats. That is, creatine supplementation protected against the loss of brain cells in response to ischemia-hypoxia.

Quoting the authors of this study: “It is our belief that supplementation with exogenous creatine during and after HI (hypoxia-ischemia), by preserving brain energy levels, with its positive consequences on calcium homeostasis and mitochondrial function, could limit, if not prevent, damage caused by HI (hypoxia-ischemia) by ameliorating SEF (secondary energy failure).”

The authors of the study proposed that the combination of several effects contributed to the life sparring effect of creatine supplementation: 1) an increase in anaerobic energy stores (ATP and PCr); 2) the prevention of energy deficiency-induced calcium overloading; 3) the prevention of mitochondrial transition pore opening (mitochondrial death); 4) and the direct antioxidant properties of creatine. Therefore, creatine administration may prove to be a course of action in human neonates exposed to hypoxia.

Complete Scientific Reference: Adcock K. H. et al. (2002) Neuroprotection of creatine supplementation in neonateal rats with transient cerebral hypoxia-ischemia. Developmental Neuroscience, Volume 24, pages 382-388.

USA Study: “Prophylactic Creatine Administration Mediates Neuroprotection in Cerebral Ischemia in Mice.”

The previously discussed Swiss study showed that creatine supplementation protects brain cells from dying following oxygen deprivation (hypoxia). In this instance, hypoxia was produced by blocking blood flow to the brain, a physiological condition known as ischemia. This study also focussed on the neonateal brain and found that creatine supplementation reduced areas of brain damage following regional hypoxia. Stroke is an example of hypoxic brain damage that might occur in adults. The mechanism of neuronal death in these instances, however, is not specific for hypoxia, but rather, involves the induction of a general death program known as apoptosis (also known as programmed cell death). In essence, environmental insult provokes neurons to literally commit suicide. It is thus not surprising that creatine supplementation protects against several forms of brain insult including Amyotrophic Lateral Sclerosis (ALS), Huntington’s disease, Parkinson’s disease, and traumatic brain injury.

USA Study Design: Briefly, this study followed the expression of two biochemical markers for apoptosis, caspase-3 activation and cytochrome c release from the mitochondria, in response to restricted blood flow to the brain. One group of mice were fed a creatine supplemented diet (2%) for one month while another group was given a normal (control) diet. Blood flow to the brain was interrupted for two hours (again, I’ll spare you the gruesome details), following which they were allowed to recovery for 24 hours before histological examination and biochemical analysis.

Results and Conclusions: In contrast to the previous study where brain damage was reduced by 25% in rats administered creatine, this study demonstrated an astounding 56% (!) reduction in area of brain damage in response to creatine treatment. Caspase-3 activity and cytochrome c release were also attenuated in the creatine treated mice, indicating that the degree of apoptosis was similarly attenuated. Once again, this study unequivocally demonstrated that creatine supplementation enhances brain survival following ischemia.

Interestingly, one week of supplementation appeared to have no effect, indicating that this effect requires more than merely increasing neuronal creatine reserves. That is, longer-term biochemical changes in brain metabolism are likely to be necessary for this effect to be fully manifested. Creatine-induced enhancement in methylation capacity is a likely candidate for a biochemical pathway giving rise to this effect.


Two independent studies have given outstanding proof that creatine protects the brain from damage after ischemic insult. Although this data was generated from rats and mice, I am willing to venture a guess that the neuroprotective effects of creatine supplementation will extend to the human species as well.

Quoting the authors of this study: “Given that creatine is a relatively safe compound, people at high risk of cerebral ischemic injury might be good candidates to receive creatine supplementation.”

Complete Scientific Reference:
Zhu S. et al. (2004) Prophylactic creatine administration mediates neuroprotection in cerebral ischemia in mice. Journal of Neuroscience, Volume 24 (26), pages 5909-5912.


Read about the effects of creatine and essential B-vitamins on brain health.

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