In the face of oxygen deprivation in the brain …

Creatine Prevents Attention Decline
… Operating as a neuroprotective supplement

By Will Block

C

Figure 1. Structure and putative phospholipids interaction mechanism of creatine and phosphorylated creatine, as phosphocreatine (aka creatine phosphate), which helps to supply energy to all the cells of the body.
LEM1506CreatineFig1_274.jpg
(click on thumbnail for full sized image)

reatine is a nitrogen-containing compound found in every cell in the body. It is synthesized in the kidney, liver, and pancreas using the amino acids arginine, glycine and methionine before entering the bloodstream. From there it is transported into the cells via the creatine transporter protein. This transporter is critical for the distribution of creatine throughout the body’s cells as well as for traversing creatine across the blood brain barrier, giving it access to the central nervous system (see Fig. 1).

Creatine itself can be phosphorylated by creatine kinase to form phosphocreatine, which is used as an energy reserve in skeletal muscles and the brain. Without phosphocreatine, we would not be able to rapidly mobilize reserves of high-energy phosphates in skeletal muscle and the brain. Phosphocreatine can anaerobically (without air) donate a phosphate group to adenosine diphosphate (ADP) to form adenosine triphosphate (ATP) during the first 2 to 7 seconds following an intense muscular or neuronal effort. ATP is the major energy currency of the cell, providing the energy for most of the energy-consuming activities of the cell.

While additional amounts of this dietary supplement can be acquired from food sources such as meat and fish, food is an inefficient source. Heat destroys creatine, so the meat and fish should be undercooked to gain the benefits of creatine. Approximately 2 to 3 pounds of raw meat or fish contain the equivalent of 5 grams of pure creatine. If one wants the full benefits of creatine, it is necessary to supply it as a supplement.

Most of the body’s creatine is stored in skeletal muscle. Thus, until recently, creatine supplementation has been associated with athletes and bodybuilders whose goal is to increase the mass of the skeletal muscle, along with the power and strength that bigger muscle mass yields.


If one wants the full benefits of
creatine, it is necessary to
supply it as a supplement.


Creatine for Age-Related Neurodegenerative Diseases

However, new uses for creatine have emerged showing that it may be important in delaying or preventing the onset of neurodegenerative diseases associated with aging. Among these are congestive heart failure, gyrate atrophy (characterized by progressive vision loss), insulin insensitivity, cancer, and high cholesterol. Creatine is not just for athletes!

Creatine for Enhanced Memory Function

In a new study, conducted at the University of Auckland in New Zealand, creatine was shown to be a neuroprotective supplement when cellular energy provision was compromised.1 Impairment or interruption of oxygen supply disrupts brain function and plays a role in neurological and neurodegenerative conditions.


Without phosphocreatine, we would
not be able to rapidly mobilize
reserves of high-energy phosphates in
skeletal muscle and the brain.


In addition to creatine’s role in the buffering, transport, and regulation of cellular energy, it is also neuroprotective in vitro against anoxic/hypoxic damage. Anoxia means a total depletion in the level of oxygen. Hypoxia means the arterial content of oxygen is insufficient. Dietary creatine supplementation has been associated with improved symptoms in neurological disorders defined by impaired neural energy provision.

Speed of Processing for Working Memory and Intelligence Tasks and More

But this new research is not the beginning of research on creatine use for memory. In a 2000 study, researchers found that it protected against traumatic brain injuries in people who were already using it prior to being injured.2

A few years later, researchers reported that it might be valuable for Huntington’s disease (HD).3 Then, in a 2003 study, creatine supplementation in humans was shown to have a significant positive effect on tests for both working memory and intelligence, tasks that require speed of processing.4 Then there was a study showing its ability to reduce oxidative damage in HD.5


However, new uses for creatine have
emerged showing that it may be
important in delaying or preventing
the onset of neurodegenerative
diseases associated with aging.


In another report, concerning sleep, creatine demonstrated a significant linear improvement in performance of the central executive task throughout the experiment, whereas the placebo group showed no significant effects.6

Creatine Aids Cognition in the Elderly

In another study, scientists showed a significant effect of creatine supplementation on many memory tasks.7 It was concluded that creatine supplementation aids cognition in the elderly.

A more recent study, using a double-blind, placebo-controlled protocol, found that creatine improved performance in five cognitive tasks.8 The researchers concluded that creatine influences brain energy capacity on cognitive performance.


Creatine is not just for athletes!


Then in another study, in vegetarians rather than in those who consume meat, creatine supplementation resulted in better memory.9 Also, in a larger study just last year, scientists demonstrated the feasibility of prevention trials for HD with high-dose creatine, to provide possible evidence of disease modification.10

Muscle Mass Loss Effects Elderly

By-the-way, a recent review points out that about 30% of muscle mass is lost by age 80, which is bad because muscular weakness remains a vital cause for loss of independence in the elderly population.11 Loss of independence is a typical consequence of neurodegeneration.

In relation to the brain, creatine has been shown to proffer antioxidant properties, reduce mental fatigue, protect the brain from neurotoxicity, and improve facets/components of neurological disorders like depression and bipolar disorder.

The combination of these benefits has made creatine a leading candidate in the fight against age-related neurodegenerative diseases, such as Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, long-term memory impairments associated with the progression of Alzheimer’s disease, and stroke. In the review,11 the researchers explored the normal mechanisms by which creatine is produced and its necessary physiology, while paying special attention to the importance of creatine supplementation in improving diseases and disorders associated with brain aging and outlining the clinical trials involving creatine to treat these diseases.


Creatine increases brain energy
capacity for better cognitive
performance.


Returning to the Creatine/Attention Study

In the New Zealand study, the neuroscientists investigated—for the first time in humans—the utility of creatine as a dietary supplement to protect against energetic insult of acute oxygen deprivation. Fifteen healthy adults [(10 males, 5 females) with a mean age of 31 years (21–55 years)] were supplemented with creatine and placebo treatments for 7 days, which increased brain creatine on average by 9.2%. A hypoxic gas mixture (10% oxygen) was administered for 90 minutes, causing global oxygen deficit and impairing a range of neuropsychological processes.

Creatine for Maintaining Better Health and Longevity

According to Durk Pearson & Sandy Shaw, “A variety of age-related diseases, such as neurodegenerative conditions (including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, [Progressive Supranuclear Palsy], and amyotrophic lateral sclerosis), are associated with aggregation of proteins due to improper folding. Other conditions (known as “conformational diseases”) associated with improperly folded proteins include cancer, cystic fibrosis, emphysema, liver disease, prion disease (such as mad cow) and even chronic pain (opioid receptors misfolded in the endoplasmic reticulum).” (See “The Origami of Aging: How Small Molecules Help Maintain Proper Protein Folding for Better Health and Longevity” in the September 2008 issue.)


Using osmolytes such as
creatine and others may help you
postpone or even avoid many of
the diseases of aging.


From the above subtitle, the small molecules to which they refer that can help maintain proper protein folding for better health and longevity are osmolytes, an important class of natural chemical chaperones that helps stabilize the proper folding conformation of proteins. Osmolytes include betaine, inositol, taurine, glycerophosphocholine, choline, and creatine. In fact, the principal organic osmolytes in the mammalian brain include amino acids (such as proline, alanine, and glycine), choline, creatine, inositol, and taurine.1 Proteins have complex three-dimensional structures that determine their functions and stability. Thus, the quality control of protein folding is very important to health and longevity. Using osmolytes such as creatine and others may help you postpone or even avoid many of the diseases of aging.

Reference

  1. Burg MB, Ferraris JD. Intracellular organic osmolytes: function and regulation. J Biol Chem. 2008 Mar 21;283(12):7309–13.

Hypoxia-induced decrements in cognitive performance, specifically attentional capacity, were restored when participants were given creatine. Corticomotor excitability also increased. Corticomotor excitability involves cerebral cortex control, which helps improve motor performance. A neuromodulatory effect of creatine via increased energy availability is presumed to be a contributing factor of the restoration, perhaps by supporting the maintenance of appropriate neuronal membrane potentials.

The Brain Relies on Uninterrupted Energy

Our brains are dependent on an uninterrupted supply of energy to maintain electrical membrane potentials, action potential propagation, and signaling activities. Impairment or interruption of neural energy supply compromises brain function and plays a role in the pathogenesis and progression of neurological and neurodegenerative conditions.

Acute disruption of the energy supply—similar to ischemic brain injury—can be induced experimentally. When this disruption is chronic cellular structure degrades, which significantly impairs energy provision processes, including disruption of mitochondrial structure. This occurs in Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, and amyotrophic lateral sclerosis.


Creatine has been proposed as a
potential therapeutic agent because it
can replenish cellular ATP
without a reliance on oxygen.


Creatine Can Replenish Energy Stores

Figure 2. The CK/PCr system within a cell. Creatine (Cr) uptake occurs via the membrane-bound Cr transporter (CRT). Within the cell differing isotopes of creatine kinase (CK) utilize the Cr pool to shuttle energy between high-energy phosphate compounds. Examples of reversible phosphocreatine phosphorylation are shown for oxidative adenosine triphosphate (ATP) production in mitochondria and energy liberation (via ATPase) in cytosolic ATP consumption. ADP is adenosine diphosphate.
LEM1506_Fig2_274.gif
(click on thumbnail for full sized image)

Creatine has been proposed as a potential therapeutic agent because it can replenish cellular ATP without a reliance on oxygen. It is a critical component of the Creatine Kinase/Phosphocreatine (CK/PCr) system, which shapes a large metabolic network in the CNS that is highly versatile and involved in many physiological functions (see Fig. 2). The CK/PCr system is of great potential usefulness in diseases where there is a disturbance to cellular energy metabolism and diminished capacity to meet neuronal energy needs.

In the New Zealand study, creatine pretreatment offered a neuroprotective effect against anoxic and ischemic cell damage in vitro, providing enhanced intracellular phosphocreatine concentrations, protection against ATP depletion, delayed membrane depolarization, and reduced structural damage.

The aim of the study was to confirm that creatine supplementation would augment neural creatine stores, and to assess the influence of increased neural creatine availability on neuropsychological and neurophysiological measures.

Figure 3. Equipment used in the study: Transcranial magnetic stimulation (TMS); heart rate (HR); blood pressure (BP), peripheral nerve stimulation (PNS), electromyography (EMG), and arterial oxygen saturation (SpO2).
LEM1506_Fig3_274.gif
(click on thumbnail for full sized image)

When experimental hypoxia was induced, acute energy disruption occurred. The measurement of neural creatine availability—along with computer assessments of primary motor cortex—was used to derive measures of cognitive function and corticomotor excitability, respectively. See Fig. 3. Creatine increased corticomotor excitability, and prevented the decline in cognition, and particularly attentional capacity, that accompanies severe oxygen deficit. These results support the idea that creatine may be neuroprotective, a finding that has only been reported previously in vitro.

Creatine supplements may have influenced similar cellular processes to those reported in vitro: delaying hypoxia-induced membrane depolarization, effectively maintaining neuronal integrity, and better sustaining basic neuronal function.

When creatine is administered before oxidative stress, impaired protein synthesis and axonal damage are prevented, promoting greater amplitude and duration of neural activity. This is, in turn, protective against synaptic transmission failure. It also delays the onset of anoxic depolarization that ultimately reduces neuronal death.

Creatine Storage and Energy

In the present study, the creatine could have provided a more direct and abundant pool of energy as phosphocreatine, and more efficient coupling between ATP-generating and ATP-consuming sites within the cell.

Creatine stores may have enhanced anaerobic energy by prolonging the transfer of high-energy phosphates to areas of the neuron that require additional energy when oxidative glycolysis is compromised by hypoxia. These storage and energy transfer processes can slow the rate of fall in ATP levels that is typically experienced during oxygen deprivation.

Unexpectedly, the magnitude of creatine stored in the brain by supplementation did not predict the extent to which neurocognitive deficits were corrected during hypoxia. This suggests possible nonenergetic, neuromodulatory roles for creatine.


Hypoxia intervention had a profound
negative effect on a range of cognitive
functions, consistent with previous
work that has examined cognitive
performance at high altitudes.


Creatine restored the cognitive decline associated with hypoxia-induced oxygen deprivation. The hypoxia intervention had a profound negative effect on a range of cognitive functions, consistent with previous work that has examined cognitive performance at high altitudes.

Highlighting the Importance of Uninterrupted Energy

The neurocognitive index score that represents overall cognitive function was reduced by 12% with hypoxia. This reflects a drop in performance from the 60th percentile to the 45th percentile when compared to an age-matched normative data set. These are large decrements that highlight the importance of an uninterrupted energy supply for maintaining basic neuronal function to sustain complex cognitive processes.

Creatine Restores/Corrects Cognitive Deficiencies

Enhanced creatine availability was able to restore or partially correct several cognitive deficiencies, with complex attentional processes most improved by creatine (21% difference compared to placebo), perhaps via more efficient anaerobic energy delivery during the most aerobically stressful mental tasks.

These new findings also demonstrate that increased brain creatine availability has a neuromodulatory influence upon cortical excitability during acute hypoxia. Hypoxia-induced changes in excitability were associated with widespread decrements in cognition in the placebo condition, but not with creatine supplementation.

The enhanced energy-buffering capacity given by increased creatine stores may have prevented hypoxia-induced disruptions to the maintenance of cellular membrane potential. These disruptions are evident during complete oxygen deprivation, when maintenance of proper neuronal functioning is not possible.


The large decrements highlight
the importance of an uninterrupted
energy supply for maintaining basic
neuronal function to sustain complex
cognitive processes.


Corticomotor Excitability Associated with Improved Cognition

When oxygen delivery was disrupted in the presence of enhanced neural creatine levels, corticomotor excitability increased by 70% and was associated with improved cognition. This neuromodulatory response may overcome neuronal deficiencies caused by hypoxia, but might only be possible when cells are in a high-energy state.

What the Study Shows

In summary, oral creatine increases the storage of creatine in the brain and enhances availability of neural creatine. Thus it was shown to prevent deterioration to cognitive functions associated with attention and increases corticomotor excitability during oxygen deprivation. Enhanced creatine availability was able to restore or partially correct several cognitive deficiencies, with complex attentional processes most improved.

These findings provide insight into the importance of the CK/PCr energy system in the human brain, and demonstrate that 7 days of creatine supplementation has potential utility as a physical performance enhancer and neuroprotective supplement when cellular energy provision is compromised.

Because impaired energy metabolism and failure to maintain adequate membrane potential play a critical role in the pathogenesis and progression of a range of neurological and neurodegenerative conditions, creatine may be thought of as a therapeutic supplement.

References

  1. Turner CE, Byblow WD, Gant N. Creatine supplementation enhances corticomotor excitability and cognitive performance during oxygen deprivation. J Neurosci. 2015 Jan 28;35(4):1773–80.
  2. Sullivan PG, Geiger JD, Mattson MP, Scheff SW. Dietary supplement creatine protects against traumatic brain injury. Ann Neurol. 2000 Nov;48(5):723–9.
  3. Tabrizi SJ, Blamire AM, Manners DN, Rajagopalan B, Styles P, Schapira AH, Warner TT. Creatine therapy for Huntington’s disease: clinical and MRS findings in a 1-year pilot study. Neurology. 2003 Jul 8;61(1):141–2.
  4. Rae C, Digney AL, McEwan SR, Bates TC. Oral creatine monohydrate supplementation improves brain performance: a double-blind, placebo-controlled, cross-over trial. Proc Biol Sci. 2003 Oct 22;270(1529):2147–50.
  5. Hersch SM, Gevorkian S, Marder K, et al. Creatine in Huntington disease is safe, tolerable, bioavailable in brain and reduces serum 8OH2'dG. Neurology. 2006 Jan 24;66(2):250–2.
  6. McMorris T, Harris RC, Howard AN, Langridge G, Hall B, Corbett J, Dicks M, Hodgson C. Creatine supplementation, sleep deprivation, cortisol, melatonin and behavior. Physiol Behav. 2007 Jan 30;90(1):21–8.
  7. McMorris T, Mielcarz G, Harris RC, Swain JP, Howard A. Creatine supplementation and cognitive performance in elderly individuals. Neuropsychol Dev Cogn B Aging Neuropsychol Cogn. 2007 Sep;14(5):517–28.
  8. Ling J1, Kritikos M, Tiplady B.Cognitive effects of creatine ethyl ester supplementation. Behav Pharmacol. 2009 Dec;20(8):673–9.
  9. Benton D1, Donohoe R.The influence of creatine supplementation on the cognitive functioning of vegetarians and omnivores. Br J Nutr. 2011 Apr;105(7):1100–5.
  10. Rosas HD1, Doros G, Gevorkian S, et al.PRECREST: a phase II prevention and biomarker trial of creatine in at-risk Huntington disease. Neurology. 2014 Mar 11;82(10):850–7. doi: 10.1212/WNL.0000000000000187. Epub 2014 Feb 7.
  11. Smith RN, Agharkar AS, Gonzales EB. A review of creatine supplementation in age-related diseases: more than a supplement for athletes. F1000Res. 2014 Sep 15;3:222. doi: 10.12688/f1000research.5218.1. eCollection 2014. Review. PubMed PMID: 25664170


Will Block is the publisher and editorial director of Life Enhancement magazine.

Ingredients in this Article

FREE Subscription

  • You're just getting started! We have published thousands of scientific health articles. Stay updated and maintain your health.

    It's free to your e-mail inbox and you can unsubscribe at any time.
    Loading Indicator