Potential of creatine or phosphocreatine supplementation in cerebrovascular disease and in ischemic heart disease

Abstract

Creatine is of paramount importance for maintaining and managing cellular ATP stores in both physiological and pathological states. Besides these "ergogenic" actions, it has a number of additional "pleiotropic" effects, e.g., antioxidant activity, neurotransmitter-like behavior, prevention of opening of mitochondrial permeability pore and others. Creatine supplementation has been proposed for a number of conditions, including neurodegenerative diseases. However, it is likely that creatine's largest therapeutic potential is in those diseases caused by energy shortage or by increased energy demand; for example, ischemic stroke and other cerebrovascular diseases. Surprisingly, despite a large preclinical body of evidence, little or no clinical research has been carried out in these fields. However, recent work showed that high-dose creatine supplementation causes an 8-9 % increase in cerebral creatine content, and that this is capable of improving, in humans, neuropsychological performances that are hampered by hypoxia. In addition, animal work suggests that creatine supplementation may be protective in stroke by increasing not only the neuronal but also the endothelial creatine content. Creatine should be administered before brain ischemia occurs, and thus should be given for prevention purposes to patients at high risk of stroke. In myocardial ischemia, phosphocreatine has been used clinically with positive results, e.g., showing prevention of arrhythmia and improvement in cardiac parameters. Nevertheless, large clinical trials are needed to confirm these results in the context of modern reperfusion interventions. So far, the most compelling evidence for creatine and/or phosphocreatine use in cardiology is as an addition to cardioplegic solutions, where positive effects have been repeatedly reported.

The Purine Salvage Pathway and the Restoration of Cerebral ATP: Implications for Brain Slice Physiology and Brain Injury

“…These predictions were borne out [98] (Fig. 6) and furthermore demonstrated that previous observations [102] concerning the sparing of synaptic transmission and neuronal excitability by creatine were not entirely due to better ATP-dependent support for neurotransmitter release per se, but by reduced extracellular adenosine release. Similar observations of RibAde and creatine facilitating and reducing adenosine release during seizure activity, with inhibitory and excitatory actions on neuronal activity, respectively, have been made in an in vitro model of epileptiform activity [103].…”

International Society of Sports Nutrition position stand: safety and efficacy of creatine supplementation in exercise, sport, and medicine

“…The CK/PCr energy shuttle thereby connects sites of ATP production (glycolysis and mitochondrial oxidative phosphorylation) with subcellular sites of ATP utilization (ATPases) in order to fuel energy metabolism [24, 25, 27]. In this way, the CK/PCr system thereby serves as an important regulator of metabolism which may help explain the ergogenic and potential therapeutic health benefits of creatine supplementation [4, 27, 33, 36–45].

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Creatine: a miserable life without it

“…Unfortunately, in clinical studies, creatine supplementation has shown no significant positive effects in chronic neurodegenerative diseases (see above). Balestrino et al (2016) surmise that creatine may be better suited for clinical interventions in more acute situations, where tissues undergo an energy deficit crisis, e.g. during ischemic stroke in the brain or myocardial ischemic attack leading to heart infarction.…”

“…However, since creatine would have to be energetically charged to PCr before it could develop its potential, and because the tissue in question is itself energy-depleted and thus cannot use its ATP to charge PCr, creatine should then be administered preventively to patients at high risk of stroke, even before the event takes place. An alternative approach, proposed and researched successfully by the group around Valdur Saks already in the 1980s (Ruda et al 1988) and followed up by Balestrino et al (2016), is that PCr is directly administered to patients by intravenous infusion as early as possible after an ischemic heart attack and during cardiac surgery. This strategy resulted in a significant improvement in cardiac parameters and subsequent prevention of cardiac arrhythmia, which is often also a problem after cardiac surgery.…”

“…However, despite a convincing rationale with experimental clinical evidence for the addition of PCr to cardioplegic solutions, this promising intervention has not yet been widely adopted by cardiac intervention and surgery clinics. It seems that larger multi-center studies are needed so that PCr-which, due to its inherent chemical instability in aqueous solution, would have to be dissolved as freeze-dried powder directly into the cardioplegic solution just before use-can be brought to fruition for the benefit of patients with cerebral and cardiac ischemic attacks (Balestrino et al 2016).…”