Therapeutic use of creatine in brain or heart ischemia: available data and future perspectives

Creatine (Cr) is essential in safeguarding ATP levels and in moving ATP from its production site (mitochondria) to the cytoplasmic regions where it is used. Moreover, it has effects unrelated to energy metabolism, such as free radical scavenging, antiapoptotic action, and protection against excitotoxicity. Recent research has studied Cr-derived compounds (Cr benzyl ester and phos-pho-Cr-magnesium complex) that reproduce the neuroprotective effects of Cr while better crossing the neuronal plasma membrane and, hopefully, the blood-brain barrier (BBB). Intracellular levels of Cr can be increased by incubation with Cr or some of its derivatives, and this increase is protective against anoxic or ischemic damage. A large amount of experimental evidence shows that pretreatment with Cr is capable of reducing the damage induced by ischemia or anoxia in both heart and brain, and that such treatment may also be useful even after stroke or myocardial infarction (MI) has already occurred. Cr has been safely administered to patients affected by several neurological diseases, yet it has never been tested in human brain ischemia, the condition where its rationale is strongest. Phosphocreatine (PCr) has been administered after human MI, where it proved to be safe and probably helpful. Cr should be tested in the prophylactic protection against human brain ischemia and either Cr or PCr should be further tested in MI. Moreover, Cr- or PCr-derived drugs should be developed in order to overcome these molecules' limitations in crossing the BBB and the cell plasma membrane.