phosphocreatine and Stroke

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.

Topics: Animals; Dietary Supplements; Humans; Hypoxia, Brain; Myocardial Ischemia; Phosphocreatine; Stroke

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.

Topics: Blood-Brain Barrier; Brain Ischemia; Cardiotonic Agents; Creatine; Female; Forecasting; Humans; In Vitro Techniques; Male; Myocardial Infarction; Myocardial Ischemia; Neuroprotective Agents; Phosphocreatine; Stroke; Treatment Outcome

Previous (31)P-magnetic resonance spectroscopy ((31)P-MRS) studies have shown that cerebral cortical energy metabolism is abnormal in migraine and that cortical energy reserves decrease with increasing severity and duration of aura. Migrainous infarction is a rare complication of migraine with aura, and its pathophysiology is poorly understood. We used (31)P-MRS to determine whether migrainous stroke shows similar interictal abnormalities in cortical energy metabolism as severe, prolonged aura.. We used (31)P-MRS to study patients with a diagnosis of either migrainous infarction or migraine with persistent aura without infarction (aura duration >7 days) according to International Headache Society criteria. We compared clinical presentation and metabolite ratios between patient groups. We also studied healthy controls with no history of migraine.. Patients with persistent aura without infarction had lower phosphocreatine-phosphate (PCr/Pi) ratios (mean+/-SD, 1.61+/-0.10) compared with controls (1.94+/-0.35, P=0.011) and with patients with migrainous stroke (1.96+/-0.16, P<0.0001). These differences were present in cortical tissue only. In migrainous stroke patients, the metabolite ratios did not differ significantly from those of controls without migraine.. The differences in cortical energy reserves between patients with migrainous stroke and in those with migraine with persistent aura suggest that the pathomechanisms of these conditions differ and that migrainous infarction does not simply represent a particularly severe form of migrainous aura. This finding supports the revised International Headache Society criteria, which now distinguish between migrainous infarction and migraine with persistent aura without infarction.

Topics: Biomarkers; Cerebral Cortex; Diagnosis, Differential; Energy Metabolism; Magnetic Resonance Spectroscopy; Migraine Disorders; Migraine with Aura; Phosphates; Phosphocreatine; Phosphorus Radioisotopes; Predictive Value of Tests; Stroke

Localized magnetic resonance spectroscopy (MRS) yields sensitive metabolic markers to provide insight into the pathophysiology of mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) in vivo. Findings in full MELAS syndrome at 1H MRS of the brain typically include severely elevated lactate and reduced N-acetylaspartate, glutamate, myo-inositol, and total creatine concentrations in stroke-like lesions. Similar but less extreme alterations are also common in gray matter (GM) regions that appear normal at magnetic resonance imaging. Phosphorus spectroscopy of peripheral muscle permits investigation of the bioenergetic status. A decline of the phosphorylation potential indicates a low energy reserve at rest. Phosphocreatine resynthesis during post-exercise recovery is delayed pointing to reduced mitochondrial capacity. As MRS is inherently non-invasive, follow-up studies can be performed to assess treatment response quantitatively.

Topics: Adenosine Triphosphate; Adolescent; Adult; Brain; Brain Chemistry; Child; Exercise; Female; Humans; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Male; MELAS Syndrome; Muscle, Skeletal; Phosphocreatine; Retrospective Studies; Stroke

Cerebral hypoxia-ischemia (HI) is an important cause of perinatal brain damage in the term newborn. The areas most affected are the parasagittal regions of the cerebral cortex and, in severe situations, the basal ganglia. The aim of this study was to show that the newborn piglet model can be used to produce neuropathology resulting from moderate HI insult and to monitor damage for 7 days. Two acute cerebral HI were induced in newborn Large White piglets by reducing the inspired oxygen fraction to 4% and occluding the carotid arteries. Newborn piglets were resuscitated, extubated and monitored for 7 days. (31)P magnetic resonance spectroscopy (MRS) offers the ability to monitor the severity of the HI insults. Lactate (Lac) was detected in the HI group at 2 h, 3 days and 5 days after insult by (1)H MRS. Lac/n-acetylaspartate and Lac/choline and Lac/creatine ratios increased significantly (p < 0.01) in the HI group 2 h after HI insults and remained high over 7 days. For the HI group, mean T(2) values increased significantly in the parietal white matter (subcortical) for 5 days after HI insult [117.5 (+/-7.4) to 158.5 (+/-19.2) at T+3 days, 167.7 (+/-15.4) at T+5 days and 160.9 (+/-10.1) at T+7 days (p < 0.01)]. This newborn piglet model of moderate HI brain injury with reproducible cerebral damage could be use as reference for the study of neuroprotective strategy for a period of 7 days.

Topics: Animals; Animals, Newborn; Aspartic Acid; Basal Ganglia; Cerebral Cortex; Cerebrovascular Circulation; Disease Models, Animal; Energy Metabolism; Hydrogen; Hydrogen-Ion Concentration; Hypoxia-Ischemia, Brain; Ischemic Attack, Transient; Lactic Acid; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Phosphocreatine; Phosphorus Isotopes; Radiopharmaceuticals; Severity of Illness Index; Stroke; Swine

We previously reported that 20% of women with chest pain but without obstructive coronary artery disease (CAD) had stress-induced reduction in myocardial phosphocreatine-adenosine triphosphate ratio by phosphorus-31 nuclear magnetic resonance spectroscopy (abnormal MRS), consistent with myocardial ischemia. The prognostic implications of these findings are unknown.. Women referred for coronary angiography for suspected myocardial ischemia underwent MRS handgrip stress testing and follow-up evaluation. These included (1) n=60 with no CAD/normal MRS, (2) n=14 with no CAD/abnormal MRS, and (3) n=352 a reference group with CAD. Cardiovascular events were death, myocardial infarction, heart failure, stroke, other vascular events, and hospitalization for unstable angina. Cumulative freedom from events at 3 years was 87%, 57%, and 52% for women with no CAD/normal MRS, no CAD/abnormal MRS, and CAD, respectively (P<0.01). After adjusting for CAD and cardiac risk factors, a phosphocreatine-adenosine triphosphate ratio decrease of 1% increased the risk of a cardiovascular event by 4% (P=0.02). The higher event rate in women with no CAD/abnormal MRS was primarily due to hospitalization for unstable angina, which is associated with repeat catheterization and higher healthcare costs.. Among women without CAD, abnormal MRS consistent with myocardial ischemia predicted cardiovascular outcome, notably higher rates of anginal hospitalization, repeat catheterization, and greater treatment costs. Further evaluation into the underlying pathophysiology and possible treatment options for women with evidence of myocardial ischemia but without CAD is indicated.

Topics: Adenosine Triphosphate; Aged; Angina, Unstable; Cardiac Catheterization; Cohort Studies; Coronary Angiography; Coronary Stenosis; Cost-Benefit Analysis; Disease-Free Survival; Female; Follow-Up Studies; Hand Strength; Health Care Costs; Heart Failure; Hospitalization; Humans; Life Tables; Magnetic Resonance Spectroscopy; Middle Aged; Myocardial Infarction; Myocardial Ischemia; Myocardium; Outcome Assessment, Health Care; Phosphocreatine; Prognosis; Risk Factors; Stroke; United States