Utilization of Cyclocreatine Phosphate, an Analogue of Creatine Phosphate, by Mouse Brain During Ischemia and Its Sparing Action on Brain Energy Reserves

Brains of mice fed the creatine analogue cyclocreatine accumulated 10 γmol/g fresh wt. of cyclocreatine, of which 93% occurred as the synthetic phosphagen, cyclocreatine‐P (l‐carboxymethyl‐2‐imino‐3‐phosphonoimidazolidine). In brains containing cyclocreatine‐P 2‐ , creatine‐P (phosphocreatine) levels were lowered 40%; levels of ATP, P 1 , and glucose were not altered: glutamate levels were lowered 17%: and aspartate levels were lowered 56%, relative to controls. When cyclocreatine was removed from the diet, brain cyclocreatine levels decreased with a half‐life of 17 to 28 days. Ischemia was initiated in brains by decapitation of mice previously injected with the centrally acting muscle relaxant mephenesin. The initial creatine‐P pool of 2‐3 γmol/g was completely depleted within 1 min in ischemic brains of both control and cyclocreatine‐fed mice. In brains of cyclocreatine‐fed mice, the much larger cyclocreatine‐P pool of 9.3 γmol/g decreased to 6 γmol/g after 2 min and to 2.2 γrnol/g after 4 min of ischemia, with a correspondingly increased accumulation of P 1 . Levels of total cellular ATP were sustained slightly longer during ischemia in brains containing cyclocreatine‐P. Available energy reserves of control brains were almost completely depleted after 2 min of ischemia, whereas generation and utilization of high‐energy phosphate continued for more than 3 min after initiation of ischemia in brains of cyclocreatine‐fed mice. These data suggest that during ischemic episodes cyclocreatine‐P can function as a supplemental reservoir of high‐energy phosphate and prolong the time required to exhaust the available energy stores of ischemic brain.