Energy metabolism and BCL-2 function in models of cerebral ischemia/reperfusion.

摘要

Morbidity and mortality resulting from cardiac arrest and resuscitation is a major health problem; most of those who survive exhibit some degree of neurological impairment due to irreversible injury caused by cerebral ischemia and reperfusion. The objectives of this study were to characterize the metabolic perturbation accompanying these events and examine the compounds that could potentially ameliorate damage and normalize metabolism during recovery.; The study employed a canine system of cardiac arrest and resuscitation in which postischemic administration of acetyl-L-carnitine (ALCAR) has been demonstrated to provide neuroprotection (Rosenthal et al., 1992). Up to five-fold increases in the level of carnitine and its short acyl esters of cerebrospinal fluid and cortical tissue indicated that ALCAR could traverse the blood-brain barrier. immediate, postischemic administration of ALCAR was found to decrease the rate of glucose utilization by canine cortical brain slices incubated in vitro. Likewise, the presence of ALCAR during these incubations reduced indicators of anaerobic metabolism. In competition experiments, the presence of ALCAR inhibited the amount of {dollar}sp{lcub}14{rcub}{dollar}CO{dollar}sb2{dollar} produced by the slices from U-{dollar}sp{lcub}14{rcub}{dollar}C-glucose and l-{dollar}sp{lcub}14{rcub}{dollar}C-acetate. These results suggest that ALCAR could, through donating acetyl units, potentiate aerobic energy metabolism to inhibit the deleterious lactic acidosis associated with anaerobic metabolism.; This study was also concerned with developing a cellular model that would mimic the subcellular metabolic changes that occur following cerebral ischemia and reperfusion in vivo. This included the lack of immediate loss of viability following treatment, but an initiation of the process of delayed neuronal death in the ensuing hours and days. Thirty minutes of exposure of GTI-7 murine hypothalamic tumor cells to chemical hypoxia/aglycemia caused little immediate loss in cell number. Cell death was apparent within 16 hours of reenergization, and increased to 64% by 72 hours. The expression of human Bcl-2, a protein noted for its anti-death activity, inhibited the loss in viability by 35%. Bcl-2 expression was associated with lower levels of oxidized lipid and a normalization of compromised mitochondrial respiratory functions. Together, these observations demonstrate that Bcl-2 can protect neural cells in vitro from injury that parallels damage that accompanies ischemia and reperfusion; and, this protection may be accomplished through an antioxidative mechanism.