Churn S B, Taft W C, DeLorenzo R J
Department of Neurology, Medical College of Virginia, Virginia Commonwealth University, Richmond 23298.
Stroke. 1990 Nov;21(11 Suppl):III112-6.
Cerebral ischemia produces a disruption of calcium homeostasis in neurons. This may explain the extreme sensitivity of these cells to ischemic insult. Prolonged increases in calcium levels may produce irreversible damage to the cell by altering important calcium-dependent enzyme systems such as calcium/calmodulin-dependent protein kinase II. Five minutes of acute forebrain ischemia in the gerbil produced a significant decrease in calcium/calmodulin-dependent protein kinase II activity as early as 10 seconds postischemia and persisting up to 7 days after insult. Because hypothermia protects against ischemia-induced cell death in the gerbil, we examined the effect of ischemia on cell death and calcium/calmodulin-dependent protein kinase II at different intracerebral temperatures: hyperthermia (39 degrees C), normothermia (36 degrees C), and hypothermia (32 degrees C). In ischemic animals, hyperthermia produced severe loss of neurons in CA1 and moderate loss in CA3-CA4 subregions. Normothermia in ischemic animals produced severe loss of neurons in the CA1 subregion. Hypothermic ischemic animals showed no significant loss of neurons in any hippocampal region. Ischemia produced a severe decrease (17 +/- 6% of control) in calcium/calmodulin-dependent kinase II activity in hyperthermic animals, a moderate decrease (55 +/- 15% of control) in normothermic animals, and no decrease of enzyme activity in hypothermic animals. Thus, lowering and raising intracerebral temperature decreased and increased, respectively, the extent of ischemia-induced damage in the gerbil. Because ischemia-induced effects on calcium/calmodulin-dependent protein kinase II activity are rapid and long-lasting, hypothermia may protect through preservation of calcium/calmodulin-dependent protein kinase II activity.
脑缺血会导致神经元内钙稳态的破坏。这可能解释了这些细胞对缺血性损伤的极端敏感性。钙水平的持续升高可能会通过改变重要的钙依赖性酶系统，如钙/钙调蛋白依赖性蛋白激酶II，对细胞产生不可逆的损害。沙鼠急性前脑缺血5分钟后，早在缺血后10秒钙/钙调蛋白依赖性蛋白激酶II活性就显著降低，并持续到损伤后7天。由于低温可保护沙鼠免受缺血诱导的细胞死亡，我们研究了在不同脑内温度下（高热（39℃）、正常体温（36℃）和低温（32℃））缺血对细胞死亡和钙/钙调蛋白依赖性蛋白激酶II的影响。在缺血动物中，高热导致CA1区神经元严重丢失，CA3-CA4亚区中度丢失。缺血动物的正常体温导致CA1亚区神经元严重丢失。低温缺血动物在任何海马区均未显示出明显的神经元丢失。缺血导致高热动物的钙/钙调蛋白依赖性激酶II活性严重降低（为对照的17±6%），正常体温动物中度降低（为对照的55±15%），而低温动物的酶活性没有降低。因此，降低和升高脑内温度分别降低和增加了沙鼠缺血诱导损伤的程度。由于缺血对钙/钙调蛋白依赖性蛋白激酶II活性的影响迅速且持久，低温可能通过保留钙/钙调蛋白依赖性蛋白激酶II活性起到保护作用。
