Kondoh T, Lee S H, Low W C
Department of Neurosurgery, University of Minnesota Medical School, Minneapolis, USA.
Neurosurgery. 1995 Nov;37(5):948-54. doi: 10.1227/00006123-199511000-00014.
Cerebral ischemia can result in varying degrees of tissue damage. Conditions of severe ischemia can produce extensive areas of irreversible injury, whereas in conditions of moderate ischemia, tissue damage may be reversible, as in the region of the ischemic penumbra. The reversibility of tissue damage in the penumbral region is of clinical interest, because the characterization of conditions underlying this reversible state may provide information needed for the development of new therapeutic approaches for treatment. Our previous studies demonstrated neurochemical alterations in the levels of dopamine (DA) within the striatum after cerebral ischemia. In the present study, we postulate that these changes may be caused, in part, by alterations in transmitter release and reuptake. To test this hypothesis, forebrain ischemia was induced in Sprague-Dawley rats (Harlan, Indianapolis, IN) by means of bilateral common carotid artery occlusion and hemorrhagic hypotension. Cerebral blood flow (CBF) in the striatum was measured by the method of hydrogen clearance, and the extracellular DA ([DA]e) levels were measured by in vivo microdialysis. Varied reductions of CBF were induced and maintained for 5 hours. Three subgroups were established retrospectively according to the degree of CBF reduction: 67.7, 35.6, and 13.2% of normal CBF in the mild, moderate, and severe ischemic groups, respectively. The induction of ischemia resulted in 1.9-, 9.3-, and 122.3-fold increases in [DA]e above baseline in the mild, moderate, and severe ischemia groups, respectively. At 3 hours after the induction of ischemia, high potassium (100 mmol/L) or Nomifensin (Sigma, St. Louis, MO) (10 mmol/L), a DA uptake blocker, was administrated via a microdialysis probe to stimulate DA release while reductions in CBF were maintained continuously. Thirteen rats were used in the study of the release of DA by potassium or Nomifensin in nonischemic conditions. The administration of high potassium or Nomifensin stimulated DA release in conditions of mild and moderate ischemia. The increase in DA release by potassium stimulation was higher in rats with mild ischemia (106.6-fold) than that in normal rats (22.3-fold). This suggests a hyperexcitability of DA terminals under mild ischemia, as compared with nonischemic conditions. On the other hand, Nomifensin increased [DA]e levels more in moderately ischemic brains than in control brains, suggesting that DA uptake is up-regulated in the former case. The increased release of DA by potassium and Nomifensin was sustained after stimulation in conditions of mild and moderate ischemia. The high level of [DA]e with severe ischemia after ischemic induction was sustained throughout the period of study and was not stimulated by potassium or Nomifensin. We conclude that under conditions of mild and moderate ischemia, DA terminals become highly excitable and reuptake mechanisms are compromised. These changes of DA metabolism during mild and moderate ischemia may explain the sustainability of neurons in the "penumbra" condition of cerebral ischemia and the transformation of the ischemic penumbra to a necrotic core.
脑缺血可导致不同程度的组织损伤。严重缺血情况可产生大面积不可逆损伤，而在中度缺血情况下，如缺血半暗带区域，组织损伤可能是可逆的。半暗带区域组织损伤的可逆性具有临床意义，因为对这种可逆状态潜在条件的表征可为开发新的治疗方法提供所需信息。我们之前的研究表明，脑缺血后纹状体内多巴胺（DA）水平发生神经化学改变。在本研究中，我们推测这些变化可能部分是由递质释放和再摄取的改变引起的。为验证这一假设，通过双侧颈总动脉闭塞和出血性低血压的方法，在斯普拉格 - 道利大鼠（Harlan，印第安纳波利斯，印第安纳州）中诱导前脑缺血。采用氢清除法测量纹状体中的脑血流量（CBF），并通过体内微透析测量细胞外DA（[DA]e）水平。诱导并维持不同程度的CBF降低5小时。根据CBF降低程度回顾性地建立三个亚组：轻度、中度和重度缺血组分别为正常CBF的67.7%、35.6%和13.2%。缺血诱导导致轻度、中度和重度缺血组的[DA]e分别比基线水平升高1.9倍、9.3倍和122.3倍。在缺血诱导后3小时，通过微透析探针给予高钾（100 mmol/L）或诺米芬辛（Sigma，圣路易斯，密苏里州）（10 mmol/L，一种DA摄取阻滞剂）以刺激DA释放，同时持续维持CBF降低。13只大鼠用于非缺血条件下钾或诺米芬辛刺激DA释放的研究。在轻度和中度缺血条件下，高钾或诺米芬辛的给药刺激了DA释放。与正常大鼠（22.3倍）相比，轻度缺血大鼠中钾刺激引起的DA释放增加更高（106.6倍）。这表明与非缺血条件相比，轻度缺血下DA终末存在过度兴奋性。另一方面，诺米芬辛在中度缺血脑内比对照脑内使[DA]e水平升高更多，表明在前一种情况下DA摄取上调。在轻度和中度缺血条件下，刺激后钾和诺米芬辛引起的DA释放增加持续存在。缺血诱导后重度缺血时[DA]e的高水平在整个研究期间持续存在，且不受钾或诺米芬辛刺激。我们得出结论，在轻度和中度缺血条件下，DA终末变得高度兴奋且再摄取机制受损。轻度和中度缺血期间DA代谢的这些变化可能解释了脑缺血“半暗带”状态下神经元的可持续性以及缺血半暗带向坏死核心的转变。
