Kahle Kristopher T, Simard J Marc, Staley Kevin J, Nahed Brian V, Jones Pamela S, Sun Dandan
Departments of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
Physiology (Bethesda). 2009 Aug;24:257-65. doi: 10.1152/physiol.00015.2009.
The brain achieves homeostasis of its intracellular and extracellular fluids by precisely regulating the transport of solute and water across its major cellular barriers: endothelia of the blood-brain barrier (BBB), choroid plexus epithelia, and neuroglial cell membranes. Cerebral edema, the pathological accumulation of fluid in the brain's intracellular and extracellular spaces, is a major cause of morbidity and mortality following stroke and other forms of ischemic brain injury. Until recently, mechanisms of cerebral edema formation have been obscure; consequently, its treatment has been empiric and suboptimal. Here, we provide a paradigm for understanding ischemic cerebral edema, showing that its molecular pathogenesis is a complex yet step-wise process that results largely from impaired astrocytic cell volume regulation and permeability alterations in the cerebral microvasculature, both of which arise from pathological changes in the activities of specific ion channels and transporters. Recent data has implicated the bumetanide-sensitive NKCC1, an electroneutral cotransporter expressed in astrocytes and the BBB, in cerebral edema formation in several different rodent models of stroke. Pharmacological inhibition or genetic deficiency of NKCC1 decreases ischemia-induced cell swelling, BBB breakdown, cerebral edema, and neurotoxicity. Combination pharmacological strategies that include NKCC1 as a target might thus prove beneficial for the treatment of ischemic, and potentially other types of, cerebral edema.
大脑通过精确调节溶质和水跨其主要细胞屏障的转运来实现细胞内液和细胞外液的稳态，这些屏障包括血脑屏障（BBB）的内皮细胞、脉络丛上皮细胞和神经胶质细胞膜。脑水肿是指大脑细胞内和细胞外间隙中液体的病理性积聚，是中风和其他形式缺血性脑损伤后发病和死亡的主要原因。直到最近，脑水肿形成的机制仍不清楚；因此，其治疗一直是经验性的且效果欠佳。在此，我们提供了一个理解缺血性脑水肿的范例，表明其分子发病机制是一个复杂但逐步的过程，主要源于星形胶质细胞体积调节受损和脑微血管通透性改变，这两者均由特定离子通道和转运体活性的病理变化引起。最近的数据表明，布美他尼敏感的NKCC1（一种在星形胶质细胞和血脑屏障中表达的电中性共转运体）在几种不同的啮齿动物中风模型的脑水肿形成中起作用。NKCC1的药理抑制或基因缺陷可减少缺血诱导的细胞肿胀、血脑屏障破坏、脑水肿和神经毒性。因此，以NKCC1为靶点的联合药理策略可能对缺血性脑水肿以及潜在的其他类型脑水肿的治疗有益。
