Wilke Scott, Thomas Robert, Allcock Natalie, Fern Robert
Department of Neurology, University of Washington, Seattle, Washington, USA.
J Neuropathol Exp Neurol. 2004 Aug;63(8):872-81. doi: 10.1093/jnen/63.8.872.
In developing CNS white matter (WM), the period of early myelination is characterized by a heightened sensitivity to ischemic injury. Using an in situ (isolated) preparation, we show that the mechanism of acute ischemic injury of immature WM oligodendroglial involves Ca2+ influx though non-NMDA type glutamate receptors (GluRs). The Ca2+-influx and acute cell death that was evoked by ischemic conditions (oxygen and glucose withdrawal) in identified P10 rat optic nerve oligodendroglia were blocked by removing extracellular Ca2+ or by CNQX, a selective non-NMDA GluR antagonist. The selective Na-K-Cl cotransport (NKCC) inhibitor bumetanide was also highly protective, even though NKCC expression is restricted to astrocytes in this tissue. Bumetanide largely prevented the non-NMDA GluR-mediated [Ca2+]i rise evoked by ischemia in oligodendroglia, suggesting that it interfered with ischemic glutamate release. In control WM, glutamate-like reactivity was located mainly in astrocytes and oligodendroglia identified using ultrastructural criteria. In ischemic WM, astrocyte glutamate-like reactivity was reduced, an effect countered by bumetanide. We suggest a model in which NKCC-dependent injury and release of glutamate from astrocytes activates glutamate receptors on oligodendroglia, resulting in Ca2+-influx and acute cell death.
在中枢神经系统白质（WM）发育过程中，早期髓鞘形成阶段的特点是对缺血性损伤高度敏感。我们采用原位（分离）制备方法，发现未成熟WM少突胶质细胞急性缺血性损伤的机制涉及通过非NMDA型谷氨酸受体（GluRs）的Ca2+内流。去除细胞外Ca2+或使用选择性非NMDA GluR拮抗剂CNQX可阻断P10大鼠视神经少突胶质细胞在缺血条件（缺氧和无糖）下诱发的Ca2+内流和急性细胞死亡。选择性钠钾氯协同转运体（NKCC）抑制剂布美他尼也具有高度保护作用，尽管在该组织中NKCC的表达仅限于星形胶质细胞。布美他尼在很大程度上阻止了少突胶质细胞中缺血诱发的非NMDA GluR介导的[Ca2+]i升高，表明它干扰了缺血性谷氨酸释放。在对照WM中，使用超微结构标准鉴定，谷氨酸样反应主要位于星形胶质细胞和少突胶质细胞中。在缺血性WM中，星形胶质细胞的谷氨酸样反应性降低，布美他尼可对抗这种效应。我们提出了一个模型，其中NKCC依赖性损伤和星形胶质细胞释放谷氨酸激活少突胶质细胞上的谷氨酸受体，导致Ca2+内流和急性细胞死亡。
