Department of Pathology, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA; Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
Department of Pathology, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Neuron. 2023 May 17;111(10):1591-1608.e4. doi: 10.1016/j.neuron.2023.02.020. Epub 2023 Mar 8.
Post-hemorrhagic hydrocephalus (PHH) refers to a life-threatening accumulation of cerebrospinal fluid (CSF) that occurs following intraventricular hemorrhage (IVH). An incomplete understanding of this variably progressive condition has hampered the development of new therapies beyond serial neurosurgical interventions. Here, we show a key role for the bidirectional Na-K-Cl cotransporter, NKCC1, in the choroid plexus (ChP) to mitigate PHH. Mimicking IVH with intraventricular blood led to increased CSF [K] and triggered cytosolic calcium activity in ChP epithelial cells, which was followed by NKCC1 activation. ChP-targeted adeno-associated viral (AAV)-NKCC1 prevented blood-induced ventriculomegaly and led to persistently increased CSF clearance capacity. These data demonstrate that intraventricular blood triggered a trans-choroidal, NKCC1-dependent CSF clearance mechanism. Inactive, phosphodeficient AAV-NKCC1-NT51 failed to mitigate ventriculomegaly. Excessive CSF [K] fluctuations correlated with permanent shunting outcome in humans following hemorrhagic stroke, suggesting targeted gene therapy as a potential treatment to mitigate intracranial fluid accumulation following hemorrhage.
出血后脑积水（PHH）是指在脑室出血（IVH）后发生的危及生命的脑脊液（CSF）积聚。由于对这种进行性变化的疾病缺乏全面的了解，除了连续的神经外科干预外，新疗法的发展一直受到阻碍。在这里，我们发现双向钠-钾-2 氯共转运蛋白 NKCC1 在脉络丛（ChP）中对减轻 PHH 起着关键作用。用脑室血模拟 IVH 会导致 CSF [K]增加，并引发 ChP 上皮细胞胞质内钙活性增加，随后 NKCC1 被激活。靶向脉络丛的腺相关病毒（AAV）-NKCC1 可防止血诱导的脑室扩大，并导致持续增加的 CSF 清除能力。这些数据表明，脑室血触发了一种跨脉络丛、NKCC1 依赖性 CSF 清除机制。无活性、磷酸化缺陷的 AAV-NKCC1-NT51 不能减轻脑室扩大。脑出血后 CSF [K]的过度波动与人类永久性分流的结果相关，提示靶向基因治疗可能是减轻出血后颅内液体积聚的一种潜在治疗方法。
