溶血磷脂酸作为蛛网膜下腔出血后脑积水的脑脊液脂质，通过 TRPV4 诱导的 NKCC1 过度激活来驱动脑脊液积聚。
Lysophosphatidic acid as a CSF lipid in posthemorrhagic hydrocephalus that drives CSF accumulation via TRPV4-induced hyperactivation of NKCC1.
机构信息
Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3, 2200, Copenhagen, Denmark.
Department of Neurosurgery, Neuroscience Centre, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark.
出版信息
Fluids Barriers CNS. 2022 Sep 6;19(1):69. doi: 10.1186/s12987-022-00361-9.
BACKGROUND
A range of neurological pathologies may lead to secondary hydrocephalus. Treatment has largely been limited to surgical cerebrospinal fluid (CSF) diversion, as specific and efficient pharmacological options are lacking, partly due to the elusive molecular nature of the CSF secretion apparatus and its regulatory properties in physiology and pathophysiology.
METHODS
CSF obtained from patients with subarachnoid hemorrhage (SAH) and rats with experimentally inflicted intraventricular hemorrhage (IVH) was analyzed for lysophosphatidic acid (LPA) by alpha-LISA. We employed the in vivo rat model to determine the effect of LPA on ventricular size and brain water content, and to reveal the effect of activation and inhibition of the transient receptor potential vanilloid 4 (TRPV4) ion channel on intracranial pressure and CSF secretion rate. LPA-mediated modulation of TRPV4 was determined with electrophysiology and an ex vivo radio-isotope assay was employed to determine the effect of these modulators on choroid plexus transport.
RESULTS
Elevated levels of LPA were observed in CSF obtained from patients with subarachnoid hemorrhage (SAH) and from rats with experimentally-inflicted intraventricular hemorrhage (IVH). Intraventricular administration of LPA caused elevated brain water content and ventriculomegaly in experimental rats, via its action as an agonist of the choroidal transient receptor potential vanilloid 4 (TRPV4) channel. TRPV4 was revealed as a novel regulator of ICP in experimental rats via its ability to modulate the CSF secretion rate through its direct activation of the Na/K/2Cl cotransporter (NKCC1) implicated in CSF secretion.
CONCLUSIONS
Together, our data reveal that a serum lipid present in brain pathologies with hemorrhagic events promotes CSF hypersecretion and ensuing brain water accumulation via its direct action on TRPV4 and its downstream regulation of NKCC1. TRPV4 may therefore be a promising future pharmacological target for pathologies involving brain water accumulation.
背景
一系列的神经病理学可能导致继发性脑积水。治疗方法主要局限于外科脑脊液（CSF）分流，因为缺乏特定且有效的药物选择，部分原因是 CSF 分泌装置的难以捉摸的分子性质及其在生理学和病理生理学中的调节特性。
方法
通过 alpha-LISA 分析蛛网膜下腔出血（SAH）患者和实验性脑室出血（IVH）大鼠的 CSF 中溶血磷脂酸（LPA）的含量。我们采用体内大鼠模型来确定 LPA 对脑室大小和脑含水量的影响，并揭示瞬时受体电位香草醛 4（TRPV4）离子通道的激活和抑制对颅内压和 CSF 分泌率的影响。用电生理学方法确定 LPA 对 TRPV4 的调节作用，并采用放射性同位素测定法确定这些调节剂对脉络丛转运的影响。
结果
在蛛网膜下腔出血（SAH）患者和实验性脑室出血（IVH）大鼠的 CSF 中观察到 LPA 水平升高。脑室内给予 LPA 会导致实验大鼠脑含水量增加和脑室扩大，这是由于 LPA 作为脉络丛瞬时受体电位香草醛 4（TRPV4）通道的激动剂发挥作用。通过其直接激活与 CSF 分泌有关的 Na+/K+/2Cl-共转运体（NKCC1），TRPV4 被揭示为实验大鼠 ICP 的新型调节因子。
结论
我们的数据表明，存在于出血性事件相关的脑病理学中的一种血清脂质通过其对 TRPV4 的直接作用及其对 NKCC1 的下游调节，促进 CSF 过度分泌并随之导致脑水积聚。因此，TRPV4 可能是涉及脑水积聚的病理的有前途的未来药物靶点。
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