Department of Neuroscience, University of Copenhagen, Blegdamsvej 3B, Copenhagen, DK-2200, Denmark.
Department of Neurosurgery, University of Michigan, Ann Arbor, USA.
Fluids Barriers CNS. 2023 Jul 4;20(1):53. doi: 10.1186/s12987-023-00448-x.
Hydrocephalus constitutes a complex neurological condition of heterogeneous origin characterized by excessive cerebrospinal fluid (CSF) accumulation within the brain ventricles. The condition may dangerously elevate the intracranial pressure (ICP) and cause severe neurological impairments. Pharmacotherapies are currently unavailable and treatment options remain limited to surgical CSF diversion, which follows from our incomplete understanding of the hydrocephalus pathogenesis. Here, we aimed to elucidate the molecular mechanisms underlying development of hydrocephalus in spontaneously hypertensive rats (SHRs), which develop non-obstructive hydrocephalus without the need for surgical induction.
Magnetic resonance imaging was employed to delineate brain and CSF volumes in SHRs and control Wistar-Kyoto (WKY) rats. Brain water content was determined from wet and dry brain weights. CSF dynamics related to hydrocephalus formation in SHRs were explored in vivo by quantifying CSF production rates, ICP, and CSF outflow resistance. Associated choroid plexus alterations were elucidated with immunofluorescence, western blotting, and through use of an ex vivo radio-isotope flux assay.
SHRs displayed brain water accumulation and enlarged lateral ventricles, in part compensated for by a smaller brain volume. The SHR choroid plexus demonstrated increased phosphorylation of the Na/K/2Cl cotransporter NKCC1, a key contributor to choroid plexus CSF secretion. However, neither CSF production rate, ICP, nor CSF outflow resistance appeared elevated in SHRs when compared to WKY rats.
Hydrocephalus development in SHRs does not associate with elevated ICP and does not require increased CSF secretion or inefficient CSF drainage. SHR hydrocephalus thus represents a type of hydrocephalus that is not life threatening and that occurs by unknown disturbances to the CSF dynamics.
脑积水是一种复杂的神经疾病，具有异源性，其特征是脑室内脑脊液（CSF）过度积聚。这种情况可能会使颅内压（ICP）升高，并导致严重的神经损伤。目前尚无药物治疗方法，治疗选择仍然局限于手术性 CSF 分流术，这是由于我们对脑积水发病机制的认识不完整。在这里，我们旨在阐明自发性高血压大鼠（SHR）发生脑积水的分子机制，SHR 会发展为非梗阻性脑积水，而无需手术诱导。
磁共振成像（MRI）用于描绘 SHR 和对照 Wistar-Kyoto（WKY）大鼠的脑和 CSF 体积。通过湿重和干重确定脑水含量。通过定量 CSF 产生率、ICP 和 CSF 流出阻力，在体内研究与 SHR 脑积水形成相关的 CSF 动力学。通过免疫荧光、Western blot 和离体放射性同位素通量测定，阐明与脑积水形成相关的脉络丛改变。
SHR 出现脑水蓄积和侧脑室扩大，部分由脑体积较小补偿。SHR 脉络丛中 Na/K/2Cl 共转运蛋白 NKCC1 的磷酸化增加，这是脉络丛 CSF 分泌的关键贡献者。然而，与 WKY 大鼠相比，SHR 的 CSF 产生率、ICP 或 CSF 流出阻力均未升高。
SHR 脑积水的发展与 ICP 升高无关，不需要增加 CSF 分泌或 CSF 引流效率降低。因此，SHR 脑积水代表了一种非致命性的脑积水，其发生机制与 CSF 动力学的未知紊乱有关。
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