PDF(Pubmed)
Abstract：
BACKGROUND: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.
摘要：
背景：脑积水是一种异质性的复杂神经系统疾病，其特征是脑室内脑脊液（CSF）积聚过多。这种情况可能会危险地升高颅内压（ICP）并导致严重的神经系统损害。药物疗法目前不可用，治疗选择仍然限于手术脑脊液转流，这源于我们对脑积水发病机制的不完全理解。这里,我们旨在阐明自发性高血压大鼠（SHR）脑积水发展的分子机制，无需手术诱导即可发展为非阻塞性脑积水。
方法：使用磁共振成像来描绘SHR和对照Wistar-Kyoto（WKY）大鼠的脑和CSF体积。根据湿重和干脑重确定脑水含量。通过量化CSF生产率，在体内探索了与SHR中脑积水形成相关的CSF动力学。ICP,和脑脊液流出阻力。相关的脉络丛改变用免疫荧光阐明，西方印迹,并通过使用离体放射性同位素通量测定。
结果：SHR显示脑积水和侧脑室增大，部分由较小的大脑体积补偿。SHR脉络丛显示Na/K/2Cl-协同转运蛋白NKCC1的磷酸化增加，这是脉络丛CSF分泌的关键贡献者。然而,脑脊液生产率都没有，ICP,与WKY大鼠相比，SHR的CSF流出阻力也没有升高。
结论：SHR中脑积水的发展与ICP升高无关，并且不需要增加CSF分泌或低效的CSF引流。因此，SHR脑积水代表一种不危及生命的脑积水，并且由于对CSF动力学的未知干扰而发生。
方法：使用磁共振成像来描绘SHR和对照Wistar-Kyoto（WKY）大鼠的脑和CSF体积。根据湿重和干脑重确定脑水含量。通过量化CSF生产率，在体内探索了与SHR中脑积水形成相关的CSF动力学。ICP,和脑脊液流出阻力。相关的脉络丛改变用免疫荧光阐明，西方印迹,并通过使用离体放射性同位素通量测定。
结果：SHR显示脑积水和侧脑室增大，部分由较小的大脑体积补偿。SHR脉络丛显示Na/K/2Cl-协同转运蛋白NKCC1的磷酸化增加，这是脉络丛CSF分泌的关键贡献者。然而,脑脊液生产率都没有，ICP,与WKY大鼠相比，SHR的CSF流出阻力也没有升高。
结论：SHR中脑积水的发展与ICP升高无关，并且不需要增加CSF分泌或低效的CSF引流。因此，SHR脑积水代表一种不危及生命的脑积水，并且由于对CSF动力学的未知干扰而发生。
