背景:特发性颅内高压(IIH)是一种以颅内压(ICP)升高为特征的疾病,视力受损,和头痛。IIH的大多数病例发生在育龄妇女中,虽然年龄,BMI,女性并不涵盖IIH病理生理学的所有方面。已经在IIH中鉴定了系统性代谢失调,具有雄激素过量的特征。然而,肥胖/激素扰动与脑脊液动力学之间的机械耦合仍未解决.
方法:雌性Wistar大鼠要么喂食高脂饮食(HFD)21周,要么暴露于睾酮辅助治疗28天以概括IIH因果驱动因素。脑脊液(CSF)和血睾酮水平用质谱测定,ICP和CSF动力学与体内实验,并且通过转录组学和基于离体同位素的通量测定揭示了脉络丛的功能。
结果:HFD喂养的大鼠出现ICP升高(65%),伴随着CSF流出阻力增加(50%),而CSF分泌率或脉络丛基因表达没有改变。慢性睾酮辅助治疗瘦鼠引起ICP(55%)和CSF分泌率(85%)升高,与脉络丛Na+活性增加相关,K+,2Cl-combransporter,NKCC1。
结论:HFD引起的实验性大鼠ICP升高伴随着CSF引流能力的降低。辅助睾酮,模仿在女性IIH患者中观察到的雄激素过量,CSF分泌率升高,因此ICP升高。因此,肥胖诱导的雄激素失调可能有助于IIH的疾病机制。
BACKGROUND: Idiopathic intracranial hypertension (
IIH) is a condition characterized by increased intracranial pressure (ICP), impaired vision, and headache. Most cases of
IIH occur in obese women of childbearing age, though age, BMI, and female sex do not encompass all aspects of
IIH pathophysiology. Systemic metabolic dysregulation has been identified in
IIH with a profile of androgen excess. However, the mechanistic coupling between obesity/hormonal perturbations and cerebrospinal fluid dynamics remains unresolved.
METHODS: Female Wistar rats were either fed a high fat diet (HFD) for 21 weeks or exposed to adjuvant testosterone treatment for 28 days to recapitulate IIH causal drivers. Cerebrospinal fluid (CSF) and blood testosterone levels were determined with mass spectrometry, ICP and CSF dynamics with in vivo experimentation, and the choroid plexus function revealed with transcriptomics and ex vivo isotope-based flux assays.
RESULTS: HFD-fed rats presented with increased ICP (65%), which was accompanied by increased CSF outflow resistance (50%) without altered CSF secretion rate or choroid plexus gene expression. Chronic adjuvant testosterone treatment of lean rats caused elevated ICP (55%) and CSF secretion rate (85%), in association with increased activity of the choroid plexus Na+,K+,2Cl- cotransporter, NKCC1.
CONCLUSIONS: HFD-induced ICP elevation in experimental rats occurred with decreased CSF drainage capacity. Adjuvant testosterone, mimicking the androgen excess observed in female IIH patients, elevated the CSF secretion rate and thus ICP. Obesity-induced androgen dysregulation may thus contribute to the disease mechanism of
IIH.