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.
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。