Investigation into the Choroid Plexus Molecular Mechanisms Underlying Idiopathic Intracranial Hypertension

Pascual-Baixauli, Ester (2021). Investigation into the Choroid Plexus Molecular Mechanisms Underlying Idiopathic Intracranial Hypertension. PhD thesis The Open University.



Idiopathic Intracranial Hypertension (IIH) is a rare condition characterised by increased intracranial pressure for unknown reasons. It predominantly affects obese women of child-bearing age, and it has been linked to altered sex hormone levels. While the mechanisms underlying IIH are unknown, IIH is thought to be related to an impairment of cerebrospinal fluid (CSF) dynamics, including CSF hypersecretion by the choroid plexus (CP). The present study was designed to explore the effects of diet on CSF secretion in the rat with the aim to unravel possible pathogenic mechanisms underlying IIH. Other parameters, such as sex and elevated cytokines in CSF, were also studied. A high-fat diet (HFD) was able to increase both body weight and CSF secretion in male and female rats. While the differences appeared earlier in males, they were larger in females. Furthermore, elevated levels of cytokines (TNFα, CCL2, IL-6, IL-17, hydrocortisone) in CSF of HFD-fed male rats were tested, from which hydrocortisone was the only one found to potentiate HFD-induced CSF hypersecretion.

In females, weight and plasma testosterone concentration positively correlated with CSF secretion. Females under HFD supplemented with peanut butter (HFD+PB) showed the highest CSF secretion rates, body weights and testosterone levels. HFD+PB rats also had the highest deregulation in CP gene expression. In HFD+PB rats, most of the genes related to CSF secretion remained unaltered; however, two transporters, Slc4a10 and Kcna6, and several tight junction molecules (TJs), including ZO-1, were downregulated. In vitro tests using a CP cell model showed that testosterone was able to alter gene expression including decreased expression of TJs including ZO-1, Slc4a10, and overexpression of AQP1 and ATP1A1. Additionally, testosterone was also able to decrease barrier functionality in the in vitro CP model. It is hypothesised that, in IIH, obesity and elevated testosterone levels increase CP permeability, altering CSF dynamics.

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