Investigation into the Choroid Plexus Molecular Mechanisms Underlying Idiopathic Intracranial Hypertension

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

Cerebrospinal fluid dynamics modulation by diet and cytokines in rats.

Background Idiopathic intracranial hypertension (IIH) is a neurological disorder characterised by raised cerebrospinal fluid (CSF) pressure in the absence of any intracranial pathology. IIH mainly affects women with obesity between the ages of 15 and 45. Two possible mechanisms that could explain the increased CSF pressure in IIH are excessive CSF production by the choroid plexus (CP) epithelium or impaired CSF drainage from the brain. However, the molecular mechanisms controlling these mechanisms in IIH remain to be determined. Methods In vivo ventriculo-cisternal perfusion (VCP) and variable rate infusion (VRI) techniques were used to assess changes in rates of CSF secretion and resistance to CSF drainage in female and male Wistar rats fed either a control (C) or high-fat (HF) diet (under anaesthesia with 20 μl/100 g medetomidine, 50 μl/100 g ketamine i.p). In addition, CSF secretion and drainage were assessed in female rats following treatment with inflammatory mediators known to be elevated in the CSF of IIH patients: C-C motif chemokine ligand 2 (CCL2), interleukin (IL)-17 (IL-17), IL-6, IL-1β, tumour necrosis factor-α (TNF-α), as well as glucocorticoid hydrocortisone (HC). Results Female rats fed the HF diet had greater CSF secretion compared to those on control diet (3.18 ± 0.12 μl/min HF, 1.49 ± 0.15 μl/min control). Increased CSF secretion was seen in both groups following HC treatment (by 132% in controls and 114% in HF) but only in control rats following TNF-α treatment (137% increase). The resistance to CSF drainage was not different between control and HF fed female rats (6.13 ± 0.44 mmH O min/μl controls, and 7.09 ± 0.26 mmH O min/μl HF). and when treated with CCL2, both groups displayed an increase in resistance to CSF drainage of 141% (controls) and 139% (HF) indicating lower levels of CSF drainage. Conclusions Weight loss and therapies targeting HC, TNF-α and CCL2, whether separately or in combination, may be beneficial to modulate rates of CSF secretion and/or resistance to CSF drainage pathways, both factors likely contributing to the raised intracranial pressure (ICP) observed in female IIH patients with obesity.</p

Ahora / Ara

La cinquena edició del microrelatari per l’eradicació de la violència contra les dones de l’Institut Universitari d’Estudis Feministes i de Gènere «Purificación Escribano» de la Universitat Jaume I vol ser una declaració d’esperança. Aquest és el moment en el qual les dones (i els homes) hem de fer un pas endavant i eliminar la violència sistèmica contra les dones. Ara és el moment de denunciar el masclisme i els micromasclismes començant a construir una societat més igualitària. Cadascun dels relats del llibre és una denúncia i una declaració que ens encamina cap a un món millor