Investigation Into The Molecular Mechanisms Underlying Idiopathic Intracranial Hypertension

Alimajstorovic, Zerin (2017). Investigation Into The Molecular Mechanisms Underlying Idiopathic Intracranial Hypertension. PhD thesis The Open University.

DOI: https://doi.org/10.21954/ou.ro.0000c351

Abstract

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 obese women 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 epithelium or impaired CSF drainage back into the venous blood but the molecular mechanisms controlling these in IIH remain to be determined.

In vivo ventriculo-cisternal perfusion and variable rate infusion techniques assessed changes in rates of CSF secretion/resistance to CSF drainage in male and female Wistar rats fed either a normal control or high-fat (HF) diet, following treatment with inflammatory mediators already found to be elevated in the CSF of IIH patients: chemokine (C-C motif) ligand 2 (CCL2), interleukin (IL)-17 (IL-17), IL-6, IL-1β, tumour necrosis factor-α (TNF-α), as well as adipocyte-derived hormone leptin and the glucocorticoid hydrocortisone (HC).

Female Wistar rats raised on a HF diet were shown to have the highest CSF secretion and lowest CSF drainage rates under untreated conditions. Increased CSF secretion was observed in rats of all genders and diets following TNF-α or HC treatment, however the greatest increase by TNF-α and HC over basal levels was observed in female rats raised on a HF diet. In addition, female rats on a HF diet, treated with CCL2 or IL-17, displayed an increase in resistance to CSF drainage when compared to untreated controls (indicating lower levels of CSF drainage).

Therapies targeting HC, TNF-α, CCL2 and/or IL-17, 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 observed in obese female IIH patients.

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