Cerebrospinal fluid dynamics modulation by diet and cytokines in rats

Abstract

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 mmH2O min/μl controls, and 7.09 ± 0.26 mmH2O 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.