Modelling idiopathic intracranial hypertension in rats: contributions of high fat diet and testosterone to intracranial pressure and cerebrospinal fluid production

Abstract

Background Idiopathic intracranial hypertension (IIH) is a condition characterized by increased intracranial pressure (ICP), impaired vision, and headache. Most cases of IIH occur in obese women of childbearing age, though age, BMI, and female sex do not encompass all aspects of IIH pathophysiology. Systemic metabolic dysregulation has been identified in IIH with a profile of androgen excess. However, the mechanistic coupling between obesity/hormonal perturbations and cerebrospinal fluid dynamics remains unresolved. 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.

CSF hyperdynamics in rats mimicking the obesity and androgen excess characteristic of patients with idiopathic intracranial hypertension

“…To that end, we employed a female rat model of obesity to determine different aspects of CSF flow. We previously demonstrated that rats fed a high-fat diet became overweight and presented with an elevated ICP and reduced CSF drainage capacity [ 34 ], aligned with other studies also illustrating various other IIH features, including papilledema [ 33 , 78 ]. The extent of the ICP elevation in these high-fat diet-fed rats, however, did not recapitulate the minimum doubling of opening lumbar pressure detected in IIH patients [ 79 ], possibly because of the limited weight gain observed in this cohort.…”

“…Obesity-induced neuroendocrine imbalances and metabolic inflammation, which may be present in IIH patients, could therefore be absent from this rat cohort at this early time point [ 81 ]. Alternatively, one could speculate that the high sugar/high fat diet employed in the earlier studies on rats becoming obese on such ‘Western diet’ [ 33 , 34 , 78 ] could modulate the ICP in ways that are currently unknown, but absent in the Zucker rats that become obese on regular chow. The diet on which rats, and potentially humans, become obese on, may thus have direct implications on CSF drainage and possibly other ICP-related physiological aspects including blood flow.…”

“…An experimental animal model recapitulating IIH symptomatology would allow a complete characterization of the contributions from variables involved in CSF dynamics. To this end, previous studies have employed high-fat diet (HFD) to induce obesity in female rodents with demonstration of some degree of elevated ICP in these rats, in part due to their reduced CSF drainage capacity [ 33 , 34 ], although with no obvious changes to CSF flow rates [ 34 ].…”

“…Among many other putative factors contributing to IIH etiology, such as altered levels of hormones, inflammatory markers, and enzyme activity [ 35 – 37 ], most notable is androgen (testosterone) excess in serum and CSF of IIH patients, differentiating them from unaffected obese females [ 36 ]. Notably, treatment of lean female rats with adjuvant testosterone leads to increased CSF production and elevated ICP, in part due to elevated activity of the choroid plexus Na + ,K + ,2Cl − cotransporter NKCC1 [ 34 ] which is a key contributor to CSF production [ 38 – 41 ], suggesting a possible connection between IIH-related testosterone burden and disturbed CSF dynamics.…”

“…Neither obesity nor androgen levels can be readily manipulated in patient populations to determine their contributions to IIH etiology. High-fat diet animal models have not reached obesity levels fully recapitulating those observed in the IIH patient group [ 33 , 34 ], indicating that an updated animal model combining adequate obesity and adjuvant testosterone might better illustrate the potential contribution of altered CSF dynamics to IIH symptoms. To this end, we have employed genetically obese female Zucker rats with and without adjuvant testosterone to determine the impact of a combination of these factors in IIH etiology and symptomatology, including ICP, brain fluid dynamics, choroid plexus function, and ventricular morphology.…”