A glucagon-like peptide-1 receptor agonist reduces intracranial pressure in a rat model of hydrocephalus

GLP-1R agonists show promise as a therapeutic agent to lower intracranial pressure in rodents.</jats:p

Guide to preclinical models used to study the pathophysiology of idiopathic intracranial hypertension.

Idiopathic intracranial hypertension (IIH) is characterised by raised intracranial pressure (ICP) and papilloedema in the absence of an identifiable secondary cause typically occurring in young women with obesity. The impact is considerable with the potential for blindness, chronic disabling headaches, future risk of cardiovascular disease and marked healthcare utilisation. There have been marked advances in our understanding the pathophysiology of IIH including the role of androgen excess. Insight into pathophysiological underpinnings has arisen from astute clinical observations, studies, and an array of preclinical models. This article summarises the current literature pertaining to the pathophysiology of IIH. The current preclinical models relevant to gaining mechanistic insights into IIH are then discussed. In vitro and in vivo models which study CSF secretion and the effect of potentially pathogenic molecules have started to glean important mechanistic insights. These models are also useful to evaluate novel therapeutic targets to abrogate CSF secretion. Importantly, in vitro CSF secretion assays translate into relevant changes in ICP in vivo. Models of CSF absorption pertinent to IIH, are less well established but highly relevant and of future interest. There is no fully developed in vivo model of IIH but this remains an area of importance. Progress is being made to improve our understanding of the underlying aetiology in IIH including the characterisation of disease biomarkers and their mechanistic role in driving disease pathology. Preclinical models, used to evaluate IIH mechanisms are yielding important mechanistic insights. Further work to refine these techniques will provide translatable insights into disease aetiology

Increased systemic and adipose 11β-HSD1 activity in idiopathic intracranial hypertension.

Context Idiopathic intracranial hypertension (IIH) is a disease of raised intracranial pressure (ICP) of unknown aetiology. Reductions in glucocorticoid metabolism are associated with improvements in IIH disease activity. The basal IIH glucocorticoid metabolism yet to be assessed. Objective To determine the basal glucocorticoid phenotype in IIH and assess the effects of weight loss on the IIH glucocorticoid phenotype. Design A retrospective case-control study and a separate exploratory analysis of a prospective randomised intervention study. Methods The case-control study compared female IIH patients to body mass index, age, and sex-matched controls. The randomised intervention study, different IIH patients were randomized to either a community weight management intervention, or bariatric surgery, with patients assessed at baseline and 12 months. Glucocorticoid levels were determined utilising 24-hour urinary steroid profiles alongside the measurement of adipose tissue 11β-HSD1 activity. Results Compared to control subjects, patients with active IIH had increased systemic 11β-hydroxysteroid dehydrogenase (11β-HSD1) and 5α-reductase activity. The intervention study demonstrated that weight loss following bariatric surgery reduced systemic 11β-HSD1 and 5α-reductase activity. Reductions in these were associated with reduced ICP. Subcutaneous adipose tissue explants demonstrated elevated 11β-HSD1 activity compared to samples from matched controls. Conclusion We demonstrate that in IIH, there is a phenotype of elevated systemic and adipose 11β-HSD1 activity in excess to that mediated by obesity. Bariatric surgery to induce weight loss was associated with reductions in 11β-HSD1 activity and decreased ICP. These data reflect new insights into the IIH phenotype and further point towards metabolic dysregulation as a feature of IIH