A new experimental mouse model of water intoxication with sustained increased intracranial pressure and mild hyponatremia without side effects of antidiuretics

Abstract

The most used experimental mouse model of hyponatremia and elevated intracranial pressure (ICP) is intraperitoneal injection of water in combination with antidiuretics. This model of water intoxication (WI) results in extreme pathological changes and death within 1 h. To improve preclinical studies of the pathophysiology of elevated ICP, we characterized diuresis, cardiovascular parameters, blood ionogram and effects of antidiuretics in this model. We subsequently developed a new mouse model with mild hyponatremia and sustained increased ICP. To investigate the classical protocol (severe WI), C57BL/6mice were anesthetized and received an intraperitoneal injection of 20% body weight of MilliQ water with or without 0.4 µg•kg −1 desmopressin acetate (dDAVP). Corresponding Sham groups were also studied. In the new WI protocol (mild WI), 10% body weight of a solution containing 6.5 mM NaHCO 3 , 1.125 mM KCl and 29.75 mM NaCl was intraperitoneally injected. By severe WI, ICP and mean arterial pressure increased until brain stem herniation occurred (23 ± 3 min after injection). The cardiovascular effects were accelerated by dDAVP. Severe WI induced a halt to urine production irrespective of the use of dDAVP. Following the new mild WI protocol, ICP also increased but was sustained at a pathologically high level without inducing herniation. Mean arterial pressure and urine production were not affected during mild WI. In conclusion, the new mild WI protocol is a superior experimental model to study the pathophysiological effects of elevated ICP induced by water intoxication.

Deletion of aquaporin‐4 improves capillary blood flow distribution in brain edema

“…In this work, we found perturbed capillary blood flow dynamics in unanesthetized mice undergoing mild brain edema (Bordoni et al, 2020). Moreover, the removal of AQP4 water channels played a beneficial role for microvascular blood flow, in addition to its general effects on edema formation, affecting how the In the late stage of pathological conditions associated with severe flow-restriction, as within the ischemic penumbra in stroke, low RTH values may indicate widespread collapse of the capillary network (Engedal et al, 2018).…”

Glymphatic fluid transport is suppressed by the aquaporin‐4 inhibitor AER‐271

“…To assess whether AER‐271 inhibits in vivo AQP4 water permeability, AER‐271 was first tested in a mouse model of acute severe hyponatremia, that is, water intoxication (Bordoni et al, 2020; Thrane et al, 2011). Intraperitoneal injection of distilled water in mice results in plasma hyponatremia, which creates an osmotic gradient from brain to blood, with the brain having more osmolytes.…”

Quantification of Capillary Perfusion in an Animal Model of Acute Intracranial Hypertension

“…The combination of Cushing reflex elements and vegetative coma after ICPpeak is in line with a diagnosis of brain herniation damaging the medulla oblongata of the brainstem, which is a typical characteristic of severe WI animal model. 19 We selected OCT imaging to evaluate the changes in the perfusion of the brain capillary bed due to its advantage of performing high-speed volumetric scans with high spatial resolution without the usage of exogenous fluorescent contrast agents. These characteristics allowed us to identify the changes in single capillaries during the fast development of IH and brain edema during WI.…”

“…0.96 mm; Intramedic Clay Adams, Becton Dickinson, NJ) and collected urines as previously described. 19 Blood pressure (BP) was monitored using a blood pressure monitor (WPI Inc., Sarasota, FL) through a polyethylene tube, PE-10 (I.D. 0.28 mm, O.D.…”

“…We induced WI as previously described. 19 Briefly, a solution 0.4 lg$kg -1 of desmopressin (dDAVP, Sigma-Aldrich) in sterile water was injected through a peritoneal catheter (PE-10) using an infusion pump (GenieTouch Syringe pump, Kent Scientific Corporation, Torrington, CT). The total volume injected per mouse was 20% of the body weight (BW), injected over a 2-min period.…”