Blood brain barrier is impermeable to solutes and permeable to water after experimental pediatric cardiac arrest

Abstract

Pediatric asphyxial cardiac arrest (CA) results in unfavorable neurological outcome in most survivors. Development of neuroprotective therapies is contingent upon understanding the permeability of intravenously delivered medications through the blood brain barrier (BBB). In a model of pediatric CA we sought to characterize BBB permeability to small and large molecular weight substances. Additionally, we measured the percent brain water after CA. Asphyxia of 9 min was induced in 16-18 day-old rats. The rats were resuscitated and the BBB permeability to small (sodium fluorescein and gadoteridol) and large (immunoglobulin G, IgG) molecules was assessed at 1, 4, and 24 h after asphyxial CA or sham surgery. Percent brain water was measured post-CA and in shams using wet-to-dry brain weight. Fluorescence, gadoteridol uptake, or IgG staining at 1, 4 h and over the entire 24 h post-CA did not differ from shams, suggesting absence of BBB permeability to these solutes. Cerebral water content was increased at 3 h post-CA vs. sham. In conclusion, after 9 min of asphyxial CA there is no BBB permeability over 24 h to conventional small or large molecule tracers despite the fact that cerebral water content is increased early post-CA indicating the development of brain edema. Evaluation of novel therapies targeting neuronal death after pediatric CA should include their capacity to cross the BBB.

Functionalized Phenylbenzamides Inhibit Aquaporin-4 Reducing Cerebral Edema and Improving Outcome in Two Models of CNS Injury

“…In collaboration with several independent investigators, we explored the use of AER-271 in other animal models where AQP4 mediates the edematous movement of water. In a pediatric rat model of asphyxial cardiac arrest, global cytotoxic/ionic cerebral edema is observed postresuscitation (Tress et al, 2014). In this model AER-271 was observed to prevent CE, improve early outcomes and reduce neuronal death and neuroinflammation (Wallisch et al, 2018).…”

Effects of Pringle maneuver and partial hepatectomy on the pharmacokinetics and blood–brain barrier permeability of sodium fluorescein in rats

“…Because of these characteristics, FL has been used extensively as an in vivo marker to determine the changes in the paracellular permeability of BBB in different diseases (Kaya and Ahishali, 2011). In most experiments, investigators use the absolute brain concentrations of FL as a measure of BBB permeability (Cao et al, 2015;Nishioku et al, 2010;Oppenheim et al, 2013;Tress et al, 2014). However, this approach may result in inaccuracies if the systemic exposure of the marker, such as area under the plasma concentrationtime curve (AUC), is also altered by the disease or the intervention.…”

Glibenclamide Produces Region-Dependent Effects on Cerebral Edema in a Combined Injury Model of Traumatic Brain Injury and Hemorrhagic Shock in Mice

“…For example, after 9 min asphyxial cardiac arrest, an *0.5% global increase in BW is seen and associated with significant neuronal death and neurological impairment. 72 After TBI, a 0.5% increase in BW in the uninjured brain appears to contribute to elevations in ICP, suggesting clinical relevance: in CCI alone, ICP increases to *13-14 mm Hg and is not affected by glibenclamide; 31 however, the addition of shock in our model results in an ICP increase to *20 mm Hg by the end of the resuscitation. 27 This diffuse edema is challenging to treat, and in our model of CCI+HS the only agents to decrease contralateral %BW have been an experimental blood substitute (polynitroxylated pegylated hemoglobin-A 27 ), and glibenclamide as shown in our current report.…”