Mitigating the effects of Endothelin-1 following a minimally invasive surgery reduces the blood-brain barrier permeability in a rabbit model of intracerebral hemorrhage

Abstract

Objective: The aim of the current study is to evaluate if ETB inhibition following ICH can mitigate the deleterious impact of ET-1, e.g., BBB disruption, and improve neurological function. Methods: A total of 90 male rabbits (2.8–3.4 kg) were randomly assigned to the following groups (n = 10 per group): normal control (NC), pseudo-control (PC), drug control using normal saline (DC), model control (MC + ICH), minimally invasive surgery (MIS + ICH), minimally invasive surgery + ET-1 receptor agonist (MIS + IRL1620 + ICH), IRL1620 + ICH, ET-1 receptor antagonist (BQ788 + ICH), and IS + BQ788 + ICH. ICH was induced in all groups except for NC, DC and PC groups.In MIS, MIS + BQ788, and MIS + IRL1620 groups, at the 6-hour mark following ICH, MIS was used to evacuate the hematoma followed by immediate drug (BQ788 or IRL1620 or saline) injection into the ear vein. On day 3, all rabbits were evaluated by purdy score and then sacrificed. The perihematomal brain tissue was removed to determine the expression of ET-1 and MMP-9 by immunohistochemical procedures. MDA expression was evaluated by ELISA, and BBB permeability was evaluated using Evens Blue (EB) methods. Brain water was determined using a dry-wet weighing method. Results: The purdy score, ET-1, MDA, MMP-9, BWC, and BBB permeability were decreased in groups treated with BQ788 and increased in groups treated with IRL1620. The combination of MIS + BQ788 markedly decreased these deleterious outcomes (purdy score, ET-1, MDA, MMP-9, BWC, and BBB permeability) compared to the MIS group. Conclusions: Using a non-selective antagonist of ETB, deleterious outcomes associated with increased levels of ET-1 following ICH were ameliorated.

Keywords

• Intracerebral hemorrhage
• Endothelin-1
• ETB receptor
• Malondialdehyde
• Matrix metalloproteinase-9