Association between vasoactive peptide urotensin II in plasma and cerebral vasospasm after aneurysmal subarachnoid hemorrhage: a potential therapeutic target.
Fiche publication
Date publication
octobre 2018
Journal
Journal of neurosurgery
Auteurs
Membres identifiés du Cancéropôle Est :
Pr PROUST François
Tous les auteurs :
Clavier T, Mutel A, Desrues L, Lefevre-Scelles A, Gastaldi G, El Amki M, Dubois M, Melot A, Wurtz V, Curey S, Gérardin E, Proust F, Compère V, Castel H
Lien Pubmed
Résumé
OBJECTIVECerebral vasospasm (VS) is a severe complication of aneurysmal subarachnoid hemorrhage (SAH). Urotensin II (UII) is a potent vasoactive peptide activating the urotensin (UT) receptor, potentially involved in brain vascular pathologies. The authors hypothesized that UII/UT system antagonism with the UT receptor antagonist/biased ligand urantide may be associated with post-SAH VS. The objectives of this study were 2-fold: 1) to leverage an experimental mouse model of SAH with VS in order to study the effect of urotensinergic system antagonism on neurological outcome, and 2) to investigate the association between plasma UII level and symptomatic VS after SAH in human patients.METHODSA mouse model of SAH was used to study the impacts of UII and the UT receptor antagonist/biased ligand urantide on VS and neurological outcome. Then a clinical study was conducted in the setting of a neurosurgical intensive care unit. Plasma UII levels were measured in SAH patients daily for 9 days, starting on the 1st day of hospitalization, and were compared with plasma UII levels in healthy volunteers.RESULTSIn the mouse model, urantide prevented VS as well as SAH-related fine motor coordination impairment. Seventeen patients with SAH and external ventricular drainage were included in the clinical study. The median plasma UII level was 43 pg/ml (IQR 14-80 pg/ml). There was no significant variation in the daily median plasma UII level (median value for the 17 patients) from day 0 to day 8. The median level of plasma UII during the 9 first days post-SAH was higher in patients with symptomatic VS than in patients without VS (77 pg/ml [IQR 33.5-111.5 pg/ml] vs 37 pg/ml [IQR 21-46 pg/ml], p < 0.05). Concerning daily measures of plasma UII levels in VS, non-VS patients, and healthy volunteers, we found a significant difference between SAH patients with VS (median 66 pg/ml [IQR 30-110 pg/ml]) and SAH patients without VS (27 pg/ml [IQR 15-46 pg/ml], p < 0.001) but no significant difference between VS patients and healthy volunteers (44 pg/ml [IQR 27-51 pg/ml]) or between non-VS patients and healthy volunteers.CONCLUSIONSThe results of this study suggest that UT receptor antagonism with urantide prevents VS and improves neurological outcome after SAH in mice and that an increase in plasma UII is associated with cerebral VS subsequent to SAH in humans. The causality link between circulating UII and VS after SAH remains to be established, but according to our data the UT receptor is a potential therapeutic target in SAH.
Mots clés
ACA = anterior cerebral artery, AUC = area under the curve, CSF = cerebrospinal fluid, DCI = delayed cerebral ischemia, EVD = external ventricular drainage, ICU = intensive care unit, IQR = interquartile range, IRB = institutional review board, MCA = middle cerebral artery, ROC = receiver operating characteristic, SAH = subarachnoid hemorrhage, SAPS II = Simplified Acute Physiology Score II, SE = standard error, UII = urotensin II, UT = urotensin (receptor), VS = vasospasm, WFNS = World Federation of Neurosurgical Societies, cerebral vasospasm, human, intensive care unit, mRS = modified Rankin Scale, mouse, subarachnoid hemorrhage, urotensin II, vascular disorders
Référence
J Neurosurg. 2018 10 1;:1-11