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  • 1
    Online Resource
    Online Resource
    Association between vasoactive peptide urotensin II in plasma and cerebral vasospasm after aneurysmal subarachnoid hemorrhage: a potential therapeutic target
    Journal of Neurosurgery Publishing Group (JNSPG) ; 2019
    In:  Journal of Neurosurgery Vol. 131, No. 4 ( 2019-10), p. 1278-1288
    Details
    In: Journal of Neurosurgery, Journal of Neurosurgery Publishing Group (JNSPG), Vol. 131, No. 4 ( 2019-10), p. 1278-1288
    Abstract: Cerebral 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. METHODS A 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. RESULTS In 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. CONCLUSIONS The 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.
    Type of Medium: Online Resource
    ISSN: 0022-3085 , 1933-0693
    URL: Article
    DOI: 10.3171/2018.4.JNS172313
    RVK:
    XA 10000
    RVK:
    XA 55270
    Language: Unknown
    Publisher: Journal of Neurosurgery Publishing Group (JNSPG)
    Publication Date: 2019
    detail.hit.zdb_id: 2026156-1
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  • 2
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    Online Resource
    Urantide Improves Cardiac Function, Modulates Systemic Cytokine Response, and Increases Survival in A Murine Model of Endotoxic Shock
    Ovid Technologies (Wolters Kluwer Health) ; 2020
    In:  Shock Vol. 54, No. 4 ( 2020-10), p. 574-582
    Details
    In: Shock, Ovid Technologies (Wolters Kluwer Health), Vol. 54, No. 4 ( 2020-10), p. 574-582
    Abstract: Urotensin II is a potent vasoactive peptide activating the the G protein-coupled urotensin II receptor UT, and is involved in systemic inflammation and cardiovascular functions. The aim of our work was to study the impact of the UT antagonist urantide on survival, systemic inflammation, and cardiac function during endotoxic shock. Methods: C57Bl/6 mice were intraperitoneally injected with lipopolysaccharide (LPS) and then randomized to be injected either by urantide or NaCl 0.9% 3, 6, and 9 h (H3, H6, H9) after LPS. The effect of urantide on the survival rate, the levels of cytokines in plasma at H6, H9, H12, the expression level of nuclear factor-kappa B (NF-κB-p65) in liver and kidney (at H12), and the cardiac function by trans-thoracic echocardiography from H0 to H9 was evaluated. Results: Urantide treatment improved survival (88.9% vs. 30% on day 6, P 〈 0.05). This was associated with changes in cytokine expression: a decrease in IL-6 (2,485 [2,280–2,751] pg/mL vs. 3,330 [3,119–3,680] pg/mL, P 〈 0.01) at H6, in IL-3 (1.0 [0.40–2.0] pg/mL vs. 5.8 [3.0–7.7] pg/mL, P 〈 0.01), and IL-1β (651 [491–1,135] pg/mL vs. 1,601 [906–3,010] pg/mL, P 〈 0.05) at H12 after LPS administration. Urantide decreased the proportion of cytosolic NF-κB-p65 in liver (1.3 [0.9–1.9] vs. 3.2 [2.3–4] , P 〈 0.01) and kidney (0.3 [0.3–0.4] vs. 0.6 [0.5–1.1] , P 〈 0.01). Urantide improved cardiac function (left ventricular fractional shortening: 24.8 [21.5–38.9] vs. 12.0 [8.7–17 .6] %, P 〈 0.01 and cardiac output: 30.3 [25.9–39.8] vs. 15.1 [13.0–16.9] mL/min, P 〈 0.0001). Conclusion: These results show a beneficial curative role of UT antagonism on cytokine response (especially IL-3), cardiac dysfunction, and survival during endotoxic shock in mice, highlighting a potential new therapeutic target for septic patients.
    Type of Medium: Online Resource
    ISSN: 1073-2322 , 1540-0514
    URL: Article
    DOI: 10.1097/SHK.0000000000001448
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2020
    detail.hit.zdb_id: 2011863-6
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