Umbelliferone prevents oxidative stress, inflammation and hematological alterations, and modulates glutamate-nitric oxide-cGMP signaling in hyperammonemic rats.

Abstract

Hepatic encephalopathy (HE) is a serious neuropsychiatric complication that occurs as a result of liver failure. Umbelliferone (UMB; 7-hydroxycoumarin) is a natural product with proven hepatoprotective activity; however, nothing has yet been reported on its protective effect against hyperammonemia, the main culprit behind the symptoms of HE. Here, we evaluated the effect of UMB against ammonium chloride (NH4Cl)-induced hyperammonemia, oxidative stress, inflammation and hematological alterations in rats. We demonstrated the modulatory role of UMB on the glutamate-nitric oxide (NO)-cGMP pathways in the cerebrum of rats. Rats received intraperitoneal injections of NH4Cl (3 times/week) for 8 weeks and concomitantly received 50 mg/kg UMB. NH4Cl-induced rats showed significantly elevated blood ammonia and liver function markers. Lipid peroxidation and NO were increased in the liver and cerebrum of rats while the antioxidant defenses were declined. UMB significantly reduced blood ammonia, liver function markers, lipid peroxidation and NO, and enhanced the antioxidant defenses in NH4Cl-induced rats. UMB significantly prevented anemia, leukocytosis, thrombocytopenia and prolongation of PT and aPTT. Hyperammonemic rats showed elevated levels of cerebral TNF-α, IL-1β and glutamine as well as increased activity and expression of Na+/K+-ATPase, effects that were significantly reversed by UMB. In addition, UMB down-regulated nitric oxide synthase and soluble guanylate cyclase in the cerebrum of hyperammonemic rats. In conclusion, this study provides evidence that UMB protects against hyperammonemia via attenuation of oxidative stress and inflammation. UMB prevents hyperammonemia associated hematological alterations and therefore represents a promising protective agent against the deleterious effects of excess ammonia.

• Authors: Mousa O Germoush, Sarah I Othman, Maha A Al-Qaraawi, Hanan M Al-Harbi, Omnia E Hussein, Gadh Al-Basher, Mohammed F Alotaibi, Hassan A Elgebaly, Mansur A Sandhu, Ahmed A Allam, Ayman M Mahmoud
• Journal: Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie (Biomed Pharmacother) Vol. 102 Pg. 392-402 (Jun 2018) ISSN: 1950-6007 [Electronic] France
• PMID: 29573618 (Publication Type: Journal Article)
• Copyright: Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Chemical References

• Antioxidants
• Biomarkers
• Umbelliferones
• Ammonium Chloride
• Glutamine
• Nitric Oxide
• Glutamic Acid
• Ammonia
• Nitric Oxide Synthase Type I
• Soluble Guanylyl Cyclase
• Sodium-Potassium-Exchanging ATPase
• Cyclic GMP

Topics

• Ammonia (blood)
• Ammonium Chloride
• Anemia (blood, complications, drug therapy, prevention & control)
• Animals
• Antioxidants (metabolism)
• Biomarkers (metabolism)
• Blood Coagulation (drug effects)
• Cerebrum (drug effects, enzymology, pathology)
• Cyclic GMP (metabolism)
• Down-Regulation (drug effects)
• Glutamic Acid (metabolism)
• Glutamine (biosynthesis)
• Hyperammonemia (blood, complications, drug therapy)
• Inflammation (blood, complications, drug therapy, pathology)
• Leukocytosis (blood, complications, drug therapy, prevention & control)
• Lipid Peroxidation (drug effects)
• Liver (pathology, physiopathology)
• Liver Function Tests
• Male
• Nitric Oxide (metabolism)
• Nitric Oxide Synthase Type I (metabolism)
• Oxidative Stress (drug effects)
• Rats, Wistar
• Signal Transduction (drug effects)
• Sodium-Potassium-Exchanging ATPase (metabolism)
• Soluble Guanylyl Cyclase (metabolism)
• Umbelliferones (pharmacology, therapeutic use)