Abstract
Hyperammonemia is a serious complication of liver disease and may lead to encephalopathy and death. This study investigated the effects of Commiphora molmol resin on oxidative stress, inflammation, and hematological alterations in ammonium chloride- (NH4Cl-) induced hyperammonemic rats, with an emphasis on the glutamate-NO-cGMP and Nrf2/ARE/HO-1 signaling pathways. Rats received NH4Cl and C. molmol for 8 weeks. NH4Cl-induced rats showed significant increase in blood ammonia, liver function markers, and tumor necrosis factor-alpha (TNF-α). Concurrent supplementation of C. molmol significantly decreased circulating ammonia, liver function markers, and TNF-α in hyperammonemic rats. C. molmol suppressed lipid peroxidation and nitric oxide and enhanced the antioxidant defenses in the liver, kidney, and cerebrum of hyperammonemic rats. C. molmol significantly upregulated Nrf2 and HO-1 and decreased glutamine and nitric oxide synthase, soluble guanylate cyclase, and Na+/K+-ATPase expression in the cerebrum of NH4Cl-induced hyperammonemic rats. Hyperammonemia was also associated with hematological and coagulation system alterations. These alterations were reversed by C. molmol. Our findings demonstrated that C. molmol attenuates ammonia-induced liver injury, oxidative stress, inflammation, and hematological alterations. This study points to the modulatory effect of C. molmol on glutamate-NO-cGMP and Nrf2/ARE/HO-1 pathways in hyperammonemia. Therefore, C. molmol might be a promising protective agent against hyperammonemia.
Highlights
Hepatic encephalopathy (HE) is a serious complication of both acute and chronic liver diseases [1, 2]
Hyperammonemic rats showed a significant (P < 0 001) increase in blood ammonia when compared with the control group of rats
C. molmol has showed multiple therapeutic effects; nothing has yet been reported on its protective effect against hyperammonemia
Summary
Hepatic encephalopathy (HE) is a serious complication of both acute and chronic liver diseases [1, 2]. HE has been estimated to occur in 10–50% of patients with transjugular intrahepatic portosystemic shunt and 30–45% of patients with cirrhosis, whereas minimal HE affects 20–60% of patients with liver disease [3]. The pathological mechanism of HE is not fully understood, ammonia is known to play a key role in HE [4]. Ammonia is a known neurotoxin and induces harmful effects to the central nervous system [5]. Blood ammonia level is strongly correlated with the Oxidative Medicine and Cellular Longevity increased risk of HE and is used as a diagnostic marker for encephalopathy [6]. Ammonia is normally detoxified in the liver via urea cycle, and if does not proceed properly, as in cases of liver failure or congenital defect of the urea cycle enzymes, ammonia increases and lead to HE [7]
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