Dextromethorphan improves locomotor activity and decreases brain oxidative stress and inflammation in an animal model of acute liver failure

Abstract

Introduction: Hepatic encephalopathy (HE) is a serious clinical problem leading to severe neurological disorders and death. No specific treatment is available for the management of HE-associated neurological damage. This study aimed to evaluate the effect of dextromethorphan (DXM) on oxidative stress and disturbed locomotor activity in an animal model of HE. Material and methods: In the current study, BALB/c mice received acetaminophen (APAP; 1000 mg/kg, intraperitoneally [IP]). Dextromethorphan (0.5, 1, 5, 10 mg/kg, subcutaneously [SC]) was injected in three doses (every 6 h), starting two hours after acetaminophen. Animals' locomotor activity, brain and plasma ammonia levels, as well as biomarkers of oxidative stress and inflammatory cytokines in the brain tissue, were assessed 24 hours after acetaminophen injection. Results: It was found that APAP administration was significantly associated with liver damage and increased plasma biomarkers of liver injury. Ammonia levels in plasma and brain tissue of APAP-treated mice also increased significantly. There was also a significant difference in motor activity between the control and APAP-treated animals. The acute liver injury also increased the brain level of pro-inflammatory cytokines (tumor necrosis factor α [TNF-α], interleukin 6 [IL-6], and interleukin 1β ). It was found that DXM could significantly improve the motor activity of animals in all doses and decrease the biomarkers of inflammation and oxidative stress in the brain tissue of animals with hyperammonemia. Conclusions: The effect of dextromethorphan on oxidative stress and inflammation seems to be a major mechanism for its neuroprotective properties in HE. Based on these data DXM could be applied as an effective pharmacological option against HE-associated brain injury.

Mitochondrial Impairment and Oxidative Stress Are Essential Mechanisms Involved in the Pathogenesis of Acute Kidney Injury

“…Samples were mixed considerably and centrifuged (10,000 ×g, 20 min, 25°C). Finally, absorbance of the upper phase was measured (λ = 532 nm) (9,(71)(72)(73)(74).…”

Hepatic encephalopathy complications are diminished by piracetam via the interaction between mitochondrial function, oxidative stress, inflammatory response, and locomotor activity

“…When the liver fails to metabolize NH 4 + to urea, the plasma and brain level of this neurotoxic molecule is significantly increased. Increased brain NH 4 + could lead to various complications, including neural and astrocyte cell death, neuroinflammation, severe oxidative stress, mitochondrial impairment, brain edema, and increased intracranial pressure [ [5] , [6] , [7] , [8] ]. Moreover, a wide range of behavioral and locomotor disturbances are also attributed to HE [ 7 , [9] , [10] , [11] ].…”

Protection of pancreatic islets from oxidative cell death by a peripherally-active morphinan with increased drug safety

“…Since oxidative stress plays a central role in beta cell failure and death and thus in the pathogenesis of diabetes and its complications, antioxidant agents are of great interest during the development of new antidiabetic medication. In this regard, it is of interest that DXM has been described to reduce oxidative stress in several tissues, probably by reducing NADPH oxidase (NOX) activity [ 7 , 9 , [28] , [29] , [30] ].…”