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

Background: of the study: Hepatic encephalopathy (HE) is a complication in which brain ammonia (NH4+) levels reach critically high concentrations because of liver failure. HE could lead to a range of neurological complications from locomotor and behavioral disturbances to coma. Several tactics have been established for subsiding blood and brain NH4+. However, there is no precise intervention to mitigate the direct neurological complications of NH4+. Purpose: It has been found that oxidative stress, mitochondrial damage, and neuro-inflammation play a fundamental role in NH4+ neurotoxicity. Piracetam is a drug used clinically in neurological complications such as stroke and head trauma. Piracetam could significantly diminish oxidative stress and improve brain mitochondrial function. Research methods: In the current study, piracetam (100 and 500 mg/kg, oral) was used in a mice model of HE induced by thioacetamide (TA, 800 mg/kg, single dose, i.p). Results: Significant disturbances in animals' locomotor activity, along with increased oxidative stress biomarkers, including reactive oxygen species formation, protein carbonylation, lipid peroxidation, depleted tissue glutathione, and decreased antioxidant capacity, were evident in the brain of TA-treated mice. Meanwhile, mitochondrial permeabilization, mitochondrial depolarization, suppression of dehydrogenases activity, and decreased ATP levels were found in the brain of the TA group. The level of pro-inflammatory cytokines was also significantly high in the brain of HE animals. Conclusion: It was found that piracetam significantly enhanced mice's locomotor activity, blunted oxidative stress biomarkers, decreased inflammatory cytokines, and improved mitochondrial indices in hyperammonemic mice. These data suggest piracetam as a neuroprotective agent which could be repurposed for the management of HE.

Low-dose ketamine improves animals' locomotor activity and decreases brain oxidative stress and inflammation in ammonia-induced neurotoxicity.

Ammonium ion (NH4 + ) is the major suspected molecule responsible for neurological complications of hepatic encephalopathy (HE). No specific pharmacological action for NH4 + -induced brain injury exists so far. Excitotoxicity is a well-known phenomenon in the brain of hyperammonemic cases. The hyperactivation of the N-Methyl- d-aspartate (NMDA) receptors by agents such as glutamate, an NH4 + metabolite, could cause excitotoxicity. Excitotoxicity is connected with events such as oxidative stress and neuroinflammation. Hence, utilizing NMDA receptor antagonists could prevent neurological complications of NH4 + neurotoxicity. In the current study, C57BL6/J mice received acetaminophen (APAP; 800 mg/kg, i.p) to induce HE. Hyperammonemic animals were treated with ketamine (0.25, 0.5, and 1 mg/kg, s.c) as an NMDA receptor antagonist. Animals' brain and plasma levels of NH4 + were dramatically high, and animals' locomotor activities were disturbed. Moreover, several markers of oxidative stress were significantly increased in the brain. A significant increase in brain tissue levels of TNF-α, IL-6, and IL-1ß was also detected in hyperammonemic animals. It was found that ketamine significantly normalized animals' locomotor activity, improved biomarkers of oxidative stress, and decreased proinflammatory cytokines. The effects of ketamine on oxidative stress biomarkers and inflammation seem to play a key role in its neuroprotective mechanisms in the current study.

Cholestasis-Associated Pulmonary Inflammation, Oxidative Stress, and Tissue Fibrosis: The Protective Role of the Biogenic Amine Agmatine.

INTRODUCTION: Cholestasis is the stoppage of bile flow, leading to the accumulation of potentially cytotoxic bile components in the liver. These cytotoxic molecules affect many organs. Cholestasis-induced lung injury is a severe complication that could lead to tissue fibrosis and respiratory distress. Substantial evidence indicates the role of oxidative stress and inflammatory response in the pathogenesis of cholestasis-associated pulmonary damage. Agmatine (AGM; 1-amino-4-guanidinobutane) is a biogenic amine endogenously synthesized in the human body. This amine provides potent anti-inflammatory and antioxidant properties. METHODS: In the current study, a series (six C57BL/6J male mice/group) of bile duct-ligated (BDL) animals were monitored at scheduled intervals (7, 14, and 28 days after the BDL operation) to ensure inflammatory response in their lung tissue (by analyzing their bronchoalveolar lavage fluid [BALF]). It was found that the level of inflammatory cells, pro-inflammatory cytokines, and IgG in the BALF reached their maximum level on day 28 after the BDL surgery. Therefore, other research groups were selected as follows: 1) Sham-operated (2.5 mL/kg normal saline, i.p., for 28 consecutive days), 2) BDL, 3) BDL + AGM (1 mg/kg/day, i.p., for 28 consecutive days), and 4) BDL + AGM (10 mg/kg/day, i.p., for 28 consecutive days). Then, the BALF was monitored at scheduled time intervals (7, 14, and 28 days post-BDL). RESULTS: It was found that pro-inflammatory cytokines (TNF-α, IL-6, and IL-1ß), bile acids, bilirubin, and inflammatory cells (monocytes, neutrophils, and lymphocytes) were significantly increased in the BALF of BDL mice. Moreover, biomarkers of oxidative stress were significantly increased in the pulmonary tissue of cholestatic animals. Lung tissue histopathological changes, tissue collagen deposition, and increased TGF-ß were also detected. It was found that AGM significantly ameliorated cholestasis-induced lung injury. CONCLUSION: The effects of AGM on inflammatory indicators, oxidative stress biomarkers, and tissue fibrosis seem to play a pivotal role in its protective properties.

Cirrhosis-induced oxidative stress in erythrocytes: The therapeutic potential of taurine.

Aim of the study: Cholestasis/cirrhosis could induce erythrocyte lysis. The incidence of various types of anemia in cirrhosis is approx. 75%. Several studies have mentioned the pivotal role of oxidative stress in this complication. Taurine (TAU) is the human body's most abundant free amino acid. TAU is known as a robust cell membrane stabilizer. Many studies have mentioned that TAU could counteract oxidative stress in various experimental models. The current study was intended to evaluate the effect of TAU on erythrocytes in cirrhotic rats. Material and methods: Bile duct ligation (BDL) surgery was carried out on rats. Then, complete blood count (CBC), hemoglobin (Hgb), hematocrit (HTC), and erythrocytes' G6PD, catalase (CAT), and superoxide dismutase (SOD) activity were measured. Moreover, biomarkers of oxidative stress were assessed, and the erythrocytes' morphological changes were monitored in the cirrhotic mice exposed to TAU (0.25%, 0.5%, and 1% w : v in drinking water). Results: Significant changes in the assessed erythrocyte parameters (G6PD activity, Hgb, HTC, and erythrocyte count) and red blood cells (RBC) morphological alterations were detected on day 42 after BDL surgery. Biomarkers of oxidative stress also did not change at the time points, except on post-BDL days 28 and 42. A significant decrease in blood parameters was evident at post-BDL day 42. All doses of TAU (0.25%, 0.5%, and 1% w : v in drinking water) significantly improved erythrocyte parameters and encountered oxidative stress in the erythrocytes of cirrhotic animals. Conclusions: These data indicate that TAU could be a safe agent to mitigate cirrhosis-induced erythrocyte damage and anemia. Further investigations are necessary to prove this in clinical settings.

Pulmonary inflammation, oxidative stress, and fibrosis in a mouse model of cholestasis: the potential protective properties of the dipeptide carnosine.

Cholestasis is a clinical complication that primarily influences the liver. However, it is well known that many other organs could be affected by cholestasis. Lung tissue is a major organ influenced during cholestasis. Cholestasis-induced lung injury could induce severe complications such as respiratory distress, serious pulmonary infections, and tissue fibrosis. Unfortunately, there is no specific pharmacological intervention against this complication. Several studies revealed that oxidative stress and inflammatory response play a role in cholestasis-induced lung injury. Carnosine (CARN) is a dipeptide found at high concentrations in different tissues of humans. CARN's antioxidant and antiinflammatory properties are repeatedly mentioned in various experimental models. This study aimed to assess the role of CARN on cholestasis-induced lung injury. Rats underwent bile duct ligation (BDL) to induce cholestasis. Broncho-alveolar lavage fluid (BALF) levels of inflammatory cells, pro-inflammatory cytokines, and immunoglobulin were monitored at scheduled intervals (7, 14, and 28 days after BDL). Moreover, lung tissue histopathological alterations and biomarkers of oxidative stress were evaluated. A significant increase in BALF inflammatory cells, TNF-α, IL-1ß, IL-6, and immunoglobulin-G (IgG) was detected in the BALF of BDL rats. Moreover, lung tissue histopathological changes, collagen deposition, increased TGF-ß, and elevated levels of oxidative stress biomarkers were evident in cholestatic animals. It was found that CARN (100 and 500 mg/kg, i.p.) significantly alleviated lung oxidative stress biomarkers, inflammatory response, tissue fibrosis, and histopathological alterations. These data indicate the potential protective properties of CARN in the management of cholestasis-induced pulmonary damage. The effects of CARN on inflammatory response and oxidative stress biomarkers seems to play a crucial role in its protective properties in the lung of cholestatic animals.

Taurine Improves Sperm Mitochondrial Indices, Blunts Oxidative Stress Parameters, and Enhances Steroidogenesis and Kinematics of Sperm in Lead-Exposed Mice.

Lead (Pb) is a highly toxic heavy metal. Pb exposure could adversely affect many organs, including the male reproductive system. Oxidative stress and mitochondrial impairment play a fundamental role in the pathogenesis of Pb-induced male reproductive system injury. Taurine (TAU) is abundantly found in mammalian bodies. The positive effects of TAU on oxidative stress biomarkers and mitochondrial function have been reported. The current study evaluated the effects of TAU on Pb-induced reproductive toxicity. Mice received Pb (20 mg/kg/day; gavage, 35 consecutive days). Then, sperm indices (quality and quantity) together with sperm kinetics, sperm mitochondrial parameters, testicular and sperm oxidative stress biomarkers, testis and plasma testosterone levels, and the expression of genes involved in the steroidogenesis process have been evaluated. Pb caused significant histopathological alterations and oxidative stress in male mice's reproductive system and sperm. Moreover, significant mitochondrial function impairment was evident in sperm isolated from Pb-treated mice. Pb exposure also suppressed the expression of StAR, 17ß-HSD, CYP11A, and 3ß-HSD genes in the male gonad. It was found that TAU (500 and 1000 mg/kg) significantly improved oxidative stress biomarkers in both male gonads and gametes of Pb-treated mice. TAU also significantly restored sperm mitochondrial function and kinetics. The expression of genes involved in steroidogenesis was also higher in TAU-treated animals. These data suggest TAU as an effective agent against Pb-induced reproductive toxicity. The effects of TAU on oxidative stress markers, mitochondrial function, and the steroidogenesis process seem to play a fundamental role in its protective properties. Further studies are warranted to detect the precise protective effects of this amino acid in the reproductive system. Lead (Pb) is a toxic element that adversely affects the male reproductive system. Mitochondrial impairment and oxidative stress have a crucial role in the Pb-induced reproductive toxicity. Taurine (TAU) could considerably improve the reproductive toxicity induced by Pb via enhancing mitochondrial function and mitigating oxidative stress indices. ΔΨ, mitochondrial membrane potential; ATP, adenosine triphosphate.