الفهرس 
Introduction and Aim of the WorkOnly 14 pages are availabe for public view
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Abstract
Sepsis, a severe inflammatory response to infection, is still the primary cause of morbidity and mortality in intensive care unit patients worldwide with an incidence rate exceeding 48 million cases and 11 million sepsis-related deaths cases per year. Acute infections in critically ill patients develop systemic inflammatory response syndrome and multiple organ dysfunction syndrome, characterized by liver, lung, cardiovascular, renal, and gastrointestinal dysfunction. The most frequent consequences of sepsis are acute liver and kidney injury. Acute renal damage is developed in about 50% of septic patients, contributing to 70% of septic patient deaths in intensive care unit whereas, the prevalence of sepsis-related liver dysfunction ranged from 34 to 46%, and hepatic failure in septic patients may reach 22%.
The present study was conducted to elucidate the protective impact of Gabapentin through different mechanisms in reducing liver and kidney injury induced by sepsis.
The study involved two separate designs: mechanistic and survival studies. Induction of sepsis was achieved via CLP model. Sixty male Wister rats were randomized into six groups: sham, Gabapentin 100 mg/kg for four days without CLP, CLP-nontreated, CLP-treated by Gabapentin 50 mg/kg for four days before CLP, Gabapentin 100 mg/kg for four days before CLP, and vitamin C 200 mg/kg as a single dose after 1 hour from the CLP surgery. Sham rats experienced the same procedure except for the ligation of the cecum. After twenty-four hours of CLP, rats were sacrificed for blood and tissue sample collection. The same set of groups was applied to a separate number of rats for the survival study, each composed of 10 rats. The period of observation was for 10 days.
Various investigations have been done using liver and kidney tissues as well as serum. These investigations include:
• Serum biochemical investigations involving measurement of liver enzymes (ALT, AST, and ALP) and serum creatinine, and BUN for the assessment of the kidney function.
• Estimation of the oxidative stress (malondialdehyde) and antioxidant status (GSH content and SOD activity) in the liver and kidney tissues.
• Measurement of serum levels of the proinflammatory cytokines (IL1β, TNF-α and IL-6).
• Quantitative real-time PCR investigation for the expression of Bax, Bcl-2, and NF-κB genes in liver and kidney tissue.
• Western blotting analysis for the expression of the hepatic p/t JNK 1/2, p/t ERK 1/2, and cleaved caspase 3 proteins and renal Nrf-2 and HO-1 proteins.
• Histopathological examination of liver and kidney tissues of rats from each group.
The present study demonstrated that the induction of sepsis via CLP produced harmful effects on the liver and kidney in both structure and function. The histopathological changes were observed in septic rats compared to normal rats. These changes were associated with increased serum liver enzymes, serum creatinine, BUN, oxidative stress, as shown by increased levels of tissue MDA, and reduced activity of SOD with a low level of GSH.
Moreover, the serum pro-inflammatory cytokines (IL1β, TNF-α, and IL-6) were elevated and the stimulation of the expression of Bax, Bcl-2, and NF-κB genes in the septic rats was observed. Additionally, sepsis induced the expression of phosphorylated JNK 1/2, phosphorylated ERK 1/2, cleaved caspase 3, Nrf-2, and HO-1 proteins. Furthermore, CLP-rats were associated with a high mortality.
Treatment with Gabapentin (50 mg/kg), Gabapentin (100 mg/kg), or vitamin C (200 mg/kg), as positive control, attenuated the biochemical changes in the septic livers and kidneys. Rats treated with Gabapentin showed improvement in survival with the restoration of normal architecture and normal functions in both liver and kidney.
In addition, Gabapentin prevented the sepsis-induced elevation in tissue oxidative stress, which was demonstrated as a decrease in MDA content and a rise in the activity of SOD and GSH levels and reduced the serum levels of proinflammatory cytokines (IL1β, TNF-α, and IL-6).
Furthermore, the relative gene expression of Bax, Bcl-2, and NF-κB was ameliorated in the septic rats treated by Gabapentin. Additionally, Gabapentin decreased the expression of phosphorylated JNK 1/2, phosphorylated ERK 1/2, cleaved caspase 3, Nrf-2, and HO-1 proteins.
In conclusion, the current study introduces strong evidence of the impact of Gabapentin on CLP-induced sepsis related acute liver and kidney injury. These effects are related to its antioxidant, anti-inflammatory, and anti-apoptotic effects. Thus, the present study suggests the promising activity of Gabapentin as a pre-operative agent to reduce the risk of sepsis after abdominal surgeries. However, more studies are needed to confirm its clinical beneficial effects.