الفهرس 
TitleOnly 14 pages are availabe for public view
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Abstract
Despite new medical and surgical therapies available and used today, OJ still has high morbidity and mortality rates. The excessive presence of endotoxins in portal and systemic circulation stimulates the systemic inflammatory response, which leads to structural and functional deleterious effects on remote organs, especially on the kidneys, lungs, Brain and heart, resulting in multiple organ dysfunction syndrome.
Cholestasis is now recognized as a disorder characterized by liver oxidants overload. Furthermore, the oxidative stress in cholestatic liver disease is a systemic phenomenon probably encompassing all tissues and organs, even those separated by the blood-brain barrier. Similarly, oxidative stress plays an important role in the pathogenesis of toxic tissue injury. Antioxidants derived from plants and other living organisms have the potential to inhibit the formation of free radicals, scavenge free radicals, interrupt free radical chain reaction, and prevent the lipid peroxidation process. Thus, natural antioxidants have the ability to decrease the deleterious effects of oxidative stress-induced pathological conditions. The use of natural antioxidants for the prevention and cure of human diseases has been practiced for thousands of years prior to the development of modern medicine with synthetic drugs and antioxidants. Most of these natural antioxidants have been scientifically proven as potential therapeutic agents in preclinical studies. Nowadays, an increase in healthy lifestyle has resulted in the routine consumption of natural ingredients over synthetic agents. The aim of the current study is to examine the effect of Ferulic acid (hydroxycinnamic acid, an organic compound. It is an abundant phenolic phytochemical found in plant cell walls), alpha lipoic acid (natural dithiol compound which is known as a co-factor in the a- ketoacid dehydrogenase mitochondrial complex and for its complex antioxidant properties) when administered alone and in combination on brain oxidative stress of BDL rats. We also sought of evaluating the activity of this combination on inflammation and apoptosis in brain as possible mechanisms involved as a result of OJ.
Six to eight weeks old male albino rats were divided in to:
- Negative control group: Rats in this group received saline at alkaline pH (7.8).
- Sham operated group: Dissection of the common bile duct but no ligature to rats was done.
- Treatment of 4 groups 1 day prior to induction of OJ
- Positive control group: Rats received the corresponding vehicle (saline at alkaline pH 7.8).
- Ferulic acid treated group: Rats were treated with ferulic acid in a dosage of 25 mg/Kg orally.
- Alpha lipoic acid treated group: Rats were treated with LA in a dosage of 25 mg/Kg Subcutaneously (SC).
- Combination group: Rats received the combination of both FA in a dosage 25 mg/Kg orally and LA in a dosage of 25 mg/Kg SC.
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On the seventh day, animals of all groups were weighted and scarificed by cervical decapitation under general anaesthesia. Blood samples were collected and the serum was separated. The liver was isolated and chilled on ice and the brain was isolated and dissected where the cortex, cerebellum and hypothalamus areas were removed and immediately frozen at -80 °C until measurements of laboratory parameters.
The parameters that were determined are:
In the serum:
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities.
Alkaline phosphatase activity.
Total bilirubin level.
In the liver:
Malondialdehyde level (MDA).
Reduced glutathione concentration (GSH).
In the brain:
Malondialdehyde level (MDA)
Reduced glutathione concentration (GSH)
Tumor necrosis factor alpha ( TNF-alpha) levels.
Caspase-3.
As regards to induction of obstructive jaundice, examination of serum of BDL rats showed an elevation in some biochemical markers as (ALT, AST, AP and bilirubin) which are the hallmark of cholestasis. On the other hand, all treatments given one day prior to BDL for 7 consecutive days, succeeded to decrease cholestatic markers in serum in each of ferulic acid, alpha lipoic acid and combination groups. A more favorable response was obtained in the mono-administration in ferulic acid group.
MDA and reduced glutathione (GSH) were used for the assessment of oxidative stress in liver tissues and different areas of brain tissue (cerebellum, cortex and hypothalamus). MDA levels was significantly increased in both tissues of positive control untreated groups compared to normal and sham groups. Reduced glutathione (GSH) levels was significantly decreased in both tissues of BDL group of rats (positive control) compared to normal and sham controls, supporting their reported crucial role in oxidative stress as result of BDL and induction of OJ. Results of the present study demonstrated that the probed drugs significantly decreased MDA levels in hepatic and brain tissues and increased GSH levels in both tissues, elucidating their antioxidant potential and their ability to alleviate oxidative stress. Combination treatment showed a synergistic reduction MDA levels and elevation of GSH levels significantly more than any of the monotherapies, illustrating a more efficient antioxidant effect.
Tumor necrosis factor alpha (TNF-alpha) expression in the brain is well established to be involved in inflammation as a result of ROS, thus its suppression or reduction could be a therapeutic target for brain protection against oxidative stress induced by OJ. Compared to the positive control group, all preventive regimens induced a significant decrease in TNF-
Summary
95
alpha in areas of brain studied (cerebellum, cortex and hypothalamus). Noteworthy, alpha lipoic acid showed the highest reduction among monotherapies utilized when compared to positive control group. The highest significant decrease in TNF-alpha level in brain among the studied groups has occurred in the combination group, demonstrating a potent anti-inflammatory effect when combining different anti-inflammatory drugs.
Strong anti-apoptotic activity has been demonstrated by alpha lipoic acid which induced a significant reduction in caspase 3 levels which is responsible for execution phase in apoptosis. Combination treatment succeeded to induce the highest significant reduction in caspase 3 levels compared to monotherapies.
Collectively, these results referred to the strong antioxidant, anti-inflammatory and anti-apoptotic activities of the studied drugs as targeted pathways for the protection of brain against OJ induced oxidative stress. Administration of ferulic acid in combination with alpha lipoic acid synergistically protected the brain against oxidative stress which may be due to different antioxidant mechanisms of the tested drugs targeting ROS. Moreover, the combination treatment showed stronger anti-inflammatory and anti-apoptotic activities in the brain compared to each of the probed drug.
Thus, this combination offers an advantage of more pronounced and effective preventive efficacy. Noteworthy was the fact that these inhibitory effects were achieved at clinically comparable low doses. Since these agents are currently used in clinical practice without any serious adverse effects, therefore this combination regimen may represent a potential new strategy for brain protection against oxidative stress induced by OJ in the future.