كلية الصيدلة.

Faculty of Pharmacy

For the degree of Master in Pharmaceutical Sciences
(Biochemistry).

Includes Bibliographic Referances.

Abstract
This study aimed to investigate the potential role of grape seed extract (GSE) or ginseng extract (G115®) to protect against some Alzheimer-like neurodegenerative disorders accompanying type 2 diabetes mellitus (T2DM), and to make a comparison between the efficiency of the 2 extracts regarding the measured parameters. Induction of T2DM was done by feeding rats high-fat diet followed by intraperitoneal injection of small single dose of streptozotocin (45 mg/kg body weight). Rats were then randomized into three groups; diabetic control, diabetic + GSE-treated and diabetic + G115®-treated. Daily oral administration of the extracts (100 mg/kg body weight each) was started after diagnosis of T2DM (one week after STZ injection), and continued for 6 consecutive months. Normal control rats were fed normal pellet diet for the whole study.
Results have shown that type 2 diabetic rats were suffering from elevated blood glucose, total cholesterol, triglycerides and glycated hemoglobin levels. Furthermore, the diabetic brain cortices showed decreased level of acetylcholine (ACh), elevated amyloid precursor protein (APP) gene expression, amyloid β1-42 (Aβ1-42) and hyperphosphorylated tau (p-tau) contents. This was in addition to elevated brain cortical tumor necrosis factor-α (TNF-α) and malondialdehyde (MDA) contents, and diminished reduced glutathione (GSH) content. These results indicated the occurrence of Alzheimer-like neurodegeneration in brain cortices of the studied type 2 diabetic rats.
Administration of GSE or G115® caused significant modulation of T2DM-induced metabolic disturbances, manifested by lowering serum levels of glucose, total cholesterol, triglycerides and blood glycated hemoglobin. Both extracts ameliorated type 2 diabetic Alzheimer-like neurodegeneration as seen in elevating ACh content, and decreasing brain cortical APP gene expression, Aβ1-42 and p-tau contents. Both exrtacts also succeeded to diminish TNF-α and MDA contents, and to elevate GSH content. When comparing both extracts together, it was found that G115® extract was significantly more potent to decrease APP mRNA expression than GSE. Meanwhile, GSE was significantly more effective to decrease MDA levels than G115® extract. It could be concluded that administration of GSE or G115® could be used to guard against the Alzheimer-like neurodegeneration induced by T2DM during the experimental period.
Key words: Type 2 diabetes mellitus; central neurodegeneration; Alzheimer’s disease; grape seed extract; ginseng extract, G115®.
Introduction and aim of the work
Type 2 diabetes mellitus (T2DM) is a metabolic disorder that is characterized by impaired insulin secretion and variable degrees of peripheral insulin resistance leading to hyperglycemia. Early symptoms are related to hyperglycemia, and include polyuria, polydipsia, and polyphagia. Later complications involve blurred vision, central and peripheral neuropathy, vascular diseases, and predisposition to infection (Eckel et al., 2011). Although long-term complications of diabetes develop gradually, they can eventually be disabling or even life-threatening.
One of the complications that accompany T2DM is Alzheimer's disease (AD), one of the major neurodegenerative disorders. Several studies have shown that patients suffering from T2DM with insulin resistance have a 30-65% increased risk for developing AD (Arvanitakis et al., 2004; Biessels et al., 2004; Burdo et al., 2009).
Alzheimer’s disease and T2DM are conditions that affect a large number of people in the industrialized countries. Both conditions are on the increase, and finding novel treatments to prevent or cure them is a major aim in research. Somewhat surprisingly, AD and T2DM share several biochemical and physiological pathways (Li and Hölscher, 2007).
A clear association has been shown between peripheral hyperinsulinemia, insulin resistance, T2DM and high risk of AD. This association had been largely borne out in epidemiological work (Watson and Craft, 2004). Insulin has functions in the brain and dysregulation of these functions may contribute to the symptoms and pathogenesis of various late-life neurodegenerative disorders, such as AD. The localization of insulin receptors in the hippocampus and medial
Introduction and aim of the work
2
temporal cortex in rats is consistent with evidence that insulin influences memory and an important aspect that links AD with T2DM (Watson and Craft, 2004; Li and Hölscher, 2007).
Aim of the work:
1. Spot the light on Alzheimer-like neurodegenerative disorder that occurs in animals with type 2 diabetes mellitus.
2. Study the effect of some natural agents as grape seed extract or ginseng extract against the development of this disorder.
3. Make a comparison between the efficiency of the 2 extracts regarding the measured parameters.

Includes CD copy for The Thesis

Includes Abstract in Arabic