الفهرس 
1 - IntroductionOnly 14 pages are availabe for public view
 |  | from | 269 |  |  |
| | | from | 269 | | |
Abstract
Aluminium is an abundant metal, commonly found in household products. It is easily ingested through diet, antacids, and vaccines. One of the hypotheses that leads to increased incidence of Alzheimer’s disease (AD) is the accumulation of aluminium in the brains’ frontal cortex and hippocampus. The present study aimed to evaluate the therapeutic role of a novel bithiophene derivative against AlCl3-induced AD in a rat model. In the present study a total number of 108 rats were allotted to six groups: group 1: naïve animals received a daily oral administration of DMSO. group 2: animals received a daily oral administration of bithiophene dissolved in DMSO (1 mg/kg,) for 30 days every other day. group 3: animals received a daily oral administration of AlCl3 (100 mg/kg/day equivalent to 20.23 mg Al3+). Groups 4 and 5: animals with Alzheimer’s disease-like pathology received an oral administration of low or high dose of the bithiophene (0.5 or 1 mg/kg/day) on each other day for 30 days (15 doses/month). group 6: animals with Alzheimer’s disease-like pathology were treated with a daily oral dose of memantine in isotonic saline (20 mg/kg/day) for 30 consecutive days. Al3+ disturbed the antioxidant milieu and elevated the lipid peroxidation and depleted the antioxidants in the frontal cortex and hippocampus. It also disturbed the synaptic neurotransmission by elevating the activities of acetylcholine esterase and monoamine oxidase resulting in the depletion of dopamine and serotonin and accumulation of glutamate and norepinephrine. Al also deteriorated the expression of genes involved in apoptosis and the production of amyloid-β plaques as well as phosphorylation of tau. Al-intoxication also caused a significant increase in the time taken by rats to allocate the hidden platform in the learning trials of MWM, concurrently resulting in reduced time spent within the platform quadrant in the probe trials. These results were confirmed by the neurodegenerative changes in the histopathology and ultrastructure of the cortex and hippocampus. The low dose of the new bithiophene derivative reversed most of the previous deleterious effects of aluminium in the cerebral cortex and hippocampus. It increased the platform quadrant time (enhancing rats’ cognitive abilities), mitigated the oxidative stress burden, restored the neurotransmitters normal levels as well as the activities of AChE and MAO. It restored the expression of genes involved in apoptosis, amyloid-β production and tau phosphorylation. It also restored the histological and ultrastructure integrity. The high dose, however, failed to enhance the rats’ cognitive abilities. It also failed to alleviate the oxidative stress burden and did not restore the normal levels of neurotransmitters or AChE, though it managed to lower the MAO levels, and expression of GSAP and GSK3-β. The high dose induced degenerative effects at both the histological and ultrastructural levels. Memantine treatment showed similar effects to the bithiophene low dose, yet it was suboptimal compared to the low dose. Memantine enhanced the rats’ cognitive abilities and alleviated much of the oxidative stress burden (MDA, SOD, GSH). It managed to lower MAO but did not affect AChE, restored neurotransmitters levels, downregulated GSAP and GSK3β. It also reverted the Al-induced histopathological and ultrastructural aberrations. Taking together, bithiophene low dose was superior to both the high dose of the same derivative and the reference drug; memantine. The bithiophene modulated the AD aetiology through antioxidant activity, prevention of neuronal and synaptic loss, and probably mitigating the formation of amyloid-β plaques and phosphorylation of tau.