الفهرس 
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Abstract
Alzheimer’s disease (AD) is a chronic, progressive, multifactorial, the most common neurodegenerative disease and considered to be the most common cause of dementia and mental deterioration in the elderly. AD characterized by loss of memory, difficulty solving problems, depression, changes in the personality and behavior, multiple cognitive impairments such as; thinking process, learning ability, orientation, comprehension, calculation, language, and judgment.
Currently, there is no available disease-modifying treatment for AD and these types of drugs are needed urgently as the available treatments only provide symptomatic relief. A second generation antioxidant called Astaxanthin (ATX), a dark red carotenoid exhibits antioxidant, anti-inflammatory, neuroprotective and antiapoptotic effects. ATX has the highest antioxidant capacity which is considered as high as 10 times more than other carotenoids with it being 500-fold higher than that of vitamin E as a singlet oxygen (O2•) quencher and 100 times more than α-tocopherol with respect to the protective effects against lipid peroxidation, It chelates several metal ions, preventing metal ion-induced oxidative stress and crosses the blood-brain barrier (BBB); allowing free access to the central nervous system.
The aim of this study was to investigate the possible therapeutic effect of astaxanthin (ATX) on Alzheimer’s disease-like rat model (AD-like) at different levels; histological, behavioral, amyloidogenic pathway, neurotransmitters and catabolizing enzymes, gene expression and neuronal-specific miRNA (miRNA-124).
The study was conducted on 50 male albino rats (150-200 gm) three months old. Alzheimer’s disease-like model was induced in rats using hydrated aluminum chloride (AlCl3.6H2O) solution that was given orally at a dose of 75 mg/kg body weight (b.wt) daily for 6 weeks. The Morris water maze (MWM) test was carried out at the end of the 6 weeks to evaluate the spatial memory and confirm the cognitive impairments in the rats. The animals were divided into two groups; group I (Control group): consisted of 10 healthy male rats that was orally treated with dimethyl sulfoxide (DMSO). group II (AD group): consisted of 40 Alzheimer-like rats that subdivided into two subgroups: group IIA: consisted of 10 untreated Alzheimer-like rats that was orally treated with DMSO. group IIB: consisted of 30 Alzheimer-like rats (subdivided into 3 groups; 10 rats each) that was orally treated with different doses of ATX dissolved in DMSO; 5, 10 and 15 mg/kg b.wt /day respectively for six weeks.
After the last day of treatment, animals were subjected to the behavioral test (MWM) then sacrificed by cervical dislocation and the brain was dissected. The cortex and hippocampus were excised from one hemisphere for the determination of amyloid beta (Aβ1-42), acetylcholine, serotonin, acetylcholinesterase, monoamine oxidase activities, malondialdehyde (MDA), nuclear factor erythroid-2-related factor 2 (Nrf2) and total RNA extraction for quantitative real time polymerase chain reaction (qPCR) for the determination of miRNA-124 and β-site amyloid precursor protein cleaving enzyme 1 (BACE1) gene expression and the other hemisphere was used for histopathological observation including H&E stain and morphometric tissue analysis.
The AD-like rats showed marked impairment in cognitive functions associated with severe changes in the cortical and hippocampus histological structures. The same rats suffered from significant derangement in neurotransmitters and their catabolizing enzymes and marked increase in Aβ1-42 content and the expression of BACE1 gene in cortex and hippocampus with severe decline in the expression of miR-124.
Astaxanthin treatment significantly and dose-dependently improved the performance of AD-like rats treated with different doses of ATX during Morris water maze and declined Aβ1-42 content, malondialdhyde content, acetylcholinesterase, monoamie oxidase activity and BACE 1 gene expression. ATX also significantly elevated the content of acetylcholine, serotonin and Nrf2 and miR-124 gene expression. The effect of ATX treatment was confirmed by histopathological observations using H&E stain and morphometric tissue analysis.
from this study we concluded that;
Astaxanthin has powerful dose-dependent therapeutic effects in the AD-like rat model.
The ATX targets multiple pathways that play key roles in the development and progression of AD including; impaired cholinergic and serotonergic neurotransmissions, oxidative stress, amyloidogenic pathway, suppressed miR-124 expression and microglial activation.
ATX has multiple actions to target these pathways including, inhibition of AChE and MAO, boosting Nrf2 pathway, suppressing BACE1 expression, enhancing miR-124 expression and inhibiting microglial activation, respectively with the end results of correcting the histological structure of the cortex and hippocampus and improving the cognitive and behavioral performance of the AD-like rats. All of these effects together with the safety and no adverse effects of ATX make it a promising therapeutic agent for Alzheimer’s disease management.
Further studies are recommended to explore the protective and therapeutic actions of ATX in AD patients.