الفهرس | Only 14 pages are availabe for public view |
Abstract There are currently 35.6 million people living with dementia globally, and 7.7 million new cases are identified each year. As the most frequent cause of dementia, Alzheimer’s disease (AD) accounts for 60–75% of all cases. Additionally, whereas mortality from other illnesses, such heart disease, have declined recently, those linked to AD have climbed by 68% in just the past ten years. Age is the primary risk factor in the etiopathogenesis of AD, and as life expectancy rises, so does the prevalence of the disease. A prominent impairment of episodic memory is a hallmark of AD. This symptom is frequently accompanied by a wide range of cognitive deficits in areas like decisionmaking, language, executive function, and visuospatial skills. As a result, AD seems to be a gradual decline in higher brain functioning that also affects judgement. Patients with Alzheimer’s live an average of 7 to 10 years after diagnosis. Further complicating early diagnosis and therapy is the lack of a clear premortem diagnosis for this illness, which can only be determined histologically postmortem by the presence of senile plaques (SPs), neurofibrillary tangles (NFTs) and neuronal and synaptic loss. There is still no effective treatment to stop or reduce the development of AD, despite the rise in cases in recent years and the associated socioeconomic costs. Only six medications, including aducanumab, donepezil, galantamine, rivastigmine, memantine, and a manufactured combination of memantine and donepezil (DP), have received food and drug administration (FDA) approval thus far. Only aducanumab is used to remove amyloid beta (Aβ) plaques; the other five are symptomatic treatments that work on two levels, either by antagonizing the cholinergic system or by blocking the N-methyl-D-aspartate receptor (NMDA-receptor). Due to side effects that are associated with these drugs especially nausea, vomiting and headache, it was a necessary to search for less side effects drugs such as natural products. An exceptional unique bioflavonoid called quercetin (QCT) is strictly recommended due to numerous therapeutic effects which have been documented including antioxidant, anti-inflammatory, anti-amyloidogenic, and neuroprotective effects. Summary and Conclusion 131 This study aimed to evaluate the neurotherapeutic effect of QCT on the expression of miR-124 in experimental AD model and to compare the efficiency of QCT to conventionally used drug; DP. The study was conducted on 40 healthy male albino rats weighted approximately 100-150 g and divided into two groups: Normal control group (GI; n=8) received standard diet, and AD group (GII; n=32) that received hydrated aluminum chloride (AlCl3.6H2O) solution that was given orally at a dose of 75 mg/kg/day for 6 weeks, subdivided into 4 subgroups (8 rats each): GII A: untreated Alzheimer rats; GII B: AD rats received QCT interperitoneally with a dose of 30 mg/kg/day for 4 weeks. GII C: AD rats received DP orally with a dose of 3 mg/kg/day for 4 weeks.; GII D: AD rats received a daily dose of the combination of QCT and DP for 4 weeks. The results of the present study indicated that untreated rats have a significantly higher Aβ1-42 contents, hyperphosphorylated tau proteins, malondialdehyde (MDA) contents, AChE activity and nuclear factor kappa B (NF-κB) contents as compared to control rats. Also, AD rats showed a significant upregulation of BACE1 gene expression and a significant suppression in miR-124 expression. from the results of the present study, it is clear that the hippocampal Aβ1-42 level and tau protein content were completely normalized in AD-like rats treated with QCT in combination with DP. In addition to previous results, the best ameliorating effect on AChE activity was observed in AD rats treated with the combined treatment regimen. In hippocampus, the treatment with DP alone or QCT alone or combined with DP significantly downregulate the expression of BACE1 and upregulate miR-124 expression compared with the untreated rats. These results suggested that the best effects were obtained in the combined treatment regimen. The biochemical results of the current study were further confirmed by the histological examination of the hippocampus tissues. The normal group revealed an intact architecture of the hippocampus with normal histological appearance. The hippocampus of AD rats showed degenerative changes and atrophy of the neuronal cells. Administration of QCT and DP resulted in marked improvement of cellular morphology to various extents as compared to the untreated rats, improvement of nerve cell morphology, decline in numbers of degenerated, pyknotic neurons, necrotic neurons associated with satellitosis and neuronophagia and result in significant reduction of optical density and also reduction of Aβ deposition. Summary and Conclusion 132 from the results obtained it can be concluded that: Quercetin is considered as a potential therapeutic agent against Alzheimer’s disease. • QCT targets multiple pathways involved in AD progression including induced amyloidogenic pathway, impaired cholinergic neurotransmission, oxidative stress, upregulation of BACE1 gene expression and downregulation of miR-124 gene expression in hippocampal tissues and enhancing the diseased AD-rats cognitive function. • from histological observation, the best results were observed in the hippocampus of animals that received the combination of QCT and DP. These observations indicated that the treatment mitigated the AD histopathological alterations in the hippocampus of AD rats and improve the morphology and distribution of nerve cells. • According to the results achieved here, we recommend the use of QCT as adjuvant therapy with DP for treatment of AD. • Further studies are required to investigate the therapeutic and protective effects of QCT in AD patients and the actual mechanism behind these effects and investigate the role of miRNAs in AD progression. |