Elmas Rumeysa YILDIRIM, Nuray ULUSOY GÜZELDEMİRCİ

ALZHEİMER HASTALIĞININ TEDAVİSİNDE KRİTİK BİR ROL OYNAYAN KOLİNESTERAZ İNHİBİTÖRLERİNDEKİ SON GELİŞMELER (2020-2022)

Alzheimer hastalığı (AD) oldukça sık rastlanılan ve majör yıkıcı bir etkiye sahip olan nörodejeneratif bir hastalıktır. Özellikle 65 yaş üstü nüfusu büyük oranda tutan, hasta kişinin nöron ölümü, hafıza kaybı, bilişsel ve kolinerjik işlev bozuklukları gibi sıkıntılarla günlük yaşamını önemli derecede etkileyen bir durumdur. Fakat son dönemde yapılan ilaç geliştirme çalışmalarının oldukça yoğun yürütülmesine rağmen, hala kişileri tamamen iyileştirebilecek veya hastalığın evresini tamamen durdurabilecek etkili bir ilaç molekülü maalesef bulunamamıştır. Bunun sebeplerinden biri de hastalığın patolojisinin nasıl ortaya çıktığının anlaşılamaması ve karmaşıklığı ile ilgilidir. Alzheimer hastalığı için kabul gören en önemli teori kolinerjik hipotezdir. Önemli bir nörotransmitter olan asetilkolin (ACh), asetilkolinesteraz (AChE) ve bütirilkolinesteraz (BuChE) isimli iki kolinesteraz enzimi (ChE) tarafından metabolize edilir. AD ile birlikte ise ChE aktivitesi artmış ve dolayısıyla asetilkolinin yıkımı tetiklenmiştir. Ayrıca AChE’in periferal anyonik bölgesi (PAS)’nin Aβ-peptid fibrillerinin oluşmasına da neden olduğu anlaşılmıştır. Bu sebeple bu hipoteze dayanarak tedavideki en etkili yaklaşım, kolinerjik sinapslarda ACh seviyesini arttırarak eski haline döndürmeye çalışan kolinesteraz inhibitörlerinin (ChEI) kullanılmasıdır. Üstelik multifonksiyonel moleküllerin tasarımları üzerine de odaklanılmıştır. Sonuç olarak hastalığın karmaşık yapısı ve etkileri göz önüne alındığında, bu alanda daha fazla çalışma yapılması gerekmektedir. Bu çalışmada son yıllardaki önemli ve dikkat çeken çalışmalar yer almış olup, bundan sonraki ilaç araştırma ve geliştirme çalışmalarına katkı sağlaması amaçlanmıştır.

Anahtar Kelimeler:

Alzheimer hastalığı (AD), kolinesteraz inhibitörleri (ChEIs), asetilkolinesteraz inhibitörleri (AChEIs), butirilkolinesteraz inhibitörleri (BuChEIs), multifonksiyonel ilaçlar, çoklu hedefe yönlendirilmiş ligandlar

RECENT ADVANCES OF CHOLINESTERASE INHIBITORS PLAYING A CRITICAL ROLE IN THE TREATMENT OF ALZHEIMER’S DISEASE (2020-2022)

Alzheimer’s disease (AD) is a common neurodegenerative disorder which has a catastrophic effect on the brain. It significantly affects people’s daily life, especially the population over the age of 65, with problems such as neuron death, memory loss, cognitive disorders, and cholinergic dysfunction. However, despite the drug development studies which have been conducted recently quite intensively, an effective drug molecule that can completely cure people or stop the stage of the disease has not been found yet, unfortunately. One of the reasons for this is the complexity of understanding of how the pathology of the disease arises. The most accepted theory for AD is the cholinergic hypothesis. Acetylcholine (ACh), an important neurotransmitter, is metabolized by two cholinesterase (ChE) enzymes named acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). With AD, ChE activity increases and thus the degradation of acetylcholine is triggered. In addition, it is understood that the peripheral anionic region (PAS) of the AChE also caused the formation of Aβ-peptide fibrils. Therefore, based on this hypothesis, the most effective approach in treatment is the use of cholinesterase inhibitors (ChEI), which try to restore ACh levels by increasing them at cholinergic synapses. Furthermore, it focused on the design of multifunctional molecules. In conclusion, considering the complex nature of the disease and its effects, it is clear that more studies are needed in this area. In this study, important and remarkable studies in recent years have been included and it aimed to contribute to future drug research andv development studies.

Keywords:

Alzheimer’s disease (AD), cholinesterase inhibitors (ChEIs), acetylcholinesterase inhibitors (AChEIs), butyrylcholinesterase inhibitors (BuChEIs), multifonctional drugs, multi-target directed ligands,

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