L-Metiyoninin Neden Olduğu Nörokognitif Yıkılma: Bir Nörodejenerasyon Fare Modeli

Abstract

Amaç: Nörodejeneratif hastalıklar geri dönüşü olmayan nöronal ve glial kayıplarla seyreden merkezi sinir sistemi yıkılımıdır. Bu hastalıklar her ne kadar nöral hücre yıkım ortak paydasında birleşseler de her biri farklı klinik bulgularla seyretmektedir. Bu hastalıklarda izlenen klinik tablo spektrumunu inceleyebilmek adına çevresel stresör olarak verilen l-metiyonin yüklemesinin yol açtığı davranış değişikliklerinin ve bu davranış değişikliklerinin temelinde olan immünohistokimyasal değişimlerin incelenmesi amaçlanmıştır. Gereç ve Yöntem: Bu çalışmada davranış ve immünohistokimya testleri için fareler 4 gruba ayrılmıştır: dişi-kontrol (n=13), dişi-metiyonin (n=12), erkek-kontrol (n=12), erkek-metiyonin (n=13). Kontrol ve deney gruplarına post-natal 6. haftadan başlayarak, 12 hafta boyunca su veya 8.2 g/kg doza ulaşacak şekilde l-metiyoninli su verilmiştir. Bu sürenin sonunda farelere anksiyete, depresyon, hafıza/öğrenme ve motor fonksiyon testleri uygulanmıştır. Davranış testlerinde kullanmadığımız farelerin (her gruptan davranış testleri öncesi rastgele seçilmiş 3 fare) beyin kesitlerinde immünohistokimyasal analizler yapılmıştır. Bulgular: L-metiyonin alan farelerde almayanlara kıyasla hipokampüs bağımlı mekansal hafızada istatistiksel olarak anlamlı bir fark görülmüştür. Depresyon ve anksiyete adına herhangi bir fark bulunmamıştır. Hipokampüs formasyonunun dentat girusunda yaptığımız immünohistokimyasal incelemede, hem dişi hem de erkek farelerde senesan astrositlerin tüm astrositlere olan oranı arasında istatistiksel olarak anlamlı bir fark saptanmamıştır. Sonuç: Kronik yüksek doz oral l-metiyonin alımı farelerde anlamlı hipokampüs bağımlı mekansal hafıza bozukluklarına yol açmıştır. Buna paralel olarak, dentat girusta senesan astrositlerin tüm astrositlere oranı da artmıştır.

Keywords

• L-metiyonin
• kognitif yıkım
• hücresel senesans

Project Number

National Institute of Neurological Disorders and Stroke Grant RO1NS073758

Neurocognitive Decline Caused by L-Methionine: A Mouse Model of Neurodegeneration

Abstract

Objective: Neurodegenerative diseases are defined by irreversible neuronal and glial loss in the central nervous system. Despite sharing neural cell loss as a common denominator, they differ in their clinical manifestations in many aspects. We aimed to analyze the behavioral changes and underlying immunohistochemical changes in mice caused by an environmental stressor, l-methionine, to assess the spectrum of clinical findings observed in these diseases. Material and Method: In this study, the mice are divided into 4 groups: female-control (n=13), female-methionine (n=12), male-control (n=12), male-methionine (n=13) to perform immunohistochemical and behavioral tests. Starting from post-natal week 6, the mice were either administered water or 8.2g/kg l-methionine for 12 weeks. Consequently, they underwent a series of behavioral tests to assess anxiety, depression, memory/learning, and motor functions. We performed immunohistochemical analysis on mice (3 randomly chosen mice from each group prior to behavior tests) which did not undergo behavioral tests. Results: Compared to the control group, mice who received l-methionine were found to have significant hippocampus dependent spatial memory deficits. No significant differences were found in regards to anxiety and depression. Our immunohistochemical analysis showed a significantly increased senescent astrocyte to all astrocyte ratio in dentate gyrus of hippocampal formation. Conclusion: Chronic administration of an oral high dose of l-methionine results in hippocampus dependent memory decline in mice. Parallel to this finding, the ratio of senescent astrocytes to all astrocytes increased in dentate gyrus.

Keywords

• L-methionine
• cognitive decline
• cellular senescence

Supporting Institution

Research reported in the present work was supported by the National Institutes of Health

Project Number

National Institute of Neurological Disorders and Stroke Grant RO1NS073758

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