Nörokinin 3 reseptörünün sıçan deneysel Alzheimer modelinde kognitif davranışlar üzerine etkisi
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Dosyalar
Tarih
2019
Yazarlar
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Yayıncı
Necmettin Erbakan Üniversitesi Sağlık Bilimleri Enstitüsü
Erişim Hakkı
info:eu-repo/semantics/openAccess
Özet
Alzheimer hastalığı (AH) yaşlanan nüfusun artmasıyla ciddi sağlık sorunu haline gelen, progresif ve geri dönüşümsüz seyreden demansın bir formu olarak kabul edilir. Genellikle yakın bellekteki hasarla başlayan, günlük yaşam aktivitelerinin kaybına kadar ilerleyen kognitif bozuklukla karakterizedir. AH'de kolinerjik ve katekolaminerjik sistemlerin yaygın olarak etkilendiği bilinmektedir. Nörokinin B (NKB), taşikininler ailesine ait bir hormondur. NKB'nin reseptörü olan nörokinin 3 reseptörü (NK3R) öğrenme ve bellek ile ilgili süreçlerde rol alır. NK3R aktivasyonunun asetilkolin (ACh), dopamin (DA) ve noradrenalin (NA) gibi birçok nörotransmitterin serbestlenmesini kolaylaştırdığı bilinmektedir. Bu bilgilere dayanarak deneysel AH modelinde, NK3R agonizminin kolinerjik ve katekolaminerjik mekanizmalar aracılığıyla davranış ve öğrenme parametreleri, nörotransmitter aktiviteleri üzerine olumlu etkilerde bulunup bu sayede kognitif fonksiyonları geliştirebileceği hipotezi kurgulanmıştır. Bu çalışmada NK3R agonisti senktid uygulamasının deneysel Alzheimer sıçan modelinde kognitif fonksiyonlar ve nörodavranışsal mekanizmalar üzerine etkilerini incelemek amaçlanmıştır. Deney Hayvanları Etik Kurulu izni alındıktan sonra 50 adet yetişkin erkek Wistar albino sıçan; 1) Kontrol grubu, 2) AH grubu, 3) Kontrol + NK3R agonisti grubu, 4) AH + NK3R agonisti (AHS) grubu, 5) AH + NK3R agonisti + antagonisti gruplarına ayrılmıştır. İntraserebroventriküler olarak amiloid beta 1-42 uygulanarak deneysel Alzheimer modeli oluşturulmuştur. NK3R agonisti ve antagonisti enjeksiyonlarını takiben davranış ve öğrenme parametrelerini değerlendirmek için açık alan (OF), Morris su labirenti (MWM) ve yeni obje tanıma testi (NORT) uygulanmıştır. Deneyin sonunda hayvanlar dekapite edilerek hipokampus, korteks ve beyin sapı dokuları toplanmıştır. Hipokampus ve korteks dokularından ELISA yöntemiyle kolinerjik mekanizmaların analizi, beyin sapı dokusundan da HPLC yöntemiyle katekolamin analizi yapılmıştır. OF testinde katedilen mesafe, hız ve hareket yüzdesi parametrelerinde grup-zaman etkisi istatistiksel olarak anlamlıydı (p<0.05). MWM'nin test aşamasında katedilen mesafe, hedef kadranda bulunma süresi parametrelerinde gruplar arasında istatistiksel olarak anlamlı fark bulundu (p<0.05). Kısa ve uzun süreli NORT'de ayrım ve tanıma indeksleri değerlendirildi. NORT'de gruplar arasında anlamlı fark görülmedi. Asetilkolinesteraz (AChE) ve kolin asetiltranferaz (ChAT) miktarı hipokampus ve korteks dokularında ELISA yöntemiyle belirlendi. AChE ve ChAT miktarında gruplar arasında istatistiksel olarak anlamlı fark bulundu (p<0.05). Sıçanların beyin sapı numunelerinde dihidroksifenil glikol (DHPG), dihidroksifenilasetik asit (DOPAC) ve DA konsantrasyonlarının gruplar arasında istatistiksel olarak anlamlı farklı olduğu gözlendi (p<0.05). NA konsantrasyonunda gruplar arasında anlamlı fark görülmedi (p>0.05). Fakat NA ve DA, AH grubunda diğer gruplara göre daha azken, AHS grubunda AH grubuna göre artmış olarak bulundu. Sonuç olarak; NK3R agonistlerinin AH patolojisi oluşturulmuş sıçanlarda kognitif fonksiyonları iyileştirmekte etkili olduğu görülmüştür. Öğrenme ve bellek performanslarındaki olumlu etkilerin kolinerjik ve katekolaminerjik mekanizmalar aracılığıyla olabileceği gözlenmiştir. Demansın normal yaşlanma ve AH için karakteristik olduğu göz önüne alındığında NK3R'nin bu tür bilişsel gerilemede olası farmakolojik uygulamalar için daha ileri düzeyde araştırılması gereklidir. Henüz kesin bir tedavisi olmayan AH'ye yönelik insanlarda ve hayvan modellerinde daha çok araştırmanın yapılmasıyla daha etkin tedavi stratejileri geliştirilebilir.
Alzheimer's disease (AD) is accepted as a form of progressive and irreversible dementia, which becomes a serious health problem with the increase of the aging population. It is characterized by cognitive impairment, which usually begins with near memory damage and progresses to loss of daily living activities. It is known that cholinergic and catecholaminergic systems are commonly affected in AD. Neurokinin B (NKB) is a hormone belonging to the tachykinins family. The neurokinin 3 receptor (NK3R), the NKB receptor, is involved in learning and memory related processes. Activation of NK3R is known to facilitate the release of many neurotransmitters such as acetylcholine (ACh), dopamine (DA) and noradrenaline (NA). Based on this information, the hypothesis of the study that NK3R agonism can have positive effects on behavioral and learning parameters through cholinergic and catecholaminergic mechanisms. The aim of this study was to investigate the effects of NK3R agonist senktide on cognitive functions and neurobehavioral mechanisms in an experimental model of AD. After obtaining the permission of the Experimental Animals Ethics Committee, 50 adult male Wistar albino rats were obtained; 1) Control group, 2) AD group, 3) Control + NK3R agonist group, 4) AD + NK3R agonist (ADS) group, 5) AD + NK3R agonist + antagonist groups. An experimental AD model was established by applying amyloid beta 1-42 intracerebroventricularly. Following NK3R agonist and antagonist injections, open field (OF), Morris water maze (MWM) and new object recognition test (NORT) were applied for behavior and learning parameters. At the end of the experiment, animals were decapitated. Then hippocampus, cortex and brain stem tissues were collected. Analysis of cholinergic mechanisms from hippocampus and cortex tissues by ELISA method and catecholamine analysis from brain stem tissue by HPLC method were performed. Group-time effect was statistically significant in the OF test (p<0.05). There was a statistically significant difference between the groups at the test stage of MWM (p<0.05). The distinction and recognition indices were evaluated in short and long term NORT. There was no significant difference in NORT between the groups. AChE and ChAT levels were determined by ELISA in hippocampus and cortex tissues. There was a statistically significant difference between AChE and ChAT levels between the groups (p<0.05). The DHPG, DOPAC and DA concentrations of brainstem samples were statistically significant between the groups (p<0.05). There was no significant difference in NA concentration between the groups (p>0.05). However, NA and DA were found to be less in AD group compared to other groups, but increased in ADS group compared to AD group. As a result; NK3R agonists were found to be effective in improving cognitive functions in rats with AD pathology. It has been observed that positive effects on learning and memory performances can be mediated by cholinergic and catecholaminergic mechanisms. NK3R should be further investigated for possible pharmacological applications in AD and other cognitive disorders. More effective treatment strategies can be developed by conducting more studies in humans and animal models for AD.
Alzheimer's disease (AD) is accepted as a form of progressive and irreversible dementia, which becomes a serious health problem with the increase of the aging population. It is characterized by cognitive impairment, which usually begins with near memory damage and progresses to loss of daily living activities. It is known that cholinergic and catecholaminergic systems are commonly affected in AD. Neurokinin B (NKB) is a hormone belonging to the tachykinins family. The neurokinin 3 receptor (NK3R), the NKB receptor, is involved in learning and memory related processes. Activation of NK3R is known to facilitate the release of many neurotransmitters such as acetylcholine (ACh), dopamine (DA) and noradrenaline (NA). Based on this information, the hypothesis of the study that NK3R agonism can have positive effects on behavioral and learning parameters through cholinergic and catecholaminergic mechanisms. The aim of this study was to investigate the effects of NK3R agonist senktide on cognitive functions and neurobehavioral mechanisms in an experimental model of AD. After obtaining the permission of the Experimental Animals Ethics Committee, 50 adult male Wistar albino rats were obtained; 1) Control group, 2) AD group, 3) Control + NK3R agonist group, 4) AD + NK3R agonist (ADS) group, 5) AD + NK3R agonist + antagonist groups. An experimental AD model was established by applying amyloid beta 1-42 intracerebroventricularly. Following NK3R agonist and antagonist injections, open field (OF), Morris water maze (MWM) and new object recognition test (NORT) were applied for behavior and learning parameters. At the end of the experiment, animals were decapitated. Then hippocampus, cortex and brain stem tissues were collected. Analysis of cholinergic mechanisms from hippocampus and cortex tissues by ELISA method and catecholamine analysis from brain stem tissue by HPLC method were performed. Group-time effect was statistically significant in the OF test (p<0.05). There was a statistically significant difference between the groups at the test stage of MWM (p<0.05). The distinction and recognition indices were evaluated in short and long term NORT. There was no significant difference in NORT between the groups. AChE and ChAT levels were determined by ELISA in hippocampus and cortex tissues. There was a statistically significant difference between AChE and ChAT levels between the groups (p<0.05). The DHPG, DOPAC and DA concentrations of brainstem samples were statistically significant between the groups (p<0.05). There was no significant difference in NA concentration between the groups (p>0.05). However, NA and DA were found to be less in AD group compared to other groups, but increased in ADS group compared to AD group. As a result; NK3R agonists were found to be effective in improving cognitive functions in rats with AD pathology. It has been observed that positive effects on learning and memory performances can be mediated by cholinergic and catecholaminergic mechanisms. NK3R should be further investigated for possible pharmacological applications in AD and other cognitive disorders. More effective treatment strategies can be developed by conducting more studies in humans and animal models for AD.
Açıklama
Doktora Tezi
Anahtar Kelimeler
Alzheimer Hastalığı, Nörokinin 3 Reseptörü, Öğrenme ve Bellek, Alzheimer's Disease, Neurokinin 3 Receptor, Learning and Memory
Kaynak
WoS Q Değeri
Scopus Q Değeri
Cilt
Sayı
Künye
Özen Koca, R. (2019). Nörokinin 3 reseptörünün sıçan deneysel alzheimer modelinde kognitif davranışlar üzerine etkisi. (Yayımlanmamış doktora tezi). Necmettin Erbakan Üniversitesi, Sağlık Bilimleri Enstitüsü Fizyoloji Anabilim Dalı, Konya.
