Publication: Deneysel otizm spektrum bozukluğu modelinde PI3K/ Akt/ mTor sinyal yolağının rolünün araştırılması
Abstract
Amaç: Bu çalışmada valproik asit (VPA) ile oluşturulan deneysel Otizm Spektrum Bozukluğu (OSB) modelinde PIK3/ Akt/ mTOR hücre içi sinyal yolağının rolü ve agmatin (AGM) tedavisinin OSB ve bu yolak üzerine etkilerinin araştırılması amaçlanmıştır. Gereç ve Yöntem: Spraque Dawley dişi sıçanlar her grupta 12 hayvan olacak şekilde kontrol (serum fizyolojik), OSB (tek doz 400 mg/ kg VPA; s.c.) ve OSB+AGM (tek doz 400 mg/ kg VPA; s.c. + postnatal 30. günden başlayarak 15 gün süreyle 50 mg/ kg AGM; i.p.) olacak şekilde gruplandırılmıştır. Davranış değerlendirmelerinde postnatal 46. günde açık alan, sükroz püskürtme, yeni obje tanıma, sosyal etkileşim ve üç odalı sosyallik testi kullanılmıştır. Davranış testlerinden sonra dekapite edilen hayvaların prefrontal kortekslerinde PI3K, Akt ve mTOR gen ekspresyonları değerlendirilmiştir. Bulgular: OSB grubunda kontrol grubuna kıyasla; açık alan testinde toplam aktivitenin, merkez alanda geçirilen sürenin ve tekrarlayan grooming davranışının arttığı, yeni obje tanıma testinde görsel öğrenme ve belleğin azaldığı, sosyal etkileşim testinde sosyalleşme davranışının azaldığı, üç odalı sosyallik testinde sosyallik ve sosyallik tercihinin azaldığı görülmüştür. AGM’nin ise tekrarlayan davranışları hafiflettiği, görsel öğrenme ve belleği artırdığı, sosyalleşme davranışını ve sosyallik tercihini önemli ölçüde artırdığı görülmüştür. Moleküler analizlerde AGM tedavisinin OSB’de artan PI3K, Akt, mTOR gen ekspresyonlarını istatistiksel olarak anlamlı düzeyde azalttığı görülmüştür. Sonuç: Çalışmanın bulguları ışığında PI3K/ Akt/ mTOR yolağının OSB nörobiyolojisinde önemli bir rolü olabileceği düşünülmüştür. Endojen bir molekül olan AGM’nin dışarıdan uygulanmasıyla düzeyinin artırılmasına bağlı olarak yapılan tedavinin OSB’ye ilişkin davranışsal ve moleküler parametreler üzerinde iyileşme sağlamasından yola çıkılarak gelecekte AGM sentez ve metabolizması üzerine etkili moleküllerin yeni tedavi yaklaşımları sağlayabileceği değerlendirilmiştir.
Objective: In this study, it was aimed to investigate the role of PI3K/ Akt/ mTOR intracellular signaling pathway in the ASD model created with VPA and the effect of agmatine treatment on this pathway and ASD. Material and Methods: Spraque Dawley female rats consisted of 12 animals in each group as control (saline), OSB (single dose 400 mg/ kg VPA; s.c.) and OSB+AGM (single dose 400 mg/ kg VPA; s.c. + 50 mg/ kg AGM; i.p. for 15 days from postnatal day 30). In behavioral assessments, open field, sucrose splash, new object recognition, social interaction and three chamber test were used at postnatal 46th day. PI3K, Akt and mTOR gene expressions were evaluated in the prefrontal cortices of animals decapitated after behavioral tests. Results: Compared to the control group in the ASD group; it was found that total activity and repetitive grooming behavior increased in OFT, visual learning and memory decreased in the new object recognition test, socialization behavior decreased in social interaction test, and sociability preference decreased in TCT; on the other hand, agmatine has been shown to reduce increased activity, alleviate repetitive behaviors, alleviate cognitive rigidity, increased visual learning and memory, and significantly increase socialization behavior and sociability preference. Molecular analyzes showed that agmatine significantly decreased the increased PI3K, Akt, mTOR gene expressions in ASD. Conclusion: In the light of the findings of the study, it was thought that the PI3K/ Akt/ mTOR pathway may have an important role in the neurobiology of ASD. It has been evaluated that molecules effective on AGM synthesis and metabolism in the future may provide new treatment approaches, based on the fact that the treatment performed due to the external application of AGM, which is an endogenous molecule, improves the behavioral and molecular parameters of ASD.
Objective: In this study, it was aimed to investigate the role of PI3K/ Akt/ mTOR intracellular signaling pathway in the ASD model created with VPA and the effect of agmatine treatment on this pathway and ASD. Material and Methods: Spraque Dawley female rats consisted of 12 animals in each group as control (saline), OSB (single dose 400 mg/ kg VPA; s.c.) and OSB+AGM (single dose 400 mg/ kg VPA; s.c. + 50 mg/ kg AGM; i.p. for 15 days from postnatal day 30). In behavioral assessments, open field, sucrose splash, new object recognition, social interaction and three chamber test were used at postnatal 46th day. PI3K, Akt and mTOR gene expressions were evaluated in the prefrontal cortices of animals decapitated after behavioral tests. Results: Compared to the control group in the ASD group; it was found that total activity and repetitive grooming behavior increased in OFT, visual learning and memory decreased in the new object recognition test, socialization behavior decreased in social interaction test, and sociability preference decreased in TCT; on the other hand, agmatine has been shown to reduce increased activity, alleviate repetitive behaviors, alleviate cognitive rigidity, increased visual learning and memory, and significantly increase socialization behavior and sociability preference. Molecular analyzes showed that agmatine significantly decreased the increased PI3K, Akt, mTOR gene expressions in ASD. Conclusion: In the light of the findings of the study, it was thought that the PI3K/ Akt/ mTOR pathway may have an important role in the neurobiology of ASD. It has been evaluated that molecules effective on AGM synthesis and metabolism in the future may provide new treatment approaches, based on the fact that the treatment performed due to the external application of AGM, which is an endogenous molecule, improves the behavioral and molecular parameters of ASD.