Publication: Deneysel otizm spektrum bozukluğu modelinde vortioksetinin ve nod benzeri reseptör proteini-3 aracılı inflamazom yolağının rolünün araştırılması
Abstract
Amaç: Proinflamatuar sitokinlerin oluşumunda erken basamak mekanizmalardan biri olan, mikroglia hücrelerde bulunan NOD benzeri reseptör (NLR) aracılı inflamazom aktivasyonunun OSB modelinde araştırılması ve multimodal etki mekanizması olan vortioksetinin (VORT) OSB tedavisindeki olası etkisinin valproik asit ile oluşturulan deneysel OSB spektrum bozukluğu (OSB) modelinde araştırılması amaçlanmıştır. Gereç ve Yöntem: Erkek Sprague-Dawley sıçanlar 3 gruba ayrıldı: Kontrol (n=12), OSB (n=16), OSB+VORT (n=16). Kontrol (serum fizyolojik), OSB (tek doz 400 mg/ kg VPA; s.c.) ve OSB+VORT (tek doz 400 mg/ kg VPA; s.c.+postnatal 30.günden başlayarak 15 gün süreyle 5 mg/ kg VORT; i.p). Postnatal 46 - 52 günler arasında, açık alan, sükroz püskürtme, yeni obje tanıma, sosyal etkileşim ve 3 odalı sosyallik testi uygulandı. Prefrontal kortekste NLRP3 inflamazom bileşenleri araştırıldı. NLRP3, ASC ve kaspaz-1 seviyeleri gerçek zamanlı PCR ile değerlendirildi. Bulgular: OSB modelinde kontrol grubuna kıyasla lokomotor aktivitede ve süslenme (grooming) davranışında artış görülürken, sosyalleşme ve sosyal etkileşimde azalma görüldü. Bu veriler ve model grubundaki malformasyonlar, OSB modelinin oluştuğunu doğrulamıştır. VORT tedavisi, sosyal etkileşim belirteçlerinden olan hayvanların birbirini takip etme, koklama davranışlarını istatistiksel olarak anlamlı şekilde arttırdı kaçınma davranışlarını azalttı. Moleküler analizde, NLRP3 inflamazom bileşenlerinden NLRP3, kaspaz-1 ve ASC gen ekspresyonları OSB modelinde artmıştır. VORT tedavisinin OSB modelinde artan NLRP-3, kaspaz-1 ve ASC gen ekspresyonlarını istatistiksel olarak anlamlı düzeyde azalttığı görüldü. Sonuçlar: Bu veriler ışığında, NLRP3 aracılı inflamazom yolağının OSB nörobiyolojisinde önemli rolü olabileceği, multimodal etki mekanizmasına sahip VORT’un, OSB’nin davranışsal ve moleküler parametreleri üzerine olumlu etkileri nedeniyle tedavisinde değerlendirilebilecek bir seçenek olabileceği değerlendirilmiştir.
Objective: The aim of the present study was to investigate NOD like receptor mediated inflammasome activation in macrophage and microglia cells, which is one of the early step mechanisms in the formation of proinflammatory cytokines, in autism model and also investigate the possible effect of vortioxetine (VORT), which has a multimodal mechanism of action, in the treatment of autism in a valproic acid-induced experimental rat model of autism. Materials and Methods: Male Sprague-Dawley rats were divided into 3 groups: Control (n=12), ASD (n=16), ASD+VORT(n=16). VORT (5 mg/ kg/ day) or saline was administered the male offsprings born from pregnant rat administered VPA/ saline, between postnatal 30-45 days. Open field, body splash, novel object recognition, social interaction and 3 chamber sociability tests were performed in groups on postnatal days 46-52. NLRP3 inflammasome components were investigated in prefrontal cortex. NLRP3, caspase-1 and ASC levels were measured by real time PCR. Results: ASD model showed increases in locomotor activity and repetitive behaviors like grooming despite decreases in sociabilitiy and social interactions. These findings as well as observational malformations supported the formation of an autism model. It was found that sniffing and following behaviors as social interaction markers were significantly increased and avoidance behaviour was reduced with VORT treatment. In molecular analyzes, NLRP3 inflammasome components, NLRP3, ASC and caspase-1 were increased in the ASD model. It was observed that VORT treatment statistically significantly reduced the increased NLRP-3, caspase-1 and ASC gene expressions in ASD. Conclusion: In the light of the findings of the study, it was thought that the NLRP-3 pathway may have an important role in the neurobiology of ASD. VORT, as a multimodal antidepressant, have some beneficial effects for the improvment of the behavioral and molecular parameters of ASD.
Objective: The aim of the present study was to investigate NOD like receptor mediated inflammasome activation in macrophage and microglia cells, which is one of the early step mechanisms in the formation of proinflammatory cytokines, in autism model and also investigate the possible effect of vortioxetine (VORT), which has a multimodal mechanism of action, in the treatment of autism in a valproic acid-induced experimental rat model of autism. Materials and Methods: Male Sprague-Dawley rats were divided into 3 groups: Control (n=12), ASD (n=16), ASD+VORT(n=16). VORT (5 mg/ kg/ day) or saline was administered the male offsprings born from pregnant rat administered VPA/ saline, between postnatal 30-45 days. Open field, body splash, novel object recognition, social interaction and 3 chamber sociability tests were performed in groups on postnatal days 46-52. NLRP3 inflammasome components were investigated in prefrontal cortex. NLRP3, caspase-1 and ASC levels were measured by real time PCR. Results: ASD model showed increases in locomotor activity and repetitive behaviors like grooming despite decreases in sociabilitiy and social interactions. These findings as well as observational malformations supported the formation of an autism model. It was found that sniffing and following behaviors as social interaction markers were significantly increased and avoidance behaviour was reduced with VORT treatment. In molecular analyzes, NLRP3 inflammasome components, NLRP3, ASC and caspase-1 were increased in the ASD model. It was observed that VORT treatment statistically significantly reduced the increased NLRP-3, caspase-1 and ASC gene expressions in ASD. Conclusion: In the light of the findings of the study, it was thought that the NLRP-3 pathway may have an important role in the neurobiology of ASD. VORT, as a multimodal antidepressant, have some beneficial effects for the improvment of the behavioral and molecular parameters of ASD.