Sıçanlarda deneysel sistemik inflamasyonda all-trans retinoik asit (ATRA)'in hipokampustaki etkilerinin EphA4 ve EphB2 ekspresyonu ile araştırılmas
Yükleniyor...
Dosyalar
Tarih
2024-02-12
Kurum Yazarları
Yavaş, Senem Esin
Süreli Yayın başlığı
Süreli Yayın ISSN
Cilt Başlığı
Yayınevi
Bursa Uludağ Üniversitesi
Özet
Sistemik inflamasyon, nöroinflamatuvar değişikliklere neden olarak birçok kronik psikiyatrik bozukluğun da gelişiminden ve ilerlemesinden sorumludur. Retinoik asit beyinde proliferasyon, diferansiyasyon, hücrelerin sağkalımı gibi biyolojik olayları düzenlerken, yüksek dozlarda nörotoksiktir. Eph reseptörleri hem işlevsel hem de yapısal nöronal plastisiteyi modüle ederek, hipokampal davranışları düzenlerler. Çalışmamızda nöroinflamasyon ve yüksek retinoik asit düzeylerinin hipokampusta EphA4 ve EphB2 reseptörlerinin ekspresyonları üzerine etkilerinin incelenmesi amaçlandı. Çalışmada Wistar albino dişi sıçanlar kullanıldı. Akut sistemik inflamasyon intraperitoneal 5mg/kg lipopolisakkarit (LPS) ile, kronik sistemik inflamasyon intraperitoneal 0,5mg/kg/7 gün LPS ile indüklendi. Kronik gruplarda immün yanıtın uzun süreli devamlılığı için 7 günlük aralarla 3 idame doz LPS uygulandı. Akut all trans retinoik asit (ATRA) uygulamaları 50 mg/kg dozda, kronik ATRA uygulamaları 28 gün 6 mg/kg dozda intragastrik gavaj ile gerçekleştirildi. Deneklerden elde edilen parafin beyin kesitlerine Nissl boyaması, TUNEL metodu, Iba-1, EphA4 ve EphB2 immünohistokimyası uygulandı. Akut ve kronik sistemik inflamasyonun hipokampusta mikroglial yanıtı tetiklediği, nöronal dejenerasyon ve apoptoza neden olduğu belirlendi. Sağlıklı koşullarda kronik ATRA uygulamasının düşük derecede aseptik nöroinflamatuvar yanıta neden olduğu, LPS ile indüklenen kronik mikroglial yanıtı kısmen baskıladığı saptandı. Akut ve kronik nöroinflamasyonda EphA4 ekspresyon düzeylerinin arttığı, EphB2 ekspresyonlarının azaldığı görüldü. Tekrarlanan retinoik asit uygulamaları özellikle EphB2 ekpsresyon düzeylerinde azalmaya neden oldu. Sonuç olarak, LPS ve yüksek retinoik asit kaynaklı nöronal fonksiyon kaybı Eph reseptörlerindeki azalış/artış ile ilk kez gösterildi. İnflamatuvar süreçler sonrası gelişen nöropatolojilere yönelik yeni terapötik stratejiler geliştirmede Eph reseptör ekspresyonları ile plastisitenin modülasyonu ve monitorizasyonunun yararlı olacağı düşünüldü.
Systemic inflammation causes neuroinflammatory changes and is responsible for the development and progression of many chronic psychiatric disorders. Retinoic acid regulates biological events in the brain, such as proliferation, differentiation, and cell survival, but is neurotoxic at high doses. Eph receptors regulate hippocampal behavior by modulating both functional and structural neuronal plasticity. In our study, we aimed to investigate the effects of neuroinflammation and high retinoic acid levels on the expression of EphA4 and EphB2 receptors in the hippocampus. Wistar albino female rats were used in the study. Acute systemic inflammation was induced with intraperitoneal 5mg/kg lipopolysaccharide (LPS), and chronic systemic inflammation was induced with intraperitoneal 0.5mg/kg/7 days LPS. For long-term maintenance of immune response in chronic groups, three maintenance doses of LPS were administered at 7-day intervals. Acute all-trans-retinoic acid (ATRA) administration was performed at a dose of 50 mg/kg, and chronic ATRA administration was performed by intragastric gavage at a dose of 6 mg/kg for 28 days. Nissl staining, TUNEL method, Iba-1, EphA4, and EphB2 immunohistochemistry were performed on the paraffin brain sections obtained from the subjects. Acute and chronic systemic inflammation triggered a microglial response in the hippocampus, causing neuronal degeneration and apoptosis. Chronic ATRA administration induced a low aseptic neuroinflammatory response in healthy conditions and partially suppressed the LPS-induced chronic microglial response. EphA4 expression levels increased, and EphB2 expression levels decreased in acute and chronic neuroinflammation. Repeated retinoic acid applications caused a decrease, especially in EphB2 expression levels. In conclusion, LPS and high retinoic acid-induced loss of neuronal function were demonstrated for the first time by the decrease/increase in Eph receptors. Modulation and monitoring of plasticity by Eph receptor expression may help develop new therapeutic strategies for neuropathologies that develop after inflammatory processes.
Systemic inflammation causes neuroinflammatory changes and is responsible for the development and progression of many chronic psychiatric disorders. Retinoic acid regulates biological events in the brain, such as proliferation, differentiation, and cell survival, but is neurotoxic at high doses. Eph receptors regulate hippocampal behavior by modulating both functional and structural neuronal plasticity. In our study, we aimed to investigate the effects of neuroinflammation and high retinoic acid levels on the expression of EphA4 and EphB2 receptors in the hippocampus. Wistar albino female rats were used in the study. Acute systemic inflammation was induced with intraperitoneal 5mg/kg lipopolysaccharide (LPS), and chronic systemic inflammation was induced with intraperitoneal 0.5mg/kg/7 days LPS. For long-term maintenance of immune response in chronic groups, three maintenance doses of LPS were administered at 7-day intervals. Acute all-trans-retinoic acid (ATRA) administration was performed at a dose of 50 mg/kg, and chronic ATRA administration was performed by intragastric gavage at a dose of 6 mg/kg for 28 days. Nissl staining, TUNEL method, Iba-1, EphA4, and EphB2 immunohistochemistry were performed on the paraffin brain sections obtained from the subjects. Acute and chronic systemic inflammation triggered a microglial response in the hippocampus, causing neuronal degeneration and apoptosis. Chronic ATRA administration induced a low aseptic neuroinflammatory response in healthy conditions and partially suppressed the LPS-induced chronic microglial response. EphA4 expression levels increased, and EphB2 expression levels decreased in acute and chronic neuroinflammation. Repeated retinoic acid applications caused a decrease, especially in EphB2 expression levels. In conclusion, LPS and high retinoic acid-induced loss of neuronal function were demonstrated for the first time by the decrease/increase in Eph receptors. Modulation and monitoring of plasticity by Eph receptor expression may help develop new therapeutic strategies for neuropathologies that develop after inflammatory processes.
Açıklama
Anahtar kelimeler
Nöroinflamasyon, Depresyon, All trans retinoik asit, EphA4, EphB2, Neuroinflammation, Depression, All-trans-retinoic acid
Alıntı
Yavaş, S. E. (2024). Sıçanlarda deneysel sistemik inflamasyonda all-trans retinoik asit (ATRA)'in hipokampustaki etkilerinin EphA4 ve EphB2 ekspresyonu ile araştırılması. Yayınlanmamış doktora tezi. Bursa Uludağ Üniversitesi Sağlık Bilimleri Enstitüsü.