Investigation of the Effect of Phosphodiesterase Type 9 Inhibitor PF-04447943 on Spatial Memory in Mice Using the Radial Arm Maze Test

Abstract

Objective: Phosphodiesterase-9 (PDE9) inhibitors have attracted interest for improving cognitive function by increasing intracellular cGMP, an important mediator of learning and memory. The nitric oxide (NO)/cGMP pathway plays a key role in synaptic plasticity and hippocampal long-term potentiation (LTP), while inhibition of neuronal nitric oxide synthase (nNOS) impairs cognition. This study evaluated the effects of the PDE9 inhibitor PF-04447943 on spatial memory in mice and its interaction with nNOS inhibition induced by 7-nitroindazole (7-NI). Materials and Methods: Fifty male BALB/c mice (7–8 weeks old, 20–30 g) were randomly divided into five groups (n = 10 per group): control, PF-04447943 (1 and 3 mg/kg), 7-Nitroindazole (7-NI; 5 mg/kg), and a combination treatment group (5 mg/kg 7NI and 3 mg/kg PF-04447943). Drugs were administered intraperitoneally (i.p.). The radial arm maze test was used to measure spatial memory by recording arm reentries (errors) and task completion time (latency). Results: PF-04447943 (1 and 3 mg/kg, i.p.) significantly decreased the number of errors and latency at 3 mg/kg. The nNOS inhibitor 7-NI (5 mg/kg) significantly increased both values. The combined treatment group made notably fewer mistakes and had significantly reduced latency than the 7-NI group, yet their performance was not completely restored to control levels. Conclusions: Inhibiting PDE9 may enhance spatial memory and partially alleviate cognitive impairment associated with the NO pathway; however, intact NO signalling seems essential for complete cognitive recovery.

Keywords

• Mice
• PF-04447943
• phosphodiesterase type 9 inhibitor
• radial arm maze
• spatial memory

Supporting Institution

This study was supported by the Kocaeli University Scientific Research Projects Coordination Unit (Project No: 2024/5).

Ethical Statement

The study was approved by the Kocaeli University Animal Experiments Local Ethics Committee (KOU-HADYEK) (Date: 31.01.2024, decision No: KOU-HADYEK 1/5-2024). All experimental procedures were conducted in accordance with the Guide for the Care and Use of Laboratory Animals and complied with national and international guidelines for the ethical use of laboratory animals.

Fosfodiesteraz Tip 9 İnhibitörü PF-04447943’ün Farelerde Uzamsal Bellek Üzerindeki Etkisinin Işınsal Kollu Labirent Testi Kullanılarak Araştırılması

Abstract

Amaç: Fosfodiesteraz-9 (PDE9) inhibitörleri, öğrenme ve belleğin önemli bir düzenleyicisi olan hücre içi cGMP düzeylerini artırarak bilişsel işlevleri iyileştirme potansiyelleri nedeniyle ilgi görmektedir. Nitrik oksit (NO)/cGMP yolu, sinaptik plastisite ve hipokampal uzun süreli potansiyasyon (LTP) süreçlerinde önemli bir rol oynarken, nöronal nitrik oksit sentazın (nNOS) inhibisyonunun bilişsel işlevleri bozduğu gösterilmiştir. Bu çalışmada, PDE9 inhibitörü PF-04447943'ün farelerde uzamsal bellek üzerindeki etkileri ve 7-nitroindazol (7-NI) ile oluşturulan nNOS inhibisyonu ile etkileşimi araştırılmıştır. Materyal ve Metot: Elli adet erkek BALB/c fare (7–8 haftalık, 20–30 g) rastgele beş gruba ayrılmıştır (her grup n = 10): kontrol grubu, PF-04447943 (1 ve 3 mg/kg), 7-Nitroindazol (7-NI; 5 mg/kg) ve kombinasyon tedavisi grubu (5 mg/kg 7-NI ve 3 mg/kg PF-04447943). İlaçlar intraperitoneal (i.p.) yolla uygulanmıştır. Uzaysal bellek, radyal kollu labirent testi kullanılarak, kol tekrar girişleri (hata) ve görev tamamlama süresi (latans) kaydedilerek değerlendirilmiştir. Bulgular: PF-04447943 (1 ve 3 mg/kg, i.p.) uygulaması, özellikle 3 mg/kg dozunda hata sayısını ve latensi anlamlı şekilde azalttı. nNOS inhibitörü 7-NI (5 mg/kg) ise her iki parametreyi de anlamlı olarak artırdı. Kombinasyon tedavisi uygulanan grupta, 7-NI grubuna kıyasla hata sayısı ve latens belirgin şekilde daha düşük bulundu; ancak performans tamamen kontrol düzeyine dönmedi. Sonuç: PDE9’un inhibisyonu uzaysal hafızayı artırabilir ve NO yolakla ilişkili bilişsel bozulmayı kısmen azaltabilir; ancak tam bilişsel iyileşme için sağlam NO sinyalizasyonunun gerekli olduğu görülmektedir.

Keywords

• Fare
• fosfodiesteraz tip 9 inhibitörü
• PF-04447943
• radyal kollu labirent
• uzaysal bellek

Supporting Institution

Bu çalışma, Kocaeli Üniversitesi Bilimsel Araştırma Projeleri Koordinasyon Birimi tarafından desteklenmiştir (Proje No: 2024/5).

Ethical Statement

Çalışma, Kocaeli Üniversitesi Hayvan Deneyleri Yerel Etik Kurulu (KOU-HADYEK) tarafından onaylanmıştır (Tarih: 31.01.2024, Karar No: KOU-HADYEK 1/5-2024). Tüm deneysel prosedürler, Laboratuvar Hayvanlarının Bakımı ve Kullanımı Kılavuzu'na uygun olarak yürütülmüş ve laboratuvar hayvanlarının etik kullanımına ilişkin ulusal ve uluslararası kılavuzlara riayet edilmiştir.

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