Agomelatine Alleviates Methotrexate-Induced Lung Injury by Concurrently Inhibiting CD45/CD68-Positive Immune Cell Infiltration and Modulating the BAX/BCL2 Apoptosis Pathway
Journal of Applied Toxicology, cilt.46, sa.9, ss.3034-3042, 2026 (SCI-Expanded, Scopus)
- Yayın Türü: Makale / Tam Makale
- Cilt numarası: 46 Sayı: 9
- Basım Tarihi: 2026
- Doi Numarası: 10.1002/jat.70097
- Dergi Adı: Journal of Applied Toxicology
- Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, BIOSIS, Chemical Abstracts Core, Chimica, EMBASE, Environment Index, MEDLINE
- Sayfa Sayıları: ss.3034-3042
- Anahtar Kelimeler: agomelatine, apoptosis, inflammation, methotrexate, pulmonary toxicity
- Süleyman Demirel Üniversitesi Adresli: Evet
Özet
Methotrexate (MTX)-induced pulmonary toxicity severely limits its clinical use and effective preventive strategies are lacking. This study evaluated the protective effects of agomelatine (AGO), a melatonergic antidepressant, against MTX-induced lung injury, focusing on its dual-pathway action targeting both immune cell infiltration and apoptotic signaling. Thirty-two female Wistar rats were assigned to: Control, AGO (20 mg/kg/day, p.o., 7 days), MTX (single i.p. dose, 20 mg/kg), and MTX + AGO groups. Lung tissues were examined by histopathology, immunohistochemistry (CD45+, CD68+), and RT-qPCR (BAX, BCL2). MTX administration caused marked pulmonary damage (histopathological score: 2.75 ± 0.25, p < 0.001), significant infiltration of CD45+ leukocytes and CD68+ macrophages and an elevated BAX/BCL2 ratio (3.5 ± 0.4 vs. 1.0 ± 0.2 in Control, p < 0.001). AGO cotreatment significantly ameliorated these alterations via its dual activity, lowering the histopathological score (1.25 ± 0.25, p < 0.01), reducing CD45+/CD68 immunopositivity, and restoring the BAX/BCL2 ratio toward cell survival (1.4 ± 0.3, p < 0.01 vs. MTX). These findings provide integrated immunohistochemical and molecular evidence supporting the concurrent modulation of immune cell infiltration and apoptotic signaling by AGO in MTX-induced lung injury. Given its established clinical use and favorable safety profile, AGO may represent a potential adjunctive candidate to reduce the risk of MTX-related pulmonary complications, through concurrent targeting of immune and apoptotic pathways.