ABSTRACT 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.
Usta et al. (Wed,) studied this question.