Atomoxetine attenuates methotrexate-induced lung injury in rats implicating TLR4/NF-κB and Bax/Bcl-2/caspase-3
Reham H Mohyeldin1, Ehab E Sharata1, Ayman M Ibrahim2
1Department of Pharmacology & Toxicology, Faculty of Pharmacy, Deraya University, 61111, Minia, Egypt.
Abstract:
Methotrexate (MTX) is frequently used to treat a variety of autoimmune diseases and malignancies, but its use is restricted due to a number of side effects, including lung damage. For the first time, this study attempts to assess the potential protective advantages of atomoxetine (ATOM) against MTX-induced lung damage in rats. MTX was used to cause lung damage. A total of 24 male Wistar albino rats were used in this study. Animals were randomly allocated to four experimental groups of six rats each: (Ⅰ) Control group, (Ⅱ) ATOM group, (Ⅲ) MTX group, and (Ⅳ) MTX+ATOM group. Malondialdehyde (MDA), glutathione (GSH), and superoxide dismutase (SOD) levels in the lungs were measured. ELISA was used to measure the levels of lung IL-10, interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), Bcl-2-associated X protein (Bax), and B-cell lymphoma 2 (Bcl-2). NF-κB p65 and caspase-3 were evaluated using immunohistochemistry. Toll-like receptor 4 (TLR4) and myeloid differentiation primary response 88 (MYD88) protein expression levels were assessed using the Western blot technique. A histopathological study of lung tissues was performed. Lung MDA, IL-6, TNF-α, and Bax levels were significantly increased by MTX, while GSH, SOD, IL-10, and Bcl-2 levels were significantly decreased. Additionally, this led to the overexpression of the proteins TLR4 and MYD88. Additionally, the MTX group had higher immunopositivity for both NF-κB p65 and caspase-3. All of the aforementioned biochemical and histological abnormalities were greatly improved with ATOM. ATOM significantly improved MTX-induced pulmonary injury by suppressing TLR4/MYD88/NF-κB p65 and caspase-3-mediated apoptotic signaling pathways.
Insights
Atomoxetine (ATOM) protects against methotrexate (MTX)-induced lung damage in rats by reducing inflammation and apoptosis. This study reveals ATOM
Area of Science:
- Pharmacology and Toxicology
- Pulmonary Medicine
- Immunology
Background:
- Methotrexate (MTX) is a vital drug for autoimmune diseases and cancers.
- MTX use is limited by severe side effects, notably lung damage.
- Novel therapeutic strategies are needed to mitigate MTX-induced pulmonary toxicity.
Purpose of the Study:
- To investigate the protective effects of atomoxetine (ATOM) against MTX-induced lung injury in a rat model.
- To elucidate the underlying molecular mechanisms of ATOM's protective action.
Main Methods:
- MTX was administered to induce lung damage in Wistar albino rats.
- ATOM was administered to assess its protective potential.
- Biochemical markers (MDA, GSH, SOD), cytokine levels (IL-10, IL-6, TNF-α), apoptosis markers (Bax, Bcl-2), and signaling proteins (TLR4, MYD88, NF-κB p65, caspase-3) were analyzed.
- Histopathological examination of lung tissues was performed.
Main Results:
- MTX significantly increased lung oxidative stress (MDA) and inflammation (IL-6, TNF-α), and induced apoptosis (Bax).
- MTX decreased antioxidant levels (GSH, SOD) and anti-inflammatory markers (IL-10), and upregulated pro-apoptotic (Bax) and cell death signaling proteins (TLR4, MYD88, NF-κB p65, caspase-3).
- ATOM administration significantly ameliorated these MTX-induced biochemical, molecular, and histological changes, improving lung injury.
Conclusions:
- ATOM demonstrates significant protective effects against MTX-induced pulmonary toxicity in rats.
- ATOM exerts its protective action by suppressing the TLR4/MYD88/NF-κB p65 and caspase-3-mediated apoptotic pathways.
- ATOM represents a potential therapeutic agent for mitigating MTX-associated lung damage.
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