Fluoxetine protects against methamphetamine‑induced lung inflammation by suppressing oxidative stress through the
Yun Wang1, Yu-Han Gu1, Ming Liu2
1Department of Clinical Pharmacology, School of Pharmacy, China Medical University, Shenyang, Liaoning 110122, P.R. China.
Abstract:
Methamphetamine (MA) abuse is a major public health and safety concern throughout the world and a growing burden on healthcare costs. The purpose of the present study was to investigate the protective effect of fluoxetine against MA‑induced chronic pulmonary inflammation and to evaluate the potential role of nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated antioxidative stress. Wistar rats were divided into control, MA and two fluoxetine‑treated groups. Rats in the MA and the two fluoxetine‑treated groups were treated daily with intraperitoneal injection of 10 mg/kg MA twice daily. Rats in the two fluoxetine‑treated groups were injected intragastrically with fluoxetine (2 and 10 mg/kg) once daily, respectively. After 5 weeks, the rats were euthanized and hematoxylin and eosin staining, immunohistochemistry, western blot analysis and redox assay were performed. It was demonstrated that chronic exposure to MA can induce pulmonary inflammation in rats, with the symptoms of inflammatory cell infiltration, crowded lung parenchyma, thickened septum and a reduced number of alveolar sacs. Fluoxetine attenuated pulmonary inflammation and the expression of interleukin‑6 and tumor necrosis factor‑α in rat lungs. Fluoxetine inhibited MA‑induced increases in the expression levels of serotonin transporter (SERT) and p‑p38 mitogen‑activated protein kinase (MAPK), and reversed the MA‑induced decrease in nuclear Nrf2 and human heme oxygenase‑1 in lungs. Fluoxetine at 10 mg/kg significantly reversed the reduced glutathione (GSH) level, the ratio of GSH/oxidized glutathione, and the reactive oxygen species level in rat lungs from the MA group. These findings suggested that fluoxetine, a SERT inhibitor, has a protective effect against MA‑induced lung inflammation by suppressing oxidative stress through the SERT/p38 MAPK/Nrf2 pathway in rats.
Insights
Fluoxetine protects against methamphetamine-induced lung inflammation by reducing oxidative stress. This effect is mediated through the serotonin transporter (SERT), p38 MAPK, and Nrf2 pathway, offering a potential therapeutic strategy.
Area of Science:
- Pharmacology
- Toxicology
- Pulmonary Medicine
Background:
- Methamphetamine (MA) abuse is a significant global health issue with escalating healthcare costs.
- MA-induced lung inflammation represents a serious complication of substance abuse.
- Understanding the molecular mechanisms underlying MA-induced lung injury is crucial for developing effective treatments.
Purpose of the Study:
- To investigate the protective effects of fluoxetine against chronic pulmonary inflammation induced by methamphetamine (MA).
- To evaluate the role of the nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated antioxidative stress pathway in fluoxetine's protective action.
Main Methods:
- Wistar rats were exposed to MA, with some receiving fluoxetine treatment at different doses (2 and 10 mg/kg).
- Histopathological analysis (hematoxylin and eosin staining) and biochemical assays (immunohistochemistry, western blot, redox assays) were performed on lung tissues after 5 weeks.
- Key markers of inflammation (interleukin-6, tumor necrosis factor-α), oxidative stress (glutathione, reactive oxygen species), and the SERT/p38 MAPK/Nrf2 pathway were assessed.
Main Results:
- Chronic MA exposure led to significant pulmonary inflammation, characterized by inflammatory cell infiltration and alveolar damage.
- Fluoxetine treatment attenuated MA-induced lung inflammation and reduced levels of inflammatory cytokines (interleukin-6, tumor necrosis factor-α).
- Fluoxetine normalized oxidative stress markers, increased nuclear Nrf2 and heme oxygenase-1 expression, and modulated the SERT/p38 MAPK pathway.
Conclusions:
- Fluoxetine demonstrates a significant protective effect against MA-induced chronic pulmonary inflammation in rats.
- The protective mechanism involves the suppression of oxidative stress via the serotonin transporter (SERT)/p38 mitogen-activated protein kinase (MAPK)/Nrf2 pathway.
- These findings suggest fluoxetine as a potential therapeutic agent for mitigating MA-induced lung damage.
