Dual blockade of TLR-4 and mu-opioid receptor by very low-dose naltrexone prevents respiratory depression via modulating redox homeostasis and airway inflammation in chronic obstructive pulmonary disease

Abstract

Chronic Obstructive Pulmonary Disease (COPD), is characterized by poorly irreversible airflow obstruction and abnormal inflammatory response in lungs. It represents an innate and adaptive immune response to long term exposure to noxious particles and gases, particularly cigarette smoke (CS). The current pharmacological treatment of COPD is symptomatic and mainly based on the use of bronchodilators reducing the lung function progression. The present study explores a comprehensive exploration into the therapeutic potential of Naltrexone (NTX), an FDA-approved non-peptide opioid antagonist, in managing COPD pathogenesis. NTX exhibits distinct responses across varying dosages where it implies a dose pharmacological profile, with dose-dependent targets yielding diverse effects. The study aims to uncover its efficacy in experimental mice model of COPD by observing redox homeostasis, inflammatory responses, and apoptosis encompassing variable doses. Our findings reveal promising outcomes, particularly with VLDN (100 μg/kgbw and 50 μg/kgbw), where a significant reduction in ROS, NO and positive impacts on TOS and TAS, was observed which indicates its potential as an oxidative stress modulator. Furthermore, VLDN modulated the antioxidant enzymatic activity thereby reducing the apoptotic phenomenon via caspase-3. VLDN significantly reduced the inflammatory response by inhibiting the inflammatory mediators (histamine, LDH and CRP) and suppressing cytokine production (TNF-α, IFN-γ and IL-6). The study also delved into intricate pathway where mechanistically VLDN exerted anti-inflammatory effect by inhibiting the activation of NF-kB/MAPK signalling via TLR4. These findings collectively highlight VLDN multifaceted impact in mitigating oxidative stress, inflammation influencing apoptosis in COPD management, offering valuable insights for future therapeutic strategies. © 2025