Journal Article

Ambroxol attenuates detrimental effect of LPS-induced glia-mediated neuroinflammation, oxidative stress, and cognitive dysfunction in mice brain

Park, Tae Ju, Ullah, Safi, Kim, Myeong Ok, Ali, Waqar, Park, Jun Sung, Kang, Min Hwa, Atiq, Abubakar, Ali, Jawad, Choe, Kyonghwan

2025

Overview

Neurodegenerative diseases, such as Alzheimer’s disease (AD) and Parkinson’s disease (PD), are multifactorial. Among various factors, lipopolysaccharides (LPSs) from Gram-negative bacteria, such as E. coli , are considered potential causative agents. Despite significant advancements in the field, there is still no cure. In this study, we investigated the neuroprotective effects of ambroxol against LPS-induced neuroinflammation, oxidative stress, neurodegeneration, and the associated cognitive dysfunction. Intraperitoneal injection of LPS (250 µg/kg every alternative day for a total of seven doses over 14 days) triggered glial cell activation, neuroinflammation, oxidative stress, and neurodegeneration in the mouse brain. Ambroxol treatment (30 mg/kg/day for 14 days) significantly reduced neuroinflammation and oxidative stress compared to LPS-treated mice. Immunoblotting and immunofluorescence results showed that ambroxol reduced levels of Toll-like receptor 4 (TLR4) and oxidative stress kinase phospho-c-Jun N-terminal Kinase 1 (p-JNK). It also decreased astrocyte and microglia activation in the cortex and hippocampus of LPS+ Amb-treated mice, as indicated by the downregulation of GFAP and Iba-1. Furthermore, ambroxol-reversed LPS-induced neuroinflammation by inhibiting inflammatory mediators, such as IL-1β and TNF-α, through regulation of the transcription factor p-NFkB. Persistent neuroinflammation disrupted the natural antioxidant mechanisms, leading to oxidative stress. Ambroxol treatment upregulated antioxidant markers, including Nrf-2, HO-1, and SOD, which were downregulated in the LPS-treated group. Additionally, ambroxol-inhibited lipid peroxidation, maintaining malondialdehyde levels in the mouse brain. Ambroxol also improves synaptic integrity by upregulating synaptic biomarkers, including PSD-95 and SNAP-23. Overall, ambroxol demonstrated anti-inflammatory, antioxidant, and neuroprotective effects in LPS-treated mice, highlighting its potential benefits in neurological disorders.

• Publisher: Frontiers Media SA,Frontiers Media S.A
• Subject: Alzheimer's disease / Ambroxol - pharmacology / Ambroxol - therapeutic use / Animals / Antibodies / Antioxidants / Behavior / Brain - drug effects / Brain - metabolism / Brain - pathology / c-Jun protein / Cell activation / cognitive / Cognitive Dysfunction - chemically induced / Cognitive Dysfunction - drug therapy / Cognitive Dysfunction - metabolism / Cognitive impairment / Cytokines / Dementia / Disease / Disease Models, Animal / Down-regulation / GA-binding protein / Gene regulation / Glial cells / Glial fibrillary acidic protein / Gram-negative bacteria / Immunoblotting / Immunofluorescence / Immunology / Inflammation / Kinases / Lipid peroxidation / Lipids / lipopolysaccharide / Lipopolysaccharides / Lipopolysaccharides - toxicity / Male / Membranes / Memory / Mice / Microglia / Movement disorders / Neurodegeneration / Neurodegenerative diseases / Neuroglia - drug effects / Neuroglia - immunology / Neuroglia - metabolism / Neuroglia - pathology / neuroinflammation / Neuroinflammatory Diseases - chemically induced / Neuroinflammatory Diseases - drug therapy / Neuroinflammatory Diseases - metabolism / Neurological diseases / Neuronal-glial interactions / Neuroprotective Agents - pharmacology / Oxidative stress / Oxidative Stress - drug effects / Parkinson's disease / Proteins / TLR4 protein / Toll-Like Receptor 4 - metabolism / Toxicity / Transcription factors / Tumor necrosis factor-TNF / Tumor necrosis factor-α