Rifampicin ameliorates lipopolysaccharide-induced cognitive and motor impairments via inhibition of the TLR4/MyD88/NF-κB signaling pathway in mice

ABSTRACT

Objectives

Aberrant microglial responses promote neuroinflammation in neurodegenerative diseases. However, rifampicin’s effect on cognitive and motor sequelae of inflammation remains unknown. Therefore, we investigated whether rifampicin exerts neuroprotection against lipopolysaccharide (LPS)-induced cognitive and motor impairments.

Methods

A mouse model of LPS-induced cognitive and motor impairment was established. Adult C57BL/6 mice were injected intraperitoneally with 25 mg/kg rifampicin 30 min before intraperitoneal microinjection of LPS (750 μg/kg) daily until study end. Treatments and behavioral experiments were performed once daily for 7 days. Behavioral tests and pathological/biochemical assays were performed to evaluate LPS-induced damage to the hippocampus and substantia nigra (SN).

Results

Rifampicin attenuated LPS-induced cognitive and motor impairments, based on performance in the behavioral tests. Rifampicin suppressed the release of pro-inflammatory mediators, including tumor necrosis factor-α, interleukin-1β, and prostaglandin E₂ in the serum and nitric oxide (NO) in brain tissue, and cyclooxygenase-2 and inducible nitric oxide synthase levels. Immunofluorescence revealed that rifampicin inhibited LPS-induced microglial activation in the hippocampus and SN, thus protecting the neurons. Rifampicin inhibited the activation of the toll-like receptor 4 (TLR4)/myeloid differentiation primary response 88 (MyD88)/nuclear factor kappa B (NF-κB) signaling pathway. Rifampicin downregulated TLR4 and MyD88 protein levels and inhibited NF-κB inhibitor alpha and NF-κB inhibitor kinase beta phosphorylation, thus reducing p65 nuclear transfer by inhibiting NF-κB signaling activation in LPS-treated mice.

Conclusion

Rifampicin protects against LPS-induced neuroinflammation and attenuates cognitive and motor impairments by inhibiting the TLR4/MyD88/NF-κB signaling pathway. Our findings might aid the development of novel therapies to treat progressive neurodegenerative diseases.

KEYWORDS:

• Rifampicin
• neuroinflammation
• lipopolysaccharide
• neurodegenerative diseases
• toll-like receptor 4
• cognitive impairment
• motor impairment

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This study was supported by grants from the Natural Science Foundation of China [Nos. 81200930 and 82071568], the Training program for outstanding young teachers in higher education institutions of Guangdong Province [Nos. YQ2015024], the Fundamental Research Funds for the Central Universities [Nos. 21617482] and the flagship specialty construction project of the First Affiliated Hospital of Jinan University- Department of Neurology [Nos.11001]

Notes on contributors

Lihong Zhu

Lihong Zhu, She is Department of Pathophysiology, School of Medicine, Jinan University, Guangzhou.She is mainly engaged in the study of brain function and diseases, such as Alzheimer's disease, Parkinson's disease and other neurodegenerative diseases. Now she has accumulated some experimental basis of brain science research, and further introduced the method of integrated traditional Chinese and Western medicine into the research of brain function and diseases.In recent years, she has undertaken more than 20 kinds of research projects. She has presided over more than 2.4 million yuan of vertical research projects, including general projects of National Natural Science Foundation of China, youth fund of National Natural Science Foundation of China, general projects of Provincial Natural Science Foundation of China, doctoral start projects of Provincial Natural Science Foundation of China, etc.