Integration of metabolomics and proteomics analysis to explore the mechanism of neurotoxicity induced by receipt of isoniazid and rifampicin in mice

Isoniazid (INH) and rifampicin (RIF) are co-administered in tuberculosis treatment but can cause neurotoxicity, and the mechanism is not known. To explore this mechanism, we employed an integrated approach using metabolomics analysis (MA) and proteomics analysis (PA). Male mice were divided into three groups and administered vehicle (control group), or co-administered INH (120 mg/kg) and RIF (240 mg/kg), for 7 or 14 days. Mice brains were collected for mass spectrometry-based PA and MA plus lipidomics analysis. Measurement of brain levels of malondialdehyde and superoxide dismutase revealed time-dependent brain injury after exposure to INH+RIF for 7 and 14 days. Also, 422 proteins, 35 metabolites, and 21 lipids were dysregulated and identified. MA demonstrated purine metabolism, phenylalanine, tyrosine and tryptophan biosynthesis, biosynthesis of unsaturated fatty acids, phenylalanine metabolism, and arginine biosynthesis to be disturbed significantly. PA demonstrated pathways such as lipids, amino acids, and energy metabolism to be disrupted. Peroxisome proliferator-activated receptor (PPAR) pathways were changed in energy metabolism, which led to the neurotoxicity induced by INH+RIF. Immunohistochemical analyses of PPARs in mice brains verified that PPAR-alpha and-gamma expression was downregulated. PPAR-alpha and-gamma activation might be a key target for alleviating INH+RIF-induced neurotoxicity.

Automated summary

This study used metabolomics and proteomics analysis to investigate the neurotoxicity caused by the co-administration of isoniazid and rifampicin in tuberculosis treatment. The results showed dysregulation of several metabolic pathways and disruption in energy metabolism, particularly in the PPAR pathways. Activation of PPAR-alpha and PPAR-gamma may be a key target for alleviating the neurotoxicity induced by isoniazid and rifampicin.