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Background Recent data suggested that inflammatory responses are involved in the acute or chronic phase of drug-resistant epilepsy. The aim of this study was to examine the signal pathway of Toll-like receptors (TLR) 4 mediated drug resistance in refractory epileptic rats. Methods Lithium chloride and pilocarpine were used to establish a drug-resistant epilepsy rat model. Recombinant adenovirus was used to construct a TLR4 deficient drug-resistant epileptic rat model. The expression of TLR4, p-gp, interleukin (IL)-1β, tumor necrosis factor (TNF)-α, and nuclear factor kappa B (NF-κB) were determined by Western blot and Immunohistochemical analysis. Results P-gp, TLR4, NF-κB, IL-1β, TNF-α were significantly higher in the drug-resistant epileptic rats than in the epileptic rats (all P < 0.05). Contrary, this process was reversed in TLR4-deficient epileptic rats. The expression levels of P-gp, TLR4, NF-κB, IL-1β, and TNF-α expression were significantly inhibited in TLR4-deficient rats, suggesting that TLR4, as an important upstream factor, might significantly affect the expression levels of P-gp, NF-κB, IL-1β, and TNF-α (all P < 0.05). Conclusions Our study found the expression levels of TLR4, NF-κB, IL-1β, TNF-α which were related with inflammatory signal pathway changed in drug resistant epileptic rats. Our results suggest that TLR4, as an upstream regulator, could activate the downstream NF-κB, regulate inflammatory factors IL-1β, TNF-α, and other cytokines, and affect the expression level of P-gp in drug resistant epileptic rats. We speculate TLR4 related inflammatory signal pathway might take part in the emergence of epilepsy resistance, which is important in drug resistance. Copyright © 2021. Published by Elsevier B.V.


Xinghua Tang, Xiaoxia Chen, Xinjuan Li, Huan Cheng, Jing Gan, Zhenguo Liu. The TLR4 mediated inflammatory signal pathway might be involved in drug resistance in drug-resistant epileptic rats. Journal of neuroimmunology. 2022 Apr 15;365:577802

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PMID: 35217365

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