TAK-242 ameliorates epileptic symptoms in mice by inhibiting the TLR4/NF-κB signaling pathway

Jibo Dong; Yong Liao; Bihua Wu

doi:10.21037/atm-22-2707

TAK-242 ameliorates epileptic symptoms in mice by inhibiting the TLR4/NF-κB signaling pathway

Ann Transl Med. 2022 Jul;10(14):795. doi: 10.21037/atm-22-2707.

Authors

Jibo Dong¹, Yong Liao¹, Bihua Wu¹

Affiliation

¹ Department of Geriatrics, Affiliated Hospital of North Sichuan Medical College, Institute of Neurological Diseases, North Sichuan Medical College, Nanchong, China.

Abstract

Background: There is evidence that immune inflammation plays an important role in the of epilepsy. The toll-like receptor 4 (TLR4)/nuclear factor kappa beta (NF-κB) signaling pathway is a target for the treatment of epilepsy. TAK-242 is a potent TLR4 inhibitor with neuroprotective effects. No study has examined whether TAK-242 has a protective effect on epilepsy.

Methods: Male C57BL/6 mice were randomly divided into the following 3 groups: (I) the control group; (II) the model [pentetrazol (PTZ)] group; and (III) the treatment group [PTZ + TAK-242 (3 mg/kg)], with 8 mice in each group. A mouse model of epilepsy was established via the intraperitoneal injection of PTZ (37 mg/kg). The behavioral changes of the mice were observed and scored using the Racine grading criteria. TAK-242 (3 mg/kg) was administered to establish the treatment model. The control group was intraperitoneally injected with normal saline at the same dose as the PTZ epileptogenic dose, and 3 mg/kg of normal saline was intragastrically administered. The messenger RNA (mRNA) and protein expressions of TLR4, NF-κB, and the NF-κB downstream gene tumor necrosis factor alpha (TNF-α) in the mouse brain tissues were detected by real-time quantitative polymerase chain reaction (RT-qPCR) and Western blot.

Results: Compared to the control group, the mice in the model group showed generalized tonic convulsion and involuntary falling after PTZ modeling. The results of the hematoxylin and eosin (H&E) staining showed that the treatment group had a higher number of normal neurons than the model group, and the neuronal cell morphology in the treatment group was closer to the control group. However, the occurrence of generalized tonic convulsion and involuntary falling in the mice in the treatment group was significantly improved. Comparing the Western Blot and RT-qPCR results, we detected higher TLR4, NF-KB, TNF-α protein and mRNA expression levels in the model group than the treatment group, and there was no significant difference between the control group and the treatment group.

Conclusions: TAK-242 treatment ameliorates epileptic symptoms in mice, and the mechanism by which this occurs may be related to the inhibition of the TLR4/NF-κB inflammatory pathway.

Keywords: TAK-242; epilepsy; inflammation; nuclear factor kappa beta (NF-κB); toll-like receptor 4 (TLR4).