Pharmacological Modulation of HMGB1/TLR-4/NF-κB Signaling Axis in 3-Nitropropionic Acid-Induced Neurotoxicity in Experimental Animals

Huntington’s disease (HD) is an inherited illness. 3-Nitropropionic acid (3-NPA) is a recognized neurotoxin that resembles symptoms similar to HD in laboratory animals and neuroinflammation via the activation of high mobility group box-1 (HMGB1)/Toll-like receptor-4 (TLR-4)/nuclear factor-κB (NF-κB) signaling cascade. Rifampicin (RIF) and probucol (PROB) have been shown to inhibit proposed pathway. The primary aim of this study is to investigate the impact of RIF and PROB on the HMGB1/TLR-4/NF-κB signaling cascade in 3-NPA-induced neurotoxicity. Molecular docking and molecular dynamics simulation (100 ns) were employed to assess target-binding affinity. In vivo investigation employed either sex Wistar rats. 3-NPA (10 mg/kg i.p.) was administered along with PROB (10, 20, and 40 mg/kg p.o.) and RIF (20, 40, and 80 mg/kg i.p.) for 21 days, and assessed in terms of percentage change in body weight, behavioral activities (narrow beam walk, open field test, and rotarod), quantitative real time polymerase chain reaction (qRT-PCR) (caspase-3, Bax, and Bcl-2), neuroinflammatory markers (tumor necrosis factor-alpha, interleukin-1β, and interleukin-6), Western blotting (HMGB1 and NF-κB), and immunohistochemistry (IHC) [pTLR-4]. In silico studies demonstrated that both drugs have good binding affinity and stability with different targets. In vivo investigation revealed that administration of both RIF and PROB significantly rescued 3-NPA-induced behavioral alterations, modulation of HMGB1/TLR-4/NF-κB signaling, apoptotic markers, and neuroinflammation. Both RIF and PROB showed protective effects by inhibiting HMGB1 through TLR-4, thereby further inhibiting HMGB1-mediated downstream signaling axis and apoptosis. Hence, our findings suggest that RIF and PROB may have ability to mitigate 3-NPA-induced neurotoxicity via HMGB1/TLR-4/NF-κB signaling pathway.